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Sunday, Mary Elizabeth Anne

Overview:


Oxygen (O2) is essential for life, but excessive oxygen causes tissue injury, scarring, aging, and death. We are studying mechanisms of injury mediated by O2-sensing pulmonary neuroendocrine cells, especially gastrin-releasing peptide (GRP). GRP secretion is induced by O2-related (oxidant) injury, leading to acute and chronic lung injury and pulmonary fibrosis (PF). Our key model is PF due to ionizing radiation to the thorax. This is clinically relevant to PF triggered by many environmental exposures or autoimmune diseases, as well as idiopathic pulmonary fibrosis (IPF). There is no cure for PF. We seek to reverse fibrotic responses in lung.


Positions:

Professor of Pathology

Pathology
School of Medicine

Professor in Cell Biology

Cell Biology
School of Medicine

Professor of Medicine

Medicine, Pulmonary, Allergy, and Critical Care Medicine
School of Medicine

Professor in Pediatrics

Pediatrics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1976

B.S. — University of Toronto (Canada)

M.D. 1982

M.D. — Harvard University

Ph.D. 1982

Ph.D. — Harvard University

Intern, Internal Medicine

Johns Hopkins University

Resident, Anatomic Pathology, Pathology

Madigan Army Medical Center

Research Fellow, Medicine

Massachusetts General Hospital

Research & Clinical Fellow, Pathology

Madigan Army Medical Center

Research Fellow, Pathology

Children's Hospital Boston

Grants:

Medical Scientist Training Program

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1997
End Date
June 30, 2022

Interdisciplinary Training Program in Lung Disease

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 2009
End Date
March 31, 2020

Gastrin-Releasing Peptide and Bronchopulmonary Dysplasia

Administered By
Pediatrics, Neonatology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 2011
End Date
July 31, 2018

Oxygen, Gastrin-Releasing Peptide, and Radiation-Induced Pulmonary Fibrosis

Administered By
Pathology
AwardedBy
Columbia University
Role
Principal Investigator
Start Date
August 01, 2016
End Date
July 31, 2017

The Duke Multidisciplinary Training Program in Pediatric Lung Disease

Administered By
Pediatrics, Pulmonary and Sleep Medicine
AwardedBy
National Institutes of Health
Role
Faculty Member
Start Date
September 01, 2010
End Date
August 31, 2016

Oxygen, Gastrin-Releasing Peptide, and Radiation-Induced Pulmonary Fibrosis

Administered By
Pathology
AwardedBy
Columbia University
Role
Principal Investigator
Start Date
April 01, 2016
End Date
July 31, 2016

Multidisciplinary Neonatal Training Grant

Administered By
Pediatrics, Neonatology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
April 01, 2010
End Date
June 30, 2015

Molecular Mechanisms of Pulmonary Cell Differentiation

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1990
End Date
June 30, 2008

Neuropeptides, Immunity, and Lung Injury

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 20, 2004
End Date
August 31, 2007
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Publications:

Augmented Responses to Ozone in Obese Mice Require IL-17A and Gastrin-releasing Peptide.

Ozone and obesity both increase IL-17A in the lungs. In mice, obesity augments the airway hyperresponsiveness and neutrophil recruitment induced by acute ozone exposure. Therefore, we examined the role of IL-17A in obesity-related increases in the response to ozone observed in obese mice. Lean wildtype and obese db/db mice were pretreated with IL-17A blocking or isotype antibodies, exposed to air or ozone (2 ppm for 3 h), and evaluated 24 h later. Microarray analysis of lung tissue gene expression was used to examine the mechanistic basis for effects of anti-IL-17A. Compared to lean mice, ozone-exposed obese mice had greater levels of BAL IL-17A and greater numbers of pulmonary IL-17A+ cells. Ozone-induced increases in BAL IL-23 and CCL20, cytokines important for IL-17A+ cell recruitment and activation, were also greater in obese mice. Anti-IL-17A treatment reduced ozone-induced airway hyperresponsiveness towards levels observed in lean mice. Anti-IL-17A treatment also reduced BAL neutrophils in both lean and obese mice, possibly because of reductions in CXCL1. Microarray analysis identified gastrin releasing peptide (GRP) receptor (Grpr) among those genes that were both elevated in the lungs of obese mice after ozone and reduced following anti-IL-17A treatment. Furthermore, ozone exposure increased BAL GRP to a greater extent in obese than lean mice, and GRP neutralizing antibody treatment reduced obesity-related increases in ozone-induced airway hyperresponsiveness and neutrophil recruitment. Our data indicate that IL-17A contributes to augmented responses to ozone in db/db mice. Furthermore, IL-17A appears to act at least in part by inducing expression of Grpr.

Authors
Mathews, JA; Krishnamoorthy, N; Kasahara, DI; Hutchinson, J; Cho, Y; Brand, JD; Williams, AS; Wurmbrand, AP; Ribeiro, L; Cuttitta, F; Sunday, ME; Levy, BD; Shore, SA
MLA Citation
Mathews, JA, Krishnamoorthy, N, Kasahara, DI, Hutchinson, J, Cho, Y, Brand, JD, Williams, AS, Wurmbrand, AP, Ribeiro, L, Cuttitta, F, Sunday, ME, Levy, BD, and Shore, SA. "Augmented Responses to Ozone in Obese Mice Require IL-17A and Gastrin-releasing Peptide." American journal of respiratory cell and molecular biology (September 28, 2017).
PMID
28957638
Source
epmc
Published In
American journal of respiratory cell and molecular biology
Publish Date
2017
DOI
10.1165/rcmb.2017-0071oc

Obese asthmatic patients have decreased surfactant protein A levels: Mechanisms and implications.

Eosinophils are prominent in some patients with asthma and are increased in the submucosa in a subgroup of obese patients with asthma (OAs). Surfactant protein A (SP-A) modulates host responses to infectious and environmental insults.We sought to determine whether SP-A levels are altered in OAs compared with a control group and to determine the implications of these alterations in SP-A levels in asthmatic patients.Bronchoalveolar lavage fluid from 23 lean, 12 overweight, and 20 obese subjects were examined for SP-A. Mouse tracheal epithelial cells grown at an air-liquid interface were used for mechanistic studies. SP-A-/- mice were challenged in allergen models, and exogenous SP-A therapy was given after the last challenge. Eosinophils were visualized and quantitated in lung parenchyma by means of immunostaining.Significantly less SP-A (P = .002) was detected in samples from OAs compared with those from control subjects. A univariable regression model found SP-A levels were significantly negatively correlated with body mass index (r = -0.33, P = .014), whereas multivariable modeling demonstrated that the correlation depended both on asthma status (P = .017) and the interaction of asthma and body mass index (P = .008). Addition of exogenous TNF-α to mouse tracheal epithelial cells was sufficient to attenuate SP-A and eotaxin secretion. Allergen-challenged SP-A-/- mice that received SP-A therapy had significantly less tissue eosinophilia compared with mice receiving vehicle.SP-A functions as an important mediator in resolving tissue and lavage fluid eosinophilia in allergic mouse models. Decreased levels of SP-A in OAs, which could be due to increased local TNF-α levels, might lead to impaired eosinophil resolution and could contribute to the eosinophilic asthma phenotype.

Authors
Lugogo, N; Francisco, D; Addison, KJ; Manne, A; Pederson, W; Ingram, JL; Green, CL; Suratt, BT; Lee, JJ; Sunday, ME; Kraft, M; Ledford, JG
MLA Citation
Lugogo, N, Francisco, D, Addison, KJ, Manne, A, Pederson, W, Ingram, JL, Green, CL, Suratt, BT, Lee, JJ, Sunday, ME, Kraft, M, and Ledford, JG. "Obese asthmatic patients have decreased surfactant protein A levels: Mechanisms and implications." The Journal of allergy and clinical immunology (June 14, 2017).
PMID
28624607
Source
epmc
Published In
Journal of Allergy and Clinical Immunology
Publish Date
2017
DOI
10.1016/j.jaci.2017.05.028

Bronchopulmonary dysplasia impairs L-type amino acid transporter-1 expression in human and baboon lung.

Bronchopulmonary dysplasia (BPD) is an inflammatory lung disorder common in premature infants who undergo mechanical ventilation with supplemental oxygen. Inhaled nitric oxide (iNO) has been used to prevent experimental and clinical BPD. Earlier studies showed that NO effects in alveolar epithelial cells (AEC) are mediated by S-nitrosothiol uptake via L-type amino acid transporter-1 (LAT1). Because LAT1 expression could influence the efficacy of iNO therapy, we sought to determine whether pulmonary LAT1 expression is altered in preterm baboons with experimental BPD and in human newborns susceptible to developing BPD. Using fixed lung obtained from 125 d to 140 d gestation baboon models of BPD, LAT1 immunostaining was measured in control and BPD animals. In adult controls and in 140 d gestational controls (GC), LAT1 was expressed in both type I and type II AECs. In 140 d BPD lungs, LAT1 expression density in alveolar tissue was decreased. In 125 d GC baboons, LAT1 immunostaining was largely confined to cuboidal AECs, whereas animals given 14 d of mechanical ventilation exhibited diminished alveolar septal LAT1 Labeling. The pattern in adult human donor lung was comparable to that observed in adult baboons. LAT1 was expressed in lungs obtained from some but not all very premature newborns at autopsy. In human and baboon lung, adult and newborn, pulmonary vascular cells expressed LAT1. In summary, LAT1 is expressed in AECs and pulmonary vascular cells in baboons and humans. Experimental BPD in premature baboons decreases pulmonary LAT1 expression and alters its spatial localization. Heterogeneity of functional LAT1 could affect S-nitrosothiol importation, which could impair iNO therapy. Pediatr Pulmonol. 2016;51:1048-1056. © 2016 Wiley Periodicals, Inc.

Authors
Bao, EL; Chystsiakova, A; Brahmajothi, MV; Sunday, ME; Pavlisko, EN; Wempe, MF; Auten, RL
MLA Citation
Bao, EL, Chystsiakova, A, Brahmajothi, MV, Sunday, ME, Pavlisko, EN, Wempe, MF, and Auten, RL. "Bronchopulmonary dysplasia impairs L-type amino acid transporter-1 expression in human and baboon lung." Pediatric pulmonology 51.10 (October 2016): 1048-1056.
PMID
26918397
Source
epmc
Published In
Pediatric Pulmonology
Volume
51
Issue
10
Publish Date
2016
Start Page
1048
End Page
1056
DOI
10.1002/ppul.23402

Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13-Suppressed Elastin in Airway Fibroblasts in Asthma.

Elastin synthesis and degradation in the airway and lung parenchyma contribute to airway mechanics, including airway patency and elastic recoil. IL-13 mediates many features of asthma pathobiology, including airway remodeling, but the effects of IL-13 on elastin architecture in the airway wall are not known. We hypothesized that IL-13 modulates elastin expression in airway fibroblasts from subjects with allergic asthma. Twenty-five subjects with mild asthma (FEV1, 89 ± 3% predicted) and 30 normal control subjects (FEV1, 102 ± 2% predicted) underwent bronchoscopy with endobronchial biopsy. Elastic fibers were visualized in airway biopsy specimens using Weigert's resorcin-fuchsin elastic stain. Airway fibroblasts were exposed to IL-13; a pan-matrix metalloproteinase (MMP) inhibitor (GM6001); specific inhibitors to MMP-1, -2, -3, and -8; and combinations of IL-13 with MMP inhibitors in separate conditions in serum-free media for 48 hours. Elastin (ELN) expression as well as MMP secretion and activity were quantified. Results of this study show that elastic fiber staining of airway biopsy tissue was significantly associated with methacholine PC20 (i.e., the provocative concentration of methacholine resulting in a 20% fall in FEV1 levels) in patients with asthma. IL-13 significantly suppressed ELN expression in asthmatic airway fibroblasts as compared with normal control fibroblasts. The effect of IL-13 on ELN expression was significantly correlated with postbronchodilator FEV1/FVC in patients with asthma. MMP inhibition significantly stimulated ELN expression in patients with asthma as compared with normal control subjects. Specific inhibition of MMP-1 and MMP-2, but not MMP-3 or MMP-8, reversed the IL-13-induced suppression of ELN expression. In asthma, MMP-1 and MMP-2 mediate IL-13-induced suppression of ELN expression in airway fibroblasts.

Authors
Ingram, JL; Slade, D; Church, TD; Francisco, D; Heck, K; Sigmon, RW; Ghio, M; Murillo, A; Firszt, R; Lugogo, NL; Que, L; Sunday, ME; Kraft, M
MLA Citation
Ingram, JL, Slade, D, Church, TD, Francisco, D, Heck, K, Sigmon, RW, Ghio, M, Murillo, A, Firszt, R, Lugogo, NL, Que, L, Sunday, ME, and Kraft, M. "Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13-Suppressed Elastin in Airway Fibroblasts in Asthma." American journal of respiratory cell and molecular biology 54.1 (January 2016): 41-50.
PMID
26074138
Source
epmc
Published In
American journal of respiratory cell and molecular biology
Volume
54
Issue
1
Publish Date
2016
Start Page
41
End Page
50
DOI
10.1165/rcmb.2014-0290oc

Correction: SP-A Preserves Airway Homeostasis during Mycoplasma pneumoniae Infection in Mice.

Authors
Ledford, JG; Goto, H; Potts, EN; Degan, S; Wei Chu, H; Voelker, DR; Sunday, ME; Cianciolo, GJ; Foster, WM; Kraft, M; Wright, JR
MLA Citation
Ledford, JG, Goto, H, Potts, EN, Degan, S, Wei Chu, H, Voelker, DR, Sunday, ME, Cianciolo, GJ, Foster, WM, Kraft, M, and Wright, JR. "Correction: SP-A Preserves Airway Homeostasis during Mycoplasma pneumoniae Infection in Mice." Journal of immunology (Baltimore, Md. : 1950) 195.6 (September 2015): 2917-2918.
PMID
26342104
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
195
Issue
6
Publish Date
2015
Start Page
2917
End Page
2918
DOI
10.4049/jimmunol.1501597

Correction for Zhou et al., NPAS3 is a trachealess homolog critical for lung development and homeostasis: Fig. 4.

MLA Citation
"Correction for Zhou et al., NPAS3 is a trachealess homolog critical for lung development and homeostasis: Fig. 4." Proceedings of the National Academy of Sciences 112.29 (July 21, 2015): E3970-E3970.
Source
crossref
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
29
Publish Date
2015
Start Page
E3970
End Page
E3970
DOI
10.1073/pnas.1507989112

Retraction for Zhou et al., Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

MLA Citation
"Retraction for Zhou et al., Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma." Proceedings of the National Academy of Sciences 112.14 (April 7, 2015): E1813-E1813.
Source
crossref
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
14
Publish Date
2015
Start Page
E1813
End Page
E1813
DOI
10.1073/pnas.1504672112

Radiation-induced lung injury is mitigated by blockade of gastrin-releasing peptide.

Gastrin-releasing peptide (GRP), secreted by pulmonary neuroendocrine cells, mediates oxidant-induced lung injury in animal models. Considering that GRP blockade abrogates pulmonary inflammation and fibrosis in hyperoxic baboons, we hypothesized that ionizing radiation triggers GRP secretion, contributing to inflammatory and fibrotic phases of radiation-induced lung injury (RiLI). Using C57BL/6 mouse model of pulmonary fibrosis developing ≥20 weeks after high-dose thoracic radiation (15 Gy), we injected small molecule 77427 i.p. approximately 1 hour after radiation then twice weekly for up to 20 weeks. Sham controls were anesthetized and placed in the irradiator without radiation. Lung paraffin sections were immunostained and quantitative image analyses performed. Mice exposed to radiation plus PBS had increased interstitial CD68(+) macrophages 4 weeks after radiation and pulmonary neuroendocrine cells hyperplasia 6 weeks after radiation. Ten weeks later radiation plus PBS controls had significantly increased pSmad2/3(+) nuclei/cm(2). GRP blockade with 77427 treatment diminished CD68(+), GRP(+), and pSmad2/3(+) cells. Finally, interstitial fibrosis was evident 20 weeks after radiation by immunostaining for α-smooth muscle actin and collagen deposition. Treatment with 77427 abrogated interstitial α-smooth muscle actin and collagen. Sham mice given 77427 did not differ significantly from PBS controls. Our data are the first to show that GRP blockade decreases inflammatory and fibrotic responses to radiation in mice. GRP blockade is a novel radiation fibrosis mitigating agent that could be clinically useful in humans exposed to radiation therapeutically or unintentionally.

Authors
Zhou, S; Nissao, E; Jackson, IL; Leong, W; Dancy, L; Cuttitta, F; Vujaskovic, Z; Sunday, ME
MLA Citation
Zhou, S, Nissao, E, Jackson, IL, Leong, W, Dancy, L, Cuttitta, F, Vujaskovic, Z, and Sunday, ME. "Radiation-induced lung injury is mitigated by blockade of gastrin-releasing peptide." Am J Pathol 182.4 (April 2013): 1248-1254.
PMID
23395092
Source
pubmed
Published In
The American journal of pathology
Volume
182
Issue
4
Publish Date
2013
Start Page
1248
End Page
1254
DOI
10.1016/j.ajpath.2012.12.024

Chronic treatment in vivo with β-adrenoceptor agonists induces dysfunction of airway β(2) -adrenoceptors and exacerbates lung inflammation in mice.

BACKGROUND AND PURPOSE: Inhalation of a β-adrenoceptor agonist (β-agonist) is first-line asthma therapy, used for both prophylaxis against, and acute relief of, bronchoconstriction. However, repeated clinical use of β-agonists leads to impaired bronchoprotection and, in some cases, adverse patient outcomes. Mechanisms underlying this β(2) -adrenoceptor dysfunction are not well understood, due largely to the lack of a comprehensive animal model and the uncertainty as to whether or not bronchorelaxation in mice is mediated by β(2) -adrenoceptors. Thus, we aimed to develop a mouse model that demonstrated functional β-agonist-induced β(2) -adrenoceptor desensitization in the context of allergic inflammatory airway disease. EXPERIMENTAL APPROACH: We combined chronic allergen exposure with repeated β-agonist inhalation in allergen-treated BALB/C mice and examined the contribution of β(2) -adrenoceptors to albuterol-induced bronchoprotection using FVB/NJ mice with genetic deletion of β(2) -adrenoceptors (KO). Associated inflammatory changes - cytokines (ELISA), cells in bronchoalevolar lavage and airway remodelling (histology) and β(2) -adrenoceptor density (radioligand binding) - were also measured. KEY RESULTS β(2) -Adrenoceptors mediated albuterol-induced bronchoprotection in mice. Chronic treatment with albuterol induced loss of bronchoprotection, associated with exacerbation of the inflammatory components of the asthma phenotype. CONCLUSIONS AND IMPLICATIONS: This animal model reproduced salient features of human asthma and linked loss of bronchoprotection with airway pathobiology. Accordingly, the model offers an advanced tool for understanding the mechanisms of the effects of chronic β- agonist treatment on β-adrenoceptor function in asthma. Such information may guide the clinical use of β-agonists and provide insight into development of novel β-adrenoceptor ligands for the treatment of asthma.

Authors
Lin, R; Degan, S; Theriot, BS; Fischer, BM; Strachan, RT; Liang, J; Pierce, RA; Sunday, ME; Noble, PW; Kraft, M; Brody, AR; Walker, JKL
MLA Citation
Lin, R, Degan, S, Theriot, BS, Fischer, BM, Strachan, RT, Liang, J, Pierce, RA, Sunday, ME, Noble, PW, Kraft, M, Brody, AR, and Walker, JKL. "Chronic treatment in vivo with β-adrenoceptor agonists induces dysfunction of airway β(2) -adrenoceptors and exacerbates lung inflammation in mice." Br J Pharmacol 165.7 (April 2012): 2365-2377.
PMID
22013997
Source
pubmed
Published In
British Journal of Pharmacology
Volume
165
Issue
7
Publish Date
2012
Start Page
2365
End Page
2377
DOI
10.1111/j.1476-5381.2011.01725.x

Airway fibroblasts in asthma manifest an invasive phenotype.

RATIONALE: Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor (TGF)-β1 and matrix metalloproteinases (MMPs). IL-13 is a key T(H)2 cytokine that directs many features of airway remodeling through TGF-β1 and MMPs. OBJECTIVES: We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-β1 and MMPs in asthma compared with normal controls. METHODS: Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV(1): 90 ± 3.6% pred) and 17 normal control subjects (FEV(1): 102 ± 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-β1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels. MEASUREMENTS AND MAIN RESULTS: IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, compared with normal control subjects. Inhibitors of both TGF-β1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal control subjects. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, compared with normal control subjects. In airway fibroblasts, baseline IL-13Rα2 was reduced in asthma compared with normal control subjects. CONCLUSIONS: IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-β1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.

Authors
Ingram, JL; Huggins, MJ; Church, TD; Li, Y; Francisco, DC; Degan, S; Firszt, R; Beaver, DM; Lugogo, NL; Wang, Y; Sunday, ME; Noble, PW; Kraft, M
MLA Citation
Ingram, JL, Huggins, MJ, Church, TD, Li, Y, Francisco, DC, Degan, S, Firszt, R, Beaver, DM, Lugogo, NL, Wang, Y, Sunday, ME, Noble, PW, and Kraft, M. "Airway fibroblasts in asthma manifest an invasive phenotype." Am J Respir Crit Care Med 183.12 (June 15, 2011): 1625-1632.
PMID
21471104
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
183
Issue
12
Publish Date
2011
Start Page
1625
End Page
1632
DOI
10.1164/rccm.201009-1452OC

NPAS3 is a trachealess homolog critical for lung development and homeostasis.

Trachealess (Trh) is a PAS domain transcription factor regulating Drosophila tracheogenesis. No other Trh homolog has been associated with a respiratory phenotype. Seeking homolog(s) regulating lung development, we screened murine genomic DNA using trh oligonucleotides, identifying only Npas3. Npas3 mRNA peaks in lung from E10.5 to E13.5, verified by sequencing, with immunostaining in airway epithelial cells. Npas3-null mice have reduced lung branching morphogenesis but are viable prenatally. Npas3-null newborns die in respiratory distress, with diminished alveolarization, decreased Shh, Fgf9, Fgf10, and Bmp4 mRNAs, and increased Spry2, consistent with reduced FGF signaling. Exogenous FGF10 rescues branching morphogenesis in Npas3-null lungs. In promoter reporter assays, NPAS3 directly upregulates Shh and represses Spry2. Npas3(+/-) mice have a milder lung phenotype, surviving postnatally, but develop emphysema and airways hyperreactivity. Therefore, absence of a developmentally expressed transcription factor can alter downstream gene expression and multiple signaling pathways in organogenesis. NPAS3 haploinsufficiency may also lead to emphysema and asthma.

Authors
Zhou, S; Degan, S; Potts, EN; Foster, WM; Sunday, ME
MLA Citation
Zhou, S, Degan, S, Potts, EN, Foster, WM, and Sunday, ME. "NPAS3 is a trachealess homolog critical for lung development and homeostasis." Proc Natl Acad Sci U S A 106.28 (July 14, 2009): 11691-11696.
PMID
19581591
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
28
Publish Date
2009
Start Page
11691
End Page
11696
DOI
10.1073/pnas.0902426106

SP-A preserves airway homeostasis during Mycoplasma pneumoniae infection in mice.

The lung is constantly challenged during normal breathing by a myriad of environmental irritants and infectious insults. Pulmonary host defense mechanisms maintain homeostasis between inhibition/clearance of pathogens and regulation of inflammatory responses that could injure the airway epithelium. One component of this defense mechanism, surfactant protein-A (SP-A), exerts multifunctional roles in mediating host responses to inflammatory and infectious agents. SP-A has a bacteriostatic effect on Mycoplasma pneumoniae (Mp), which occurs by binding surface disaturated phosphatidylglycerols. SP-A can also bind the Mp membrane protein, MPN372. In this study, we investigated the role of SP-A during acute phase pulmonary infection with Mp using mice deficient in SP-A. Biologic responses, inflammation, and cellular infiltration, were much greater in Mp infected SP-A(-/-) mice than wild-type mice. Likewise, physiologic responses (airway hyperresponsiveness and lung compliance) to Mp infection were more severely affected in SP-A(-/-) mice. Both Mp-induced biologic and physiologic changes were attenuated by pharmacologic inhibition of TNF-alpha. Our findings demonstrate that SP-A is vital to preserving lung homeostasis and host defense to this clinically relevant strain of Mp by curtailing inflammatory cell recruitment and limiting an overzealous TNF-alpha response.

Authors
Ledford, JG; Goto, H; Potts, EN; Degan, S; Chu, HW; Voelker, DR; Sunday, ME; Cianciolo, GJ; Foster, WM; Kraft, M; Wright, JR
MLA Citation
Ledford, JG, Goto, H, Potts, EN, Degan, S, Chu, HW, Voelker, DR, Sunday, ME, Cianciolo, GJ, Foster, WM, Kraft, M, and Wright, JR. "SP-A preserves airway homeostasis during Mycoplasma pneumoniae infection in mice." J Immunol 182.12 (June 15, 2009): 7818-7827.
PMID
19494306
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
182
Issue
12
Publish Date
2009
Start Page
7818
End Page
7827
DOI
10.4049/jimmunol.0900452

Counteracting signaling activities in lipid rafts associated with the invasion of lung epithelial cells by Pseudomonas aeruginosa.

Pseudomonas aeruginosa has the capacity to invade lung epithelial cells by co-opting the intrinsic endocytic properties of lipid rafts, which are rich in cholesterol, sphingolipids, and proteins, such as caveolin-1 and -2. We compared intratracheal Pseudomonas infection in wild type and caveolin-deficient mice to investigate the role of caveolin proteins in the pathogenesis of Pseudomonas pneumonia. Unlike wild type mice, which succumb to pneumonia, caveolin-deficient mice are resistant to Pseudomonas. We observed that Pseudomonas invasion of lung epithelial cells is dependent on caveolin-2 but not caveolin-1. Phosphorylation of caveolin-2 by Src family kinases is an essential event for Pseudomonas invasion. Our studies also reveal the existence of a distinct signaling mechanism in lung epithelial cells mediated by COOH-terminal Src kinase (Csk) that negatively regulates Pseudomonas invasion. Csk migrates to lipid raft domains, where it decreases phosphorylation of caveolin-2 by inactivating c-Src. Whereas Pseudomonas co-opts the endocytic properties of caveolin-2 for invasion, there also exists in these cells an intrinsic Csk-dependent cellular defense mechanism aimed at impairing this activity. The success of Pseudomonas in co-opting lipid raft-mediated endocytosis to invade lung epithelial cells may depend on the relative strengths of these counteracting signaling activities.

Authors
Zaas, DW; Swan, ZD; Brown, BJ; Li, G; Randell, SH; Degan, S; Sunday, ME; Wright, JR; Abraham, SN
MLA Citation
Zaas, DW, Swan, ZD, Brown, BJ, Li, G, Randell, SH, Degan, S, Sunday, ME, Wright, JR, and Abraham, SN. "Counteracting signaling activities in lipid rafts associated with the invasion of lung epithelial cells by Pseudomonas aeruginosa." J Biol Chem 284.15 (April 10, 2009): 9955-9964.
PMID
19211560
Source
pubmed
Published In
The Journal of biological chemistry
Volume
284
Issue
15
Publish Date
2009
Start Page
9955
End Page
9964
DOI
10.1074/jbc.M808629200

Gastrin-releasing peptide, immune responses, and lung disease.

Gastrin-releasing peptide (GRP) is produced by pulmonary neuroendocrine cells (PNECs), with highest numbers of GRP-positive cells present in fetal lung. Normally GRP-positive PNECs are relatively infrequent after birth, but PNEC hyperplasia is frequently associated with chronic lung diseases. To address the hypothesis that GRP mediates chronic lung injury, we present the cumulative evidence implicating GRP in bronchopulmonary dysplasia (BPD), the chronic lung disease of premature infants who survive acute respiratory distress syndrome. The availability of well-characterized animal models of BPD was a critical tool for demonstrating that GRP plays a direct role in the early pathogenesis of this disease. Potential mechanisms by which GRP contributes to injury are analyzed, with the main focus on innate immunity. Autoreactive T cells may contribute to lung injury late in the course of disease. A working model is proposed with GRP triggering multiple cell types in both the innate and adaptive immune systems, promoting cascades culminating in chronic lung disease. These observations represent a paradigm shift in the understanding of the early pathogenesis of BPD, and suggest that GRP blockade could be a novel treatment to prevent this lung disease in premature infants.

Authors
Degan, S; Lopez, GY; Kevill, K; Sunday, ME
MLA Citation
Degan, S, Lopez, GY, Kevill, K, and Sunday, ME. "Gastrin-releasing peptide, immune responses, and lung disease." Ann N Y Acad Sci 1144 (November 2008): 136-147.
PMID
19076373
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
1144
Publish Date
2008
Start Page
136
End Page
147
DOI
10.1196/annals.1418.022

Airway epithelial cells: current concepts and challenges.

The adult human bronchial tree is covered with a continuous layer of epithelial cells that play a critical role in maintaining the conduit for air, and which are central to the defenses of the lung against inhaled environmental concomitants. The epithelial sheet functions as an interdependent unit with the other lung components. Importantly, the structure and/or function of airway epithelium is deranged in major lung disorders, including chronic obstructive pulmonary disease, asthma, and bronchogenic carcinoma. Investigations regarding the airway epithelium have led to many advances over the past few decades, but new developments in genetics and stem cell/progenitor cell biology have opened the door to understanding how the airway epithelium is developed and maintained, and how it responds to environmental stress. This article provides an overview of the current state of knowledge regarding airway epithelial stem/progenitor cells, gene expression, cell-cell interactions, and less frequent cell types, and discusses the challenges for future areas of investigation regarding the airway epithelium in health and disease.

Authors
Crystal, RG; Randell, SH; Engelhardt, JF; Voynow, J; Sunday, ME
MLA Citation
Crystal, RG, Randell, SH, Engelhardt, JF, Voynow, J, and Sunday, ME. "Airway epithelial cells: current concepts and challenges." Proc Am Thorac Soc 5.7 (September 15, 2008): 772-777. (Review)
PMID
18757316
Source
pubmed
Published In
Proceedings of the American Thoracic Society
Volume
5
Issue
7
Publish Date
2008
Start Page
772
End Page
777
DOI
10.1513/pats.200805-041HR

Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function.

The purpose of the workshop was to identify still obscure or novel cellular components of the lung, to determine cell function in lung development and in health that impacts on disease, and to decide promising avenues for future research to extract and phenotype these cells. Since robust technologies are now available to identify, sort, purify, culture, and phenotype cells, progress is now within sight to unravel the origins and functional capabilities of lung cells in developmental stages and in disease. The Workshop's agenda was to first discuss the lung's embryologic development, including progenitor and stem cells, and then assess the functional and structural cells in three main compartments of the lung: (1) airway cells in bronchial and bronchiolar epithelium and bronchial glands (basal, secretory, ciliated, Clara, and neuroendocrine cells); (2) alveolar unit cells (Type 1 cells, Type 2 cells, and fibroblasts in the interstitium); and (3) pulmonary vascular cells (endothelial cells from different vascular structures, smooth muscle cells, and adventitial fibroblasts). The main recommendations were to: (1) characterize with better cell markers, both surface and nonsurface, the various cells within the lung, including progenitor cells and stem cells; (2) obtain more knowledge about gene expression in specific cell types in health and disease, which will provide insights into biological and pathologic processes; (3) develop more methodologies for cell culture, isolation, sorting, co-culture, and immortalization; and (4) promote tissue banks to facilitate the procurement of tissue from normal and from diseased lung for analysis at all levels.

Authors
Franks, TJ; Colby, TV; Travis, WD; Tuder, RM; Reynolds, HY; Brody, AR; Cardoso, WV; Crystal, RG; Drake, CJ; Engelhardt, J; Frid, M; Herzog, E; Mason, R; Phan, SH; Randell, SH; Rose, MC; Stevens, T; Serge, J; Sunday, ME; Voynow, JA; Weinstein, BM; Whitsett, J; Williams, MC
MLA Citation
Franks, TJ, Colby, TV, Travis, WD, Tuder, RM, Reynolds, HY, Brody, AR, Cardoso, WV, Crystal, RG, Drake, CJ, Engelhardt, J, Frid, M, Herzog, E, Mason, R, Phan, SH, Randell, SH, Rose, MC, Stevens, T, Serge, J, Sunday, ME, Voynow, JA, Weinstein, BM, Whitsett, J, and Williams, MC. "Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function." Proc Am Thorac Soc 5.7 (September 15, 2008): 763-766.
PMID
18757314
Source
pubmed
Published In
Proceedings of the American Thoracic Society
Volume
5
Issue
7
Publish Date
2008
Start Page
763
End Page
766
DOI
10.1513/pats.200803-025HR

Centrifugal migration of mesenchymal cells in embryonic lung.

Murine lung development begins at embryonic day (E) 9.5. Normal lung structure and function depend on the patterns of localization of differentiated cells. Pulmonary mesenchymal cell lineages have been relatively unexplored. Importantly, there has been no prior evidence of clonality of any lung cells. Herein we use a definitive genetic approach to demonstrate a common origin for proximal and distal pulmonary mesenchymal cells. A retroviral library with 3,400 unique inserts was microinjected into the airway lumen of E11.5 lung buds. After 7-11 days of culture, buds were stained for placental alkaline phosphatase (PLAP). Most PLAP+ cells are peribronchial smooth muscle cells, initially localized laterally near the hilum, then migrating down airways to the subpleural region. Laser-capture microdissection and polymerase chain reaction confirm the clonal identities of PLAP+ cells proximally and distally. Our observation of this fundamental process during lung development opens new avenues for investigation of maladaptive mesenchymal responses in lung diseases.

Authors
Shan, L; Subramaniam, M; Emanuel, RL; Degan, S; Johnston, P; Tefft, D; Warburton, D; Sunday, ME
MLA Citation
Shan, L, Subramaniam, M, Emanuel, RL, Degan, S, Johnston, P, Tefft, D, Warburton, D, and Sunday, ME. "Centrifugal migration of mesenchymal cells in embryonic lung." Dev Dyn 237.3 (March 2008): 750-757.
PMID
18297731
Source
pubmed
Published In
Developmental Dynamics
Volume
237
Issue
3
Publish Date
2008
Start Page
750
End Page
757
DOI
10.1002/dvdy.21462

Ontogeny of the eotaxins in human lung.

The ontogeny of the C-C chemokines eotaxin-1, eotaxin-2, and eotaxin-3 has not been fully elucidated in human lung. We explored a possible role for eotaxin in developing lung by determining the ontogeny of eotaxin-1 (CCL11), eotaxin-2 (CCL24), eotaxin-3 (CCL26), and the eotaxin receptor, CCR3. We tested discarded surgical samples of developing human lung tissue using quantitative RT-PCR (QRT-PCR) and immunostaining for expression of CCL11, CCL24, CCL26, and CCR3. We assessed possible functionality of the eotaxin-CCR3 system by treating lung explant cultures with exogenous CCL11 and analyzing the cultures for evidence of changes in proliferation and activation of ERK1/2, a signaling pathway associated with CCR3. QRT-PCR analyses of 22 developing lung tissue samples with gestational ages 10-23 wk demonstrated that eotaxin-1 mRNA is most abundant in developing lung, whereas mRNAs for eotaxin-2 and eotaxin-3 are minimally detectable. CCL11 mRNA levels correlated with gestational age (P < 0.05), and immunoreactivity was localized predominantly to airway epithelial cells. QRT-PCR analysis detected CCR3 expression in 16 of 19 developing lung samples. Supporting functional capacity in the immature lung, CCL11 treatment of lung explant cultures resulted in significantly increased (P < 0.05) cell proliferation and activation of the ERK signaling pathway, which is downstream from CCR3, suggesting that proliferation was due to activation of CCR3 receptors by CCL11. We conclude that developing lung expresses the eotaxins and functional CCR3 receptor. CCL11 may promote airway epithelial proliferation in the developing lung.

Authors
Haley, KJ; Sunday, ME; Porrata, Y; Kelley, C; Twomey, A; Shahsafaei, A; Galper, B; Sonna, LA; Lilly, CM
MLA Citation
Haley, KJ, Sunday, ME, Porrata, Y, Kelley, C, Twomey, A, Shahsafaei, A, Galper, B, Sonna, LA, and Lilly, CM. "Ontogeny of the eotaxins in human lung." Am J Physiol Lung Cell Mol Physiol 294.2 (February 2008): L214-L224.
PMID
18055844
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
294
Issue
2
Publish Date
2008
Start Page
L214
End Page
L224
DOI
10.1152/ajplung.00086.2007

Bombesin-like peptides modulate alveolarization and angiogenesis in bronchopulmonary dysplasia.

RATIONALE: The incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, is paradoxically rising despite medical advances. We demonstrated elevated bombesin-like peptide levels in infants that later developed BPD. In the 140-day hyperoxic baboon model of BPD, anti-bombesin antibody 2A11 abrogated lung injury. OBJECTIVES: To test the hypothesis that bombesin-like peptides mediate BPD in extremely premature baboons (born at Gestational Day 125 and given oxygen pro re nata [PRN], called the 125-day PRN model), similar to "modern-day BPD." METHODS: The 125-day animals were treated with 2A11 on Postnatal Day 1 (P1), P3, and P6. On P14 and P21, lungs were inflation-fixed for histopathologic analyses of alveolarization. Regulation of angiogenesis by bombesin was evaluated using cultured pulmonary microvascular endothelial cells. MEASUREMENTS AND MAIN RESULTS: In 125-day PRN animals, urine bombesin-like peptide levels at P2-3 are directly correlated with impaired lung function at P14. Gastrin-releasing peptide (the major pulmonary bombesin-like peptide) mRNA was elevated eightfold at P1 and remained high thereafter. At P14, 2A11 reduced alveolar wall thickness and increased the percentage of secondary septa containing endothelial cells. At P21, 2A11-treated 125-day PRN animals had improved alveolarization according to mean linear intercepts and number of branch points per millimeter squared. Bombesin promoted tubulogenesis of cultured pulmonary microvascular endothelial cells, but cocultured fetal lung mesenchymal cells abrogated this effect. CONCLUSIONS: Early bombesin-like peptide overproduction in 125-day PRN animals predicted alveolarization defects weeks later. Bombesin-like peptide blockade improved septation, with the greatest effects at P21. This could have implications for preventing BPD in premature infants.

Authors
Subramaniam, M; Bausch, C; Twomey, A; Andreeva, S; Yoder, BA; Chang, L; Crapo, JD; Pierce, RA; Cuttitta, F; Sunday, ME
MLA Citation
Subramaniam, M, Bausch, C, Twomey, A, Andreeva, S, Yoder, BA, Chang, L, Crapo, JD, Pierce, RA, Cuttitta, F, and Sunday, ME. "Bombesin-like peptides modulate alveolarization and angiogenesis in bronchopulmonary dysplasia." Am J Respir Crit Care Med 176.9 (November 1, 2007): 902-912.
PMID
17585105
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
176
Issue
9
Publish Date
2007
Start Page
902
End Page
912
DOI
10.1164/rccm.200611-1734OC

NPAS1 regulates branching morphogenesis in embryonic lung.

Drosophila trachealess (Trl), master regulator of tracheogenesis, has no known functional mammalian homolog. We hypothesized that genes similar to trachealess regulate lung development. Quantitative (Q)RT-PCR and immunostaining were used to determine spatial and temporal patterns of npas1 gene expression in developing murine lung. Immunostaining for alpha-smooth muscle actin demonstrated myofibroblasts, and protein gene product (PGP)9.5 identified neuroendocrine cells. Branching morphogenesis of embryonic lung buds was analyzed in the presence of antisense or sense oligodeoxynucleotides (ODN). Microarray analyses were performed to screen for changes in gene expression in antisense-treated lungs. QRT-PCR was used to validate the altered expression of key genes identified on the microarrays. We demonstrate that npas1 is expressed in murine embryonic lung. npas1 mRNA peaks early at Embryonic Day (E)10.5-E11.5, then drops to low levels. Sequencing verifies the identity of npas1 transcripts in embryonic lung. NPAS1 immunostaining occurs in nuclei of parabronchial mesenchymal cells, especially at the tracheal bifurcation. Arnt, the murine homolog of Tango (the heterodimerization partner for Trl) is also expressed in developing lung but at constant levels. npas1- or arnt-antisense ODN inhibit lung branching morphogenesis, with altered myofibroblast development and increased pulmonary neuroendocrine cells. On microarrays, we identify > 50 known genes down-regulated by npas1-antisense, including multiple genes regulating cell migration and cell differentiation. QRT-PCR confirms significantly decreased expression of the neurogenic genes RBP-Jk and Tle, and three genes involved in muscle development: beta-ig-h3, claudin-11, and myocardin. Npas1 can regulate myofibroblast distribution, branching morphogenesis, and neuroendocrine cell differentiation in murine embryonic lung.

Authors
Levesque, BM; Zhou, S; Shan, L; Johnston, P; Kong, Y; Degan, S; Sunday, ME
MLA Citation
Levesque, BM, Zhou, S, Shan, L, Johnston, P, Kong, Y, Degan, S, and Sunday, ME. "NPAS1 regulates branching morphogenesis in embryonic lung." Am J Respir Cell Mol Biol 36.4 (April 2007): 427-434.
PMID
17110583
Source
pubmed
Published In
American journal of respiratory cell and molecular biology
Volume
36
Issue
4
Publish Date
2007
Start Page
427
End Page
434
DOI
10.1165/rcmb.2006-0314OC

Notch-1 regulates pulmonary neuroendocrine cell differentiation in cell lines and in transgenic mice.

The notch gene family encodes transmembrane receptors that regulate cell differentiation by interacting with surface ligands on adjacent cells. Previously, we demonstrated that tumor necrosis factor-alpha (TNF) induces neuroendocrine (NE) cell differentiation in H82, but not H526, undifferentiated small cell lung carcinoma lines. We now test the hypothesis that TNF mediates NE cell differentiation in part by altering Notch gene expression. First, using RT-PCR, we determined that TNF treatment of H82, but not H526, transiently decreases notch-1 mRNA in parallel with induction of gene expression for the NE-specific marker DOPA decarboxylase (DDC). Second, we treated H82 and H526 with notch-1 antisense vs. sense oligodeoxynucleotides. Using quantitative RT-PCR and Western analyses we demonstrate that DDC mRNA and protein are increased in H82 by notch-1 antisense, whereas notch-1 mRNA and activated Notch-1 protein are decreased. mRNA for Hes1, a transcription factor downstream from activated Notch, is also decreased by Notch-1 antisense in H82 but not H526. After 7 days of Notch-1 antisense treatment, neural cell adhesion molecule (NCAM) immunoreactivity is induced in H82 but not H526. Third, we generated transgenic mice bearing notch-1 driven by the neural/NE-specific calcitonin promoter, which express activated Notch-1 in developing lung epithelium. Newborn NotchCal mouse lungs have high levels of hes1 mRNA, reflecting increased activated Notch, compared with wild-type. NotchCal lungs have decreased CGRP-positive NE cells, decreased protein gene product 9.5 (PGP9.5)-positive NE cells, and decreased gastrin-releasing peptide (GRP), CGRP, and DDC mRNA levels compared with normal littermates. Cumulatively, these observations provide further support for a role for Notch-1 signaling in regulating pulmonary NE cell differentiation.

Authors
Shan, L; Aster, JC; Sklar, J; Sunday, ME
MLA Citation
Shan, L, Aster, JC, Sklar, J, and Sunday, ME. "Notch-1 regulates pulmonary neuroendocrine cell differentiation in cell lines and in transgenic mice." Am J Physiol Lung Cell Mol Physiol 292.2 (February 2007): L500-L509.
PMID
17028268
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
292
Issue
2
Publish Date
2007
Start Page
L500
End Page
L509
DOI
10.1152/ajplung.00052.2006

Accelerated thymic maturation and autoreactive T cells in bronchopulmonary dysplasia.

RATIONALE: Bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns triggered by oxygen and barotrauma, is characterized by arrested alveolarization. Increased levels of bombesin-like peptides shortly after birth mediate lung injury: anti-bombesin antibody 2A11 protects against BPD in two baboon models. The role of adaptive immunity in BPD has not been explored previously. OBJECTIVES: Our goal was to test the hypothesis that thymic architecture and/or T-cell function is altered with BPD, leading to autoimmunity and immunodeficiency. METHODS: Thymic structure was analyzed by histopathology of thymic architecture and immunohistochemistry for thymic maturation markers (terminal deoxynucleotidyl transferase, proliferating cell nuclear antigen, CD4, and CD8). Thymic cortical epithelial cells (nurse cells) were studied using HLA-DR and protein gene product 9.5 as markers. Functional analysis was performed with "mixed lymphocyte reaction" of thymocyte or splenocyte responder cells with autologous lung cells as the stimulators. MEASUREMENTS AND MAIN RESULTS: 2A11 treatment attenuates thymic cortical involution in BPD animals, sustaining terminal deoxynucleotidyl transferase-positive prothymocytes and thymocyte proliferation. BPD animals have increased CD4(+) cells in thymic cortex and lung interstitium, which are reduced by 2A11. Conversely, cortical protein gene product 9.5/HLA-DR-positive thymic nurse cells are depleted in BPD animals, but are preserved by 2A11-treatment. Whereas fetal thymocytes and splenocytes respond to phythemagglutinin/ionomycin and to a lesser extent, to autologous lung, BPD thymocytes and splenocytes are phythemagglutinin/ionomycin-unresponsive, and yet react strongly to autologous lung. The 2A11 normalizes these responses. CONCLUSIONS: These observations suggest that bombesin-like peptides mediate premature thymic maturation and thymic nurse-cell depletion, leading to autoreactive T cells that could contribute to lung injury.

Authors
Rosen, D; Lee, J-H; Cuttitta, F; Rafiqi, F; Degan, S; Sunday, ME
MLA Citation
Rosen, D, Lee, J-H, Cuttitta, F, Rafiqi, F, Degan, S, and Sunday, ME. "Accelerated thymic maturation and autoreactive T cells in bronchopulmonary dysplasia." Am J Respir Crit Care Med 174.1 (July 1, 2006): 75-83.
PMID
16574933
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
174
Issue
1
Publish Date
2006
Start Page
75
End Page
83
DOI
10.1164/rccm.200511-1784OC

Bombesin inhibits alveolarization and promotes pulmonary fibrosis in newborn mice.

RATIONALE: Bombesin-like peptides promote fetal lung development. Normally, levels of mammalian bombesin (gastrin-releasing peptide [GRP]) drop postnatally, but these levels are elevated in newborns that develop bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by arrested alveolarization. In premature baboons with BPD, antibombesin antibodies reduce lung injury and promote alveolarization. OBJECTIVES: The present study tests whether exogenous bombesin or GRP given perinatally alters alveolar development in newborn mice. METHODS: Mice were given peptides intraperitoneally twice daily on Postnatal Days 1-3. On Day 14 lungs were inflation-fixed for histopathologic analyses of alveolarization. MEASUREMENTS AND MAIN RESULTS: Bombesin had multiple effects on Day 14 lung, when alveolarization was about half complete. First, bombesin induced alveolar myofibroblast proliferation and increased alveolar wall thickness compared with saline-treated control animals. Second, bombesin diminished alveolarization in C57BL/6 (but not Swiss-Webster) mice. We used receptor-null mice to explore which receptors might mediate these effects. Compared with wild-type littermates, bombesin-treated GRP receptor (GRPR)-null mice had increased interstitial fibrosis but reduced defects in alveolarization. Neuromedin B (NMB) receptor-null and bombesin receptor subtype 3-null mice had the same responses as their wild-type littermates. GRP had the same effects as bombesin, whereas neither NMB nor a synthetic bombesin receptor type 3 ligand had any effect. All effects of GRP were abrogated in GRPR-null mice. CONCLUSIONS: Bombesin/GRP can induce features of BPD, including interstitial fibrosis and diminished alveolarization. GRPR appears to mediate all effects of GRP, but only part of the bombesin effect on alveolarization, suggesting that novel receptors may mediate some effects of bombesin in newborn lung.

Authors
Ashour, K; Shan, L; Lee, JH; Schlicher, W; Wada, K; Wada, E; Sunday, ME
MLA Citation
Ashour, K, Shan, L, Lee, JH, Schlicher, W, Wada, K, Wada, E, and Sunday, ME. "Bombesin inhibits alveolarization and promotes pulmonary fibrosis in newborn mice." Am J Respir Crit Care Med 173.12 (June 15, 2006): 1377-1385.
PMID
16603607
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
173
Issue
12
Publish Date
2006
Start Page
1377
End Page
1385
DOI
10.1164/rccm.200507-1014OC

Histochemical analyses of altered fetal lung development following single vs multiple courses of antenatal steroids.

A single course of antenatal steroids is widely used during preterm labor to promote fetal lung maturation. However, little is known regarding efficacy and safety of multiple courses of antenatal steroids. In animal models and clinical trials, treatment with glucocorticoids can inhibit growth. The present study of single- vs multiple-course steroids in pregnant ewes analyzes the effects of steroids vs placebo on fetal lung histopathology. Single-course groups received dexamethasone (Dex) 6 mg or normal saline every 12 hr for 48 hr at 104-106 days of gestation (term = 150 days). Multiple-course groups received the first course at 76-78 days; this was repeated weekly for 5 weeks. At 108 days, lungs were analyzed using immunohistochemistry for alpha-smooth muscle actin, a myofibroblast marker and proliferating cell nuclear antigen. Cell injury/death was evaluated using TdT-mediated dUTP digoxigenin nick end labeling (TUNEL) analysis. Although fetal growth was restricted by either single or multiple courses of Dex, alveolar development was accelerated as measured by mean linear intercepts. Alveolar walls were thinner, developing septa were longer, and septal myofibroblasts were increased for both Dex groups compared with controls. Cell proliferation increased following multiple steroid courses, especially in the distal parenchyma, with a corresponding decrease in apoptosis. These observations suggest that Dex promotes alveolarization, whether given in single or multiple courses.

Authors
Pua, ZJ; Stonestreet, BS; Cullen, A; Shahsafaei, A; Sadowska, GB; Sunday, ME
MLA Citation
Pua, ZJ, Stonestreet, BS, Cullen, A, Shahsafaei, A, Sadowska, GB, and Sunday, ME. "Histochemical analyses of altered fetal lung development following single vs multiple courses of antenatal steroids." J Histochem Cytochem 53.12 (December 2005): 1469-1479.
PMID
15956023
Source
pubmed
Published In
Journal of Histochemistry and Cytochemistry
Volume
53
Issue
12
Publish Date
2005
Start Page
1469
End Page
1479
DOI
10.1369/jhc.5A6721.2005

Developmental regulation of p66Shc is altered by bronchopulmonary dysplasia in baboons and humans.

RATIONALE: The p66(Shc) adapter protein antagonizes mitogen-activated protein, or MAP, kinase, mediates oxidative stress, and is developmentally regulated in fetal mouse lungs. OBJECTIVES: To determine if p66(Shc) is similarly regulated in primates and in bronchopulmonary dysplasia (BPD), which results from oxidative injury to immature lungs. METHODS: Normal and injured lungs from humans and baboons were evaluated by Western analysis and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: In baboons, p66(Shc) decreased 80% between 125 and 175 days' gestation (p = 0.025), then doubled after term delivery at 185 days (p = 0.0013). In the hyperoxic 140-day fetal baboon BPD model, p66(Shc) expression persisted, and its localization shifted from the epithelium of gestational controls to the mesenchyme of diseased lungs, coincident with expression of proliferating cell nuclear antigen and cleaved poly(adenyl ribose) polymerase, a marker of apoptosis. Treatment with the antibombesin antibody 2A11 attenuated BPD, reduced cell proliferation, increased p66(Shc) expression 10.5-fold, and preserved epithelial p66(Shc) localization. p66(Shc) also decreased during normal human lung development, falling 87% between 18 and 24 weeks' gestation (p = 0.02). p66(Shc) was expressed throughout 18-week human lungs, became restricted to scattered epithelial cells by 24 weeks, and localized to isolated mesenchymal cells after term delivery. In contrast, p66(Shc) remained prominent in the epithelium of lungs with acute injury or mild BPD, and in the mesenchyme of lungs with severe disease. p66(Shc) localized to tissues expressing proliferating cell nuclear antigen and cleaved poly(adenyl ribose) polymerase. CONCLUSIONS: p66(Shc) expression, cell proliferation, and apoptosis are concomitantly altered during lung development and in BPD.

Authors
Lee, MK; Pryhuber, GS; Schwarz, MA; Smith, SM; Pavlova, Z; Sunday, ME
MLA Citation
Lee, MK, Pryhuber, GS, Schwarz, MA, Smith, SM, Pavlova, Z, and Sunday, ME. "Developmental regulation of p66Shc is altered by bronchopulmonary dysplasia in baboons and humans." Am J Respir Crit Care Med 171.12 (June 15, 2005): 1384-1394.
PMID
15778491
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
171
Issue
12
Publish Date
2005
Start Page
1384
End Page
1394
DOI
10.1164/rccm.200406-776OC

Control of basement membrane remodeling and epithelial branching morphogenesis in embryonic lung by Rho and cytoskeletal tension.

Local alterations in the mechanical compliance of the basement membrane that alter the level of isometric tension in the cell have been postulated to influence tissue morphogenesis. To explore whether cell tension contributes to tissue pattern formation in vivo, we modulated cytoskeletal force generation in embryonic mouse lung (embryonic days 12-14) rudiments using inhibitors of Rho-associated kinase (ROCK), myosin light chain kinase, myosin ATPase, and microfilament integrity, or a Rho stimulator (cytotoxic necrotizing factor-1). Tension inhibition resulted in loss of normal differentials in basement membrane thickness, inhibition of new terminal bud formation, and disorganization of epithelial growth patterns as well as disruption of capillary blood vessels. In contrast, increasing cell tension through Rho activation, as confirmed by quantitation of myosin light chain phosphorylation and immunohistocytochemical analysis of actin organization, accelerated lung branching and increase capillary elongation. These data suggest that changes in cytoskeletal tension mediated by Rho signaling through ROCK may play an important role in the establishment of the spatial differentials in cell growth and extracellular matrix remodeling that drive embryonic lung development.

Authors
Moore, KA; Polte, T; Huang, S; Shi, B; Alsberg, E; Sunday, ME; Ingber, DE
MLA Citation
Moore, KA, Polte, T, Huang, S, Shi, B, Alsberg, E, Sunday, ME, and Ingber, DE. "Control of basement membrane remodeling and epithelial branching morphogenesis in embryonic lung by Rho and cytoskeletal tension." Dev Dyn 232.2 (February 2005): 268-281.
PMID
15614768
Source
pubmed
Published In
Developmental Dynamics
Volume
232
Issue
2
Publish Date
2005
Start Page
268
End Page
281
DOI
10.1002/dvdy.20237

Immunomodulatory functions of the diffuse neuroendocrine system: Implications for bronchopulmonary dysplasia

Pulmonary neuroendocrine (NE) cells are believed to be the precursor of NE lung carcinomas, including well-differentiated (carcinoids) and moderately/poorly differentiated (atypical carcinoids and small-cell carcinomas, SCLCs) subtypes. In early studies, we determined mechanisms by which NE cell-derived peptides such as bombesin-like peptide (BLP) promote normal fetal lung development. Postnatally, BLP may normally regulate perinatal adaptation of the pulmonary circulation. However, elevated BLP levels in premature infants shortly after birth predict which infants are at high risk for developing bronchopulmonary dysplasia (BPD, chronic lung disease of newborns). An anti-BLP blocking antibody abrogates clinical and pathological evidence of lung injury in two baboon models of BPD. These observations indicate that BLP mediates lung injury in BPD, supporting a role for BLP as pro-inflammatory cytokines. We have directly tested the effects of BLP on eliciting inflammatory cell infiltrates in vivo. Surprisingly, mast cells are the major responding cell population. These data suggest that the diffuse NE system may be a newly recognized component of innate immunity in multiple organ systems. We speculate that overproduction of NE cell-derived peptides such as BLP may be responsible for a variety of chronic inflammatory disorders.

Authors
Sunday, ME; Shan, L; Subramaniam, M
MLA Citation
Sunday, ME, Shan, L, and Subramaniam, M. "Immunomodulatory functions of the diffuse neuroendocrine system: Implications for bronchopulmonary dysplasia." Endocrine Pathology 15.2 (June 1, 2004): 91-106. (Review)
Source
scopus
Published In
Endocrine Pathology
Volume
15
Issue
2
Publish Date
2004
Start Page
91
End Page
106

Functional diversity of notch family genes in fetal lung development.

In Drosophila, developmental signaling via the transmembrane Notch receptor modulates branching morphogenesis and neuronal differentiation. To determine whether the notch gene family can regulate mammalian organogenesis, including neuroendocrine cell differentiation, we evaluated developing murine lung. After demonstrating gene expression for notch-1, notch-2, notch-3, and the Notch ligands jagged-1 and jagged-2 in embryonic mouse lung, we tested whether altering expression of these genes can modulate branching morphogenesis. Branching of embryonic day (E) 11.5 lung buds increased when they were treated with notch-1 antisense oligodeoxynucleotides in culture compared with the corresponding sense controls, whereas notch-2, notch-3, jagged-1, or jagged-2 antisense oligos had no significant effect. To assess cell differentiation, we immunostained lung bud cultures for the neural/neuroendocrine marker PGP9.5. Antisense to notch-1 or jagged-1 markedly increased numbers of PGP9.5-positive neuroendocrine cells alone without affecting neural tissue, whereas only neural tissue was promoted by notch-3 antisense in culture. There was no significant effect on cell proliferation or apoptosis in these antisense experiments. Cumulatively, these observations suggest that interactions between distinct Notch family members can have diverse tissue-specific regulatory functions during development, arguing against simple functional redundancy.

Authors
Kong, Y; Glickman, J; Subramaniam, M; Shahsafaei, A; Allamneni, KP; Aster, JC; Sklar, J; Sunday, ME
MLA Citation
Kong, Y, Glickman, J, Subramaniam, M, Shahsafaei, A, Allamneni, KP, Aster, JC, Sklar, J, and Sunday, ME. "Functional diversity of notch family genes in fetal lung development." Am J Physiol Lung Cell Mol Physiol 286.5 (May 2004): L1075-L1083.
PMID
15064243
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
286
Issue
5
Publish Date
2004
Start Page
L1075
End Page
L1083
DOI
10.1152/ajplung.00438.2002

Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung.

Bombesin-peptide (BLP) immunoreactivity occurs at high levels in fetal lung. Previous studies showed that bombesin promotes fetal lung development. To test the hypothesis that such effects are mediated by known mammalian bombesin receptors [gastrin-releasing peptide (GRP)/bombesin-preferring receptor (GRPR), neuromedin B (NMB) receptor (NMBR), and the orphan bombesin receptor subtype-3 (BRS-3)], we analyzed the ontogeny of GRPR, NMBR, and BRS-3 gene expression in mouse lung. We examined the regulation of these three genes by dexamethasone and bombesin, which modulate lung development. Using incorporation of [3H]thymidine and [3H]choline, we then assessed whether GRP, NMB, and Leu8-phyllolitorin modulate lung growth and maturation in fetal lung explants. GRPR gene expression was detected predominantly in utero, whereas NMBR and BRS-3 genes were expressed from embryonic days 13-16 and on multiple postnatal days. All three mRNAs are present in airway epithelium and mesenchymal cells but occur in different relative patterns. These genes were regulated differently. Dexamethasone and bombesin increased GRPR mRNA, bombesin downregulated NMBR, and neither agent affected BRS-3. GRP increased incorporation of [3H]thymidine and [3H]choline in explants, whereas NMB induced cell proliferation and Leu8-phyllolitorin yielded variable results. Cumulative data suggest the involvement of multiple BLP receptors, including novel molecules, and argue against simple functional redundancy within this gene family during lung development.

Authors
Shan, L; Emanuel, RL; Dewald, D; Torday, JS; Asokanathan, N; Wada, K; Wada, E; Sunday, ME
MLA Citation
Shan, L, Emanuel, RL, Dewald, D, Torday, JS, Asokanathan, N, Wada, K, Wada, E, and Sunday, ME. "Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung." Am J Physiol Lung Cell Mol Physiol 286.1 (January 2004): L165-L173.
PMID
12959933
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
286
Issue
1
Publish Date
2004
Start Page
L165
End Page
L173
DOI
10.1152/ajplung.00436.2002

Immunomodulatory functions of the diffuse neuroendocrine system: implications for bronchopulmonary dysplasia.

Pulmonary neuroendocrine (NE) cells are believed to be the precursor of NE lung carcinomas, including well-differentiated (carcinoids) and moderately/poorly differentiated (atypical carcinoids and small-cell carcinomas, SCLCs) subtypes. In early studies, we determined mechanisms by which NE cell-derived peptides such as bombesin-like peptide (BLP) promote normal fetal lung development. Postnatally, BLP may normally regulate perinatal adaptation of the pulmonary circulation. However, elevated BLP levels in premature infants shortly after birth predict which infants are at high risk for developing bronchopulmonary dysplasia (BPD, chronic lung disease of newborns). An anti-BLP blocking antibody abrogates clinical and pathological evidence of lung injury in two baboon models of BPD. These observations indicate that BLP mediates lung injury in BPD, supporting a role for BLP as pro-inflammatory cytokines. We have directly tested the effects of BLP on eliciting inflammatory cell infiltrates in vivo. Surprisingly, mast cells are the major responding cell population. These data suggest that the diffuse NE system may be a newly recognized component of innate immunity in multiple organ systems. We speculate that overproduction of NE cell-derived peptides such as BLP may be responsible for a variety of chronic inflammatory disorders.

Authors
Sunday, ME; Shan, L; Subramaniam, M
MLA Citation
Sunday, ME, Shan, L, and Subramaniam, M. "Immunomodulatory functions of the diffuse neuroendocrine system: implications for bronchopulmonary dysplasia." Endocr Pathol 15.2 (2004): 91-106. (Review)
PMID
15299196
Source
pubmed
Published In
Endocrine Pathology
Volume
15
Issue
2
Publish Date
2004
Start Page
91
End Page
106

Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung

Bombesin-like peptide (BLP) immunoreactivity occurs at high levels in fetal lung. Previous studies showed that bombesin promotes fetal lung development. To test the hypothesis that such effects are mediated by known mammalian bombesin receptors [gastrin-releasing peptide (GRP)/bombesin-preferring receptor (GRPR), neuromedin B (NMB) receptor (NMBR), and the orphan bombesin receptor subtype-3 (BRS-3)], we analyzed the ontogeny of GRPR, NMBR, and BRS-3 gene expression in mouse lung. We examined the regulation of these three genes by dexamethasone and bombesin, which modulate lung development. Using incorporation of [3H]thymidine and [ 3H]choline, we then assessed whether GRP, NMB, and Leu 8-phyllolitorin modulate lung growth and maturation in fetal lung explants. GRPR gene expression was detected predominantly in utero, whereas NMBR and BRS-3 genes were expressed from embryonic days 13-16 and on multiple postnatal days. All three mRNAs are present in airway epithelium and mesenchymal cells but occur in different relative patterns. These genes were regulated differently. Dexamethasone and bombesin increased GRPR mRNA, bombesin downregulated NMBR, and neither agent affected BRS-3. GRP increased incorporation of [3H]thymidine and [3H]choline in explants, whereas NMB induced cell proliferation and Leu 8-phyllolitorin yielded variable results. Cumulative data suggest the involvement of multiple BLP receptors, including novel molecules, and argue against simple functional redundancy within this gene family during lung development.

Authors
Shan, L; Emanuel, RL; Dewald, D; Torday, JS; Asokanathan, N; Wada, K; Wada, E; Sunday, ME
MLA Citation
Shan, L, Emanuel, RL, Dewald, D, Torday, JS, Asokanathan, N, Wada, K, Wada, E, and Sunday, ME. "Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung." American Journal of Physiology - Lung Cellular and Molecular Physiology 286.1 30-1 (2004): L165-L173.
Source
scival
Published In
American Journal of Physiology - Lung Cellular and Molecular Physiology
Volume
286
Issue
1 30-1
Publish Date
2004
Start Page
L165
End Page
L173

Bombesin-like peptides and mast cell responses: relevance to bronchopulmonary dysplasia?

Bombesin-like peptides (BLPs) are elevated in newborns who later develop bronchopulmonary dysplasia (BPD). In baboon models, anti-BLP blocking antibodies abrogate BPD. We now demonstrate hyperplasia of both neuroendocrine cells and mast cells in lungs of baboons with BPD, compared with non-BPD controls or BLP antibody-treated BPD baboons. To determine whether BLPs are proinflammatory, bombesin was administered intratracheally to mice. Forty-eight hours later, we observed increased numbers of lung mast cells. We analyzed murine mast cells for BLP receptor gene expression, and identified mRNAs encoding bombesin receptor subtype 3 and neuromedin-B receptor (NMB-R), but not gastrin-releasing peptide receptor. Only NMB-R-null mice accumulated fewer lung mast cells after bombesin treatment. Bombesin, gastrin-releasing peptide, NMB, and a bombesin receptor subtype 3-specific ligand induced mast cell proliferation and chemotaxis in vitro. These observations support a role for multiple BLPs in promoting mast cell responses, suggesting a mechanistic link between BLPs and chronic inflammatory lung diseases.

Authors
Subramaniam, M; Sugiyama, K; Coy, DH; Kong, Y; Miller, YE; Weller, PF; Wada, K; Wada, E; Sunday, ME
MLA Citation
Subramaniam, M, Sugiyama, K, Coy, DH, Kong, Y, Miller, YE, Weller, PF, Wada, K, Wada, E, and Sunday, ME. "Bombesin-like peptides and mast cell responses: relevance to bronchopulmonary dysplasia?." Am J Respir Crit Care Med 168.5 (September 1, 2003): 601-611.
PMID
12807697
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
168
Issue
5
Publish Date
2003
Start Page
601
End Page
611
DOI
10.1164/rccm.200212-1434OC

A catalytic antioxidant attenuates alveolar structural remodeling in bronchopulmonary dysplasia.

Superoxide anion and other oxygen-free radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia. We tested the hypothesis that a catalytic antioxidant metalloporphyrin AEOL 10113 can protect against hyperoxia-induced lung injury using a fetal baboon model of bronchopulmonary dysplasia. Fetal baboons were delivered by hysterotomy at 140 days of gestation (term = 185 days) and given 100% oxygen for 10 days. Morphometric analysis of alveolar structure showed that fetal baboons on 100% oxygen alone had increased parenchymal mast cells and eosinophils, increased alveolar tissue volume and septal thickness, and decreased alveolar surface area compared with animals given oxygen as needed. Treatment with AEOL 10113 (continuous intravenous infusion) during 100% oxygen exposure partially reversed these oxygen-induced changes. Hyperoxia increased the number of neuroendocrine cells in the peripheral lung, which was preceded by increased levels of urine bombesin-like peptide at 48 hours of age. AEOL 10113 inhibited the hyperoxia-induced increases in urine bombesin-like peptide and numbers of neuroendocrine cells. An increasing trend in oxygenation index over time was observed in the 100% oxygen group but not the mimetic-treated group. These results suggest that AEOL 10113 might reduce the risk of pulmonary oxygen toxicity in prematurely born infants.

Authors
Chang, L-YL; Subramaniam, M; Yoder, BA; Day, BJ; Ellison, MC; Sunday, ME; Crapo, JD
MLA Citation
Chang, L-YL, Subramaniam, M, Yoder, BA, Day, BJ, Ellison, MC, Sunday, ME, and Crapo, JD. "A catalytic antioxidant attenuates alveolar structural remodeling in bronchopulmonary dysplasia." Am J Respir Crit Care Med 167.1 (January 1, 2003): 57-64.
PMID
12502477
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
167
Issue
1
Publish Date
2003
Start Page
57
End Page
64
DOI
10.1164/rccm.200203-232OC

Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury.

Capillary leakage and alveolar edema are hallmarks of acute lung injury (ALI). Neutrophils and serum macromolecules enter alveoli, promoting inflammation. Vascular endothelial growth factor (VEGF) causes plasma leakage in extrapulmonary vessels. Angiopoietin (Ang)-1 and -4 stabilize vessels, attenuating capillary leakage. We hypothesized that VEGF and Ang-1 and -4 modulate vessel leakage in the lung, contributing to the pathogenesis of ALI. We examined a murine model of lipopolysaccharide (LPS)-induced ALI. C57BL/6 and 129/J mice were studied at baseline and 24, 48, and 96 h after single or multiple doses of aerosolized LPS. Both strains exhibited time- and dose-dependent increases in inflammation and a deterioration of lung mechanics. Bronchoalveolar lavage (BAL) protein levels increased significantly, suggesting capillary leakage. Increased BAL neutrophil and total protein content correlated with time-dependent increased tissue VEGF and decreased Ang-1 and -4 levels, with peak VEGF and minimum Ang-1 and -4 expression after 96 h of LPS challenge. These data suggest that changes in the balance between VEGF and Ang-1 and -4 after LPS exposure may modulate neutrophil influx, protein leakage, and alveolar flooding during early ALI.

Authors
Karmpaliotis, D; Kosmidou, I; Ingenito, EP; Hong, K; Malhotra, A; Sunday, ME; Haley, KJ
MLA Citation
Karmpaliotis, D, Kosmidou, I, Ingenito, EP, Hong, K, Malhotra, A, Sunday, ME, and Haley, KJ. "Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury." Am J Physiol Lung Cell Mol Physiol 283.3 (September 2002): L585-L595.
PMID
12169578
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
283
Issue
3
Publish Date
2002
Start Page
L585
End Page
L595
DOI
10.1152/ajplung.00048.2002

Control of embryonic lung branching morphogenesis by the Rho activator, cytotoxic necrotizing factor 1.

BACKGROUND: Lung development is sensitive to physiological stresses, and its development may be impaired by physical distortion, as in patients with congenital diaphragmatic hernia. Yet, little is known about how mechanical forces can influence lung morphogenesis. Studies with cultured cells suggest that cytoskeletal tension may play a key role in growth control. Since the small GTPase Rho plays an important role in the control of cell tension generation, we carried out studies to test the hypothesis that changes in Rho-mediated cell tension may influence branching morphogenesis. METHODS: Embryonic lung buds from timed pregnant Swiss Webster mice were microdissected on Embryonic Day 12 (E12), and whole organs were cultured in serum-free medium in the presence of the Rho activator cytotoxic necrotizing factor 1 (CNF-1) for 48 h. Serial measurements of the degree of epithelial branch formation and tissue maturation were performed using light microscopy and computerized image analysis. RESULTS: At 48 h, embryonic lungs treated with 2 ng/ml CNF-1 increased their terminal bud count by 236 +/- 18% (P = 0.01) compared with 132 +/- 2% for untreated controls. However, dose-response experiments revealed biphasic behavior: at a higher dose of CNF-1 (200 ng/ml), bud number was actually decreased relative to controls (43 +/- 1%, P < 0.001). Histological analysis revealed that individual glands appeared to be more highly developed at low-dose CNF-1, whereas the high dose produced gland contraction. CONCLUSIONS: These data support a potential role for Rho and cytoskeletal tension in control of epithelial pattern formation during lung development.

Authors
Moore, KA; Huang, S; Kong, Y; Sunday, ME; Ingber, DE
MLA Citation
Moore, KA, Huang, S, Kong, Y, Sunday, ME, and Ingber, DE. "Control of embryonic lung branching morphogenesis by the Rho activator, cytotoxic necrotizing factor 1." J Surg Res 104.2 (May 15, 2002): 95-100.
PMID
12020126
Source
pubmed
Published In
Journal of Surgical Research
Volume
104
Issue
2
Publish Date
2002
Start Page
95
End Page
100
DOI
10.1006/jsre.2002.6418

Urine bombesin-like peptide elevation precedes clinical evidence of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of very low birth weight infants, associated with oxygen therapy, barotrauma, and/or infections. Improved medical care has led to a paradoxically increased incidence of BPD due to greater infant survival. Early prediction of BPD has proven challenging. Increased pulmonary neuroendocrine cells containing bombesin-like peptide immunoreactivity occur in infants with BPD. We hypothesized that elevated urine bombesin-like peptide levels precede BPD. One hundred thirty-two infants, 28-weeks gestation or less, were studied. Urine bombesin-like peptide levels, determined by radioimmunoassay, were normalized for creatinine. BPD was defined as oxygen dependence at 36 weeks postmenstrual age. A first urine bombesin-like peptide level greater than 20,000 pg/mg creatinine (12,500 fmol/mg) between postnatal days 1-4 occurred among 54% of the infants who later developed BPD (p < or = 0.001), versus 10% among non-BPD infants (specificity 90%). Multivariable logistic regression analyses revealed that elevated urine bombesin-like peptide levels are associated with BPD (odds ratio 9.9, 95% confidence interval: 3.4, 29) (p < or = 0.001) after adjusting for all confounding factors. Thus, elevated bombesin-like peptide levels in these infants at 1-4 days after birth are associated with a 10-fold increased risk of developing BPD. Utilizing urine bombesin-like peptide for screening might permit early therapeutic interventions to reduce disease progression and could provide a target for new preventive therapies.

Authors
Cullen, A; Van Marter, LJ; Allred, EN; Moore, M; Parad, RB; Sunday, ME
MLA Citation
Cullen, A, Van Marter, LJ, Allred, EN, Moore, M, Parad, RB, and Sunday, ME. "Urine bombesin-like peptide elevation precedes clinical evidence of bronchopulmonary dysplasia." Am J Respir Crit Care Med 165.8 (April 15, 2002): 1093-1097.
PMID
11956050
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
165
Issue
8
Publish Date
2002
Start Page
1093
End Page
1097
DOI
10.1164/ajrccm.165.8.2108044

Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation.

Developing rat lung lipofibroblasts express leptin beginning on embryonic day (E) 17, increasing 7- to 10-fold by E20. Leptin and its receptor are expressed mutually exclusively by fetal lung fibroblasts and type II cells, suggesting a paracrine signaling "loop." This hypothesized mechanism is supported by the following experimental data: 1) leptin stimulates the de novo synthesis of surfactant phospholipid by both fetal rat type II cells (400% x 100 ng(-1) x ml(-1) x 24 h(-1)) and adult human airway epithelial cells (85% x 100 ng(-1) x 24 h(-1)); 2) leptin is secreted by lipofibroblasts in amounts that stimulate type II cell surfactant phospholipid synthesis in vitro; 3) epithelial cell secretions such as parathyroid hormone-related protein (PTHrP), PGE(2), and dexamethasone stimulate leptin expression by fetal rat lung fibroblasts; 4) PTHrP or leptin stimulate the de novo synthesis of surfactant phospholipid (2- to 2.5-fold/24 h) and the expression of surfactant protein B (SP-B; >25-fold/24 h) by fetal rat lung explants, an effect that is blocked by a leptin antibody; and 5) a PTHrP receptor antagonist inhibits the expression of leptin mRNA by explants but does not inhibit leptin stimulation of surfactant phospholipid or SP-B expression, indicating that PTHrP paracrine stimulation of type II cell maturation requires leptin expression by lipofibroblasts. This is the first demonstration of a paracrine loop that functionally cooperates to induce alveolar acinar lung development.

Authors
Torday, JS; Sun, H; Wang, L; Torres, E; Sunday, ME; Rubin, LP
MLA Citation
Torday, JS, Sun, H, Wang, L, Torres, E, Sunday, ME, and Rubin, LP. "Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation." Am J Physiol Lung Cell Mol Physiol 282.3 (March 2002): L405-L410.
PMID
11839533
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
282
Issue
3
Publish Date
2002
Start Page
L405
End Page
L410

Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury

Capillary leakage and alveolar edema are hallmarks of acute lung injury (ALI). Neutrophils and serum macromolecules enter alveoli, promoting inflammation. Vascular endothelial growth factor (VEGF) causes plasma leakage in extrapulmonary vessels. Angiopoietin (Ang)-1 and -4 stabilize vessels, attenuating capillary leakage. We hypothesized that VEGF and Ang-1 and -4 modulate vessel leakage in the lung, contributing to the pathogenesis of ALI. We examined a murine model of lipopolysaccharide (LPS)-induced ALI. C57BL/6 and 129/J mice were studied at baseline and 24, 48, and 96 h after single or multiple doses of aerosolized LPS. Both strains exhibited time- and dose-dependent increases in inflammation and a deterioration of lung mechanics. Bronchoalveolar lavage (BAL) protein levels increased significantly, suggesting capillary leakage. Increased BAL neutrophil and total protein content correlated with time-dependent increased tissue VEGF and decreased Ang-1 and -4 levels, with peak VEGF and minimum Ang-1 and -4 expression after 96 h of LPS challenge. These data suggest that changes in the balance between VEGF and Ang-1 and -4 after LPS exposure may modulate neutrophil influx, protein leakage, and alveolar flooding during early ALI.

Authors
Karmpaliotis, D; Kosmidou, I; Ingenito, EP; Hong, K; Malhotra, A; Sunday, ME; Haley, KJ
MLA Citation
Karmpaliotis, D, Kosmidou, I, Ingenito, EP, Hong, K, Malhotra, A, Sunday, ME, and Haley, KJ. "Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury." American Journal of Physiology - Lung Cellular and Molecular Physiology 283.3 27-3 (2002): L585-L595.
Source
scival
Published In
American Journal of Physiology - Lung Cellular and Molecular Physiology
Volume
283
Issue
3 27-3
Publish Date
2002
Start Page
L585
End Page
L595

Neuroimmunologic control of asthma

The neural, neuroendocrine, and immune systems frequently are believed to be completely separate entities; however, evidence suggests that these systems interact extensively to modulate pulmonary immune responses. The functional significance of these interactions suggests that many pulmonary responses to proinflammatory stimuli are regulated by the neural and neuroendocrine systems. There is no clear delineation between the pulmonary proinflammatory responses that strictly result from the classic inflammatory cells and their mediators and those responses that largely are amplified by neuropeptides and other neural- or neuroendocrine-derived mediators. This viewpoint highlights the inherent complexity of the lung's proinflammatory responses and has implications for novel therapeutic approaches. In clinical trials, specific targeting of one component of the pulmonary inflammatory response is likely to have only limited success. Therapies that target several distinct pathways that have been implicated in these inflammatory responses are likely to be the most effective in controlling asthma. This concept of broad-spectrum targeting likely explains the effectiveness of nonspecific therapies, such as steroids, which affect multiple pathways of neuroimmune responses. It has become a priority to gain appreciation of the neuroimmunologic regulation of asthma and other forms of chronic inflammatory lung disease. Understanding such collaborating systems in development, health, and disease is a powerful paradigm for the future for elucidation of the pathophysiology of inflammatory lung diseases and for novel therapeutic approaches that could benefit patients.

Authors
Haley, KJ; Sunday, ME
MLA Citation
Haley, KJ, and Sunday, ME. "Neuroimmunologic control of asthma." Immunology and Allergy Clinics of North America 22.4 (2002): 807-825.
Source
scival
Published In
Immunology and Allergy Clinics of North America
Volume
22
Issue
4
Publish Date
2002
Start Page
807
End Page
825
DOI
10.1016/S0889-8561(02)00023-1

Erratum: Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation (American Journal of Physiology-Lung Cellular and Molecular (March 2002) 282 (L405-L410))

Authors
Torday, JS; Sun, H; Wang, L; Torres, E; Sunday, ME; Rubin, LP
MLA Citation
Torday, JS, Sun, H, Wang, L, Torres, E, Sunday, ME, and Rubin, LP. "Erratum: Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation (American Journal of Physiology-Lung Cellular and Molecular (March 2002) 282 (L405-L410))." American Journal of Physiology - Lung Cellular and Molecular Physiology 282.6 26-6 (2002): viii-.
Source
scival
Published In
American Journal of Physiology - Lung Cellular and Molecular Physiology
Volume
282
Issue
6 26-6
Publish Date
2002
Start Page
viii

Erratum: Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation (American Journal of Physiology - Lung Cellular and Molecular (March 2002) 282 (L405-L410))

Authors
Torday, JS; Sun, H; Wang, L; Torres, E; Sunday, ME; Rubin, LP
MLA Citation
Torday, JS, Sun, H, Wang, L, Torres, E, Sunday, ME, and Rubin, LP. "Erratum: Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation (American Journal of Physiology - Lung Cellular and Molecular (March 2002) 282 (L405-L410))." American Journal of Physiology - Lung Cellular and Molecular Physiology 282.4 26-4 (2002): i-.
Source
scival
Published In
American Journal of Physiology - Lung Cellular and Molecular Physiology
Volume
282
Issue
4 26-4
Publish Date
2002
Start Page
i

Fetal alveolar epithelial cells contain [D-Ala(2)]-deltorphin I-like immunoreactivity: delta- and mu-opiate receptors mediate opposite effects in developing lung.

Opiate-like peptides can regulate many cellular functions. We now map [D-Ala(2)]deltorphin I (DADTI)-like immunoreactivity (DADTI-LI) in developing mouse lung and analyze potential functional roles. Most DADTI-LI-positive cells were alveolar cells negative for prosurfactant protein (proSP)-C immunoreactivity. Peak numbers of DADTI-LI-positive cells occurred on embryonic Day 18, decreasing postnatally. To analyze developmental effects of DADTI, e17-18 lung explants were treated with [D-Ala(2)]deltorphin II (DADTII, soluble DADTI analogue, delta-receptor-specific) versus dermorphin (mu-receptor-specific). Type II pneumocyte differentiation, assessed by [(3)H]choline incorporation into saturated phosphatidylcholine and proSP-C immunostaining, was inhibited by DADTII but stimulated by dermorphin. Cell proliferation, measured as [(3)H]-thymidine incorporation and proliferating cell nuclear antigen immunostaining, was stimulated by DADTII and inhibited by dermorphin. All effects were dose-dependent. DADTII-inhibited choline incorporation was reversed by the delta-blocker, naltrindole. Unexpectedly, DADTII-stimulated thymidine incorporation was augmented by naltrindole and reversed by naloxone (mu-blocker). Although dermorphin-stimulated choline incorporation was appropriately blocked by binaltorphimine, dermorphin-inhibited thymidine incorporation was reversed by delta, kappa-, or mu-blockers. The delta- and mu-receptor messenger RNAs occurred pre- and postnatally, whereas kappa-receptor transcripts occurred mainly prenatally. All three receptor proteins were present in epithelial and mesenchymal cells in e18 lung. Thus, DADTI-LI from proSP-C-immunonegative alveolar cells could regulate development via both direct and indirect effects involving multiple opiate receptors.

Authors
Sunday, ME; Haley, KJ; Emanuel, RL; Torday, JS; Asokananthan, N; Sikorski, KA; Tooyama, I; Kimura, H; Renda, T; Erspamer, V
MLA Citation
Sunday, ME, Haley, KJ, Emanuel, RL, Torday, JS, Asokananthan, N, Sikorski, KA, Tooyama, I, Kimura, H, Renda, T, and Erspamer, V. "Fetal alveolar epithelial cells contain [D-Ala(2)]-deltorphin I-like immunoreactivity: delta- and mu-opiate receptors mediate opposite effects in developing lung." Am J Respir Cell Mol Biol 25.4 (October 2001): 447-456.
PMID
11694450
Source
pubmed
Published In
American journal of respiratory cell and molecular biology
Volume
25
Issue
4
Publish Date
2001
Start Page
447
End Page
456
DOI
10.1165/ajrcmb.25.4.4072

Developmental expression of neurokinin A and functional neurokinin-2 receptors in lung.

Peribronchial smooth muscle constriction causes airway stretch, an important mechanical force in developing lung. Little is known about factors influencing these spontaneously active muscle elements. We measured contractile activity of neurokinin (NK) receptors on fetal intrapulmonary smooth muscle by tracheal perfusion assay (n = 11). Injecting either capsaicin or the NK(2) receptor agonist [NLE(10)]NKA resulted in significant (P < 0.05) bronchoconstriction. A specific NK(2) receptor antagonist inhibited constriction caused by endogenous tachykinins released by capsaicin. We then examined NK(2) receptor (n = 44) and NKA (n = 23) ontogeny in human lung. NKA immunostaining was identified in peribronchial nerves in samples with gestational age >12 wk. NK(2) receptor protein was identified in peribronchial and perivascular smooth muscle. These results indicate that endogenous tachykinins released by the developing lung act via NK(2) receptors to cause smooth muscle constriction. We speculate that tachykinins could modulate lung development.

Authors
Haley, KJ; Sunday, ME; Osathanondh, R; Du, J; Vathanaprida, C; Karpitsky, VV; Krause, JE; Lilly, CM
MLA Citation
Haley, KJ, Sunday, ME, Osathanondh, R, Du, J, Vathanaprida, C, Karpitsky, VV, Krause, JE, and Lilly, CM. "Developmental expression of neurokinin A and functional neurokinin-2 receptors in lung." Am J Physiol Lung Cell Mol Physiol 280.6 (June 2001): L1348-L1358.
PMID
11350816
Source
pubmed
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
280
Issue
6
Publish Date
2001
Start Page
L1348
End Page
L1358

Differential expression of VEGF isoforms in mouse during development and in the adult

Vascular endothelial growth factor (VEGF), a factor that is critical for development of the vascular system in mouse embryos, exists as at least three isoforms, VEGF120, VEGF164, and VEGF188. The isoforms have different affinities for heparan sulfate as well as for the three known VEGF receptors, VEGFR-1 (Flt-1), VEGFR-2 (Flk-1), and neuropilin-1, suggesting that different VEGF isoforms may play distinct roles in vascular development. To determine whether there are differences in the organ-specific expression patterns that would support this concept, we used a quantitative RNase protection assay (RPA) to determine the distribution of different VEGF isoform mRNA in developing and adult mouse organs. Results revealed that the ratios of the three VEGF isoforms changed during organ development and that adult organs expressed different levels of the three VEGF isoforms. Because the lung expressed the highest levels of VEGF188 isoform, we used VEGF isoform-specific in situ hybridization in the developing lung and determined that type II alveolar epithelial cells were expressing high levels of VEGF188 mRNA. Finally, targeted exon deletion of the VEGF gene revealed that mice that developed in the absence of the heparan sulfate binding isoforms VEGF164 and VEGF188, displayed a variety of vascular defects, including abnormal pulmonary vascular development. Our results support the concept that different VEGF isoforms have distinct functions in vascular development. © 2001 Wiley-Liss, Inc.

Authors
Ng, YS; Rohan, R; Sunday, ME; Demello, DE; D'Amore, PA
MLA Citation
Ng, YS, Rohan, R, Sunday, ME, Demello, DE, and D'Amore, PA. "Differential expression of VEGF isoforms in mouse during development and in the adult." Developmental Dynamics 220.2 (February 10, 2001): 112-121.
Source
scopus
Published In
Developmental Dynamics
Volume
220
Issue
2
Publish Date
2001
Start Page
112
End Page
121
DOI
10.1002/1097-0177(2000)9999:9999<::AID-DVDY1093>3.0.CO;2-D

Differential expression of VEGF isoforms in mouse during development and in the adult.

Vascular endothelial growth factor (VEGF), a factor that is critical for development of the vascular system in mouse embryos, exists as at least three isoforms, VEGF120, VEGF164, and VEGF188. The isoforms have different affinities for heparan sulfate as well as for the three known VEGF receptors, VEGFR-1 (Flt-1), VEGFR-2 (Flk-1), and neuropilin-1, suggesting that different VEGF isoforms may play distinct roles in vascular development. To determine whether there are differences in the organ-specific expression patterns that would support this concept, we used a quantitative RNase protection assay (RPA) to determine the distribution of different VEGF isoform mRNA in developing and adult mouse organs. Results revealed that the ratios of the three VEGF isoforms changed during organ development and that adult organs expressed different levels of the three VEGF isoforms. Because the lung expressed the highest levels of VEGF188 isoform, we used VEGF isoform-specific in situ hybridization in the developing lung and determined that type II alveolar epithelial cells were expressing high levels of VEGF188 mRNA. Finally, targeted exon deletion of the VEGF gene revealed that mice that developed in the absence of the heparan sulfate binding isoforms VEGF164 and VEGF188, displayed a variety of vascular defects, including abnormal pulmonary vascular development. Our results support the concept that different VEGF isoforms have distinct functions in vascular development.

Authors
Ng, YS; Rohan, R; Sunday, ME; Demello, DE; D'Amore, PA
MLA Citation
Ng, YS, Rohan, R, Sunday, ME, Demello, DE, and D'Amore, PA. "Differential expression of VEGF isoforms in mouse during development and in the adult." Developmental dynamics : an official publication of the American Association of Anatomists 220.2 (February 2001): 112-121. (Academic Article)
Source
manual
Published In
Developmental Dynamics
Volume
220
Issue
2
Publish Date
2001
Start Page
112
End Page
121
DOI
10.1002/1097-0177(2000)9999:99993.0.CO;2-D

Differential expression of VEGF isoforms in mouse during development and in the adult.

Vascular endothelial growth factor (VEGF), a factor that is critical for development of the vascular system in mouse embryos, exists as at least three isoforms, VEGF120, VEGF164, and VEGF188. The isoforms have different affinities for heparan sulfate as well as for the three known VEGF receptors, VEGFR-1 (Flt-1), VEGFR-2 (Flk-1), and neuropilin-1, suggesting that different VEGF isoforms may play distinct roles in vascular development. To determine whether there are differences in the organ-specific expression patterns that would support this concept, we used a quantitative RNase protection assay (RPA) to determine the distribution of different VEGF isoform mRNA in developing and adult mouse organs. Results revealed that the ratios of the three VEGF isoforms changed during organ development and that adult organs expressed different levels of the three VEGF isoforms. Because the lung expressed the highest levels of VEGF188 isoform, we used VEGF isoform-specific in situ hybridization in the developing lung and determined that type II alveolar epithelial cells were expressing high levels of VEGF188 mRNA. Finally, targeted exon deletion of the VEGF gene revealed that mice that developed in the absence of the heparan sulfate binding isoforms VEGF164 and VEGF188, displayed a variety of vascular defects, including abnormal pulmonary vascular development. Our results support the concept that different VEGF isoforms have distinct functions in vascular development.

Authors
Ng, YS; Rohan, R; Sunday, ME; Demello, DE; D'Amore, PA
MLA Citation
Ng, YS, Rohan, R, Sunday, ME, Demello, DE, and D'Amore, PA. "Differential expression of VEGF isoforms in mouse during development and in the adult." Dev Dyn 220.2 (February 2001): 112-121.
PMID
11169844
Source
pubmed
Published In
Developmental Dynamics
Volume
220
Issue
2
Publish Date
2001
Start Page
112
End Page
121
DOI
10.1002/1097-0177(2000)9999:9999<::AID-DVDY1093>3.0.CO;2-D

Stromelysin-3 suppresses tumor cell apoptosis in a murine model.

Stromelysin-3 (STR-3) is a matrix metalloproteinase with a unique pattern of expression and substrate specificity. During embryogenesis and remodeling of normal adult tissues, STR-3 is produced by stromal cells in direct contact with epithelial cells undergoing regional apoptosis and selective cell survival. STR-3 is also overexpressed by interdigitating stromal cells in primary epithelial malignancies. Although STR-3 does not degrade classic extracellular matrix components, the enzyme promotes the establishment of local tumors in nude mice by as yet undefined mechanisms. STR-3 is induced when malignant epithelial cells come into contact with surrounding stromal elements; the active stromal cell-derived 45 kDa enzyme is subsequently processed to a 35 kDa protein without enzymatic activity. We have generated MCF-7 transfectants expressing wild type or catalytically inactive 45 kDa STR-3 (STR-3wt and STR-3cat-) or secreted 35 kDa STR-3 (35 kDa STR-3sec) and evaluated their implantation and survival in nude mice. Tumors developed significantly more rapidly in animals receiving STR-3wt, rather than vector-only, STR-3cat- or 35 kDa STR-3sec transfectants. Most importantly, STR-3wt tumors had a significantly lower percentage of apoptotic cells than tumors derived from vector-only, STR-3cat- or 35 kDa STR-3sec transfectants. Taken together, these studies suggest that the active STR-3 enzyme may increase tumor take by suppressing tumor cell apoptosis and that 45 kDa to 35 kDa STR-3 processing limits STR-3 activity at the tumor/stromal interface. Because STR-3 is secreted as an active enzyme rather than a proform, subsequent 45 kDa to 35 kDa STR-3 processing may represent a novel mechanism for regulating enzymatic activity.

Authors
Wu, E; Mari, BP; Wang, F; Anderson, IC; Sunday, ME; Shipp, MA
MLA Citation
Wu, E, Mari, BP, Wang, F, Anderson, IC, Sunday, ME, and Shipp, MA. "Stromelysin-3 suppresses tumor cell apoptosis in a murine model." J Cell Biochem 82.4 (2001): 549-555.
PMID
11500932
Source
pubmed
Published In
Journal of Cellular Biochemistry
Volume
82
Issue
4
Publish Date
2001
Start Page
549
End Page
555

Developmental expression of neurokinin A and functional neurokinin-2 receptors in lung

Peribronchial smooth muscle constriction causes airway stretch, an important mechanical force in developing lung. Little is known about factors influencing these spontaneously active muscle elements. We measured contractile activity of neurokinin (NK) receptors on fetal intrapulmonary smooth muscle by tracheal perfusion assay (n = 11). Injecting either capsaicin or the NK2 receptor agonist [NLE10]NKA resulted in significant (P < 0.05) bronchoconstriction. A specific NK2 receptor antagonist inhibited constriction caused by endogenous tachykinins released by capsaicin. We then examined NK2 receptor (n = 44) and NKA (n = 23) ontogeny in human lung. NKA immunostaining was identified in peribronchial nerves in samples with gestational age >12 wk. NK2 receptor protein was identified in peribronchial and perivascular smooth muscle. These results indicate that endogenous tachykinins released by the developing lung act via NK2 receptors to cause smooth muscle constriction. We speculate that tachykinins could modulate lung development.

Authors
Haley, KJ; Sunday, ME; Osathanondh, R; Du, J; Vathanaprida, C; Karpitsky, VV; Krause, JE; Lilly, CM
MLA Citation
Haley, KJ, Sunday, ME, Osathanondh, R, Du, J, Vathanaprida, C, Karpitsky, VV, Krause, JE, and Lilly, CM. "Developmental expression of neurokinin A and functional neurokinin-2 receptors in lung." American Journal of Physiology - Lung Cellular and Molecular Physiology 280.6 24-6 (2001): L1348-L1358.
Source
scival
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
280
Issue
6 24-6
Publish Date
2001
Start Page
L1348
End Page
L1358

Direct effects of corticotropin-releasing hormone and thyrotropin-releasing hormone on fetal lung explants

Fetal lung produces corticotropin-releasing hormone (CRH) without known direct effects. We tested the hypothesis that CRH can directly regulate lung development. In baboon fetal lung explants, CRH strongly induces surfactant phospholipid synthesis and SP-C immunostaining, plus [3H]thymidine incorporation. CRH receptor mRNA was detected in lung from multiple baboons at e125. Testing thyrotropin (TRH) as a specificity control, we did demonstrate different direct effects with only modest stimulation of surfactant phospholipid synthesis and strong induction of cytidylyltransferase gene expression. Therefore, CRH, similar to ACTH and glucocorticoids, is a potent inducer of cell differentiation in fetal lung. © 2000 Published by Elsevier Science Inc.

Authors
Emanuel, RL; Torday, JS; Asokananthan, N; Sunday, ME
MLA Citation
Emanuel, RL, Torday, JS, Asokananthan, N, and Sunday, ME. "Direct effects of corticotropin-releasing hormone and thyrotropin-releasing hormone on fetal lung explants." Peptides 22.12 (2001): 1819-1829.
Source
scival
Published In
Peptides
Volume
22
Issue
12
Publish Date
2001
Start Page
1819
End Page
1829

Direct effects of corticotropin-releasing hormone and thyrotropin-releasing hormone on fetal lung explants.

Fetal lung produces corticotropin-releasing hormone (CRH) without known direct effects. We tested the hypothesis that CRH can directly regulate lung development. In baboon fetal lung explants, CRH strongly induces surfactant phospholipid synthesis and SP-C immunostaining, plus [(3)H]thymidine incorporation. CRH receptor mRNA was detected in lung from multiple baboons at e125. Testing thyrotropin (TRH) as a specificity control, we did demonstrate different direct effects with only modest stimulation of surfactant phospholipid synthesis and strong induction of cytidylyltransferase gene expression. Therefore, CRH, similar to ACTH and glucocorticoids, is a potent inducer of cell differentiation in fetal lung.

Authors
Emanuel, RL; Torday, JS; Asokananthan, N; Sunday, ME
MLA Citation
Emanuel, RL, Torday, JS, Asokananthan, N, and Sunday, ME. "Direct effects of corticotropin-releasing hormone and thyrotropin-releasing hormone on fetal lung explants." Peptides 21.12 (December 2000): 1819-1829.
PMID
11150642
Source
pubmed
Published In
Peptides
Volume
21
Issue
12
Publish Date
2000
Start Page
1819
End Page
1829

Bombesin-like peptide and receptors in lung injury models: diverse gene expression, similar function.

We previously demonstrated that bombesin-like peptide (BLP) mediates lung injury in premature infants with bronchopulmonary dysplasia (BPD). We now investigate gene expression and function of BLP (gastrin-releasing peptide, GRP) and BLP-receptors (GRP-R and BRS-3) in lung from two baboon BPD models. In the "interrupted gestation model," only GRP mRNA was up-regulated. In the "hyperoxic model," GRP-R mRNA was up-regulated. In lung explants from O2-treated animals, all BPD animals responded to 1nM bombesin, whereas non-BPD animals did not; the opposite effect was observed with a BLP blocking antibody. Cumulatively, these observations suggest that novel BLPs and/or BLP receptors are likely to be implicated in the pathogenesis of BPD.

Authors
Cullen, A; Emanuel, RL; Torday, JS; Asokananthan, N; Sikorski, KA; Sunday, ME
MLA Citation
Cullen, A, Emanuel, RL, Torday, JS, Asokananthan, N, Sikorski, KA, and Sunday, ME. "Bombesin-like peptide and receptors in lung injury models: diverse gene expression, similar function." Peptides 21.11 (November 2000): 1627-1638.
PMID
11090916
Source
pubmed
Published In
Peptides
Volume
21
Issue
11
Publish Date
2000
Start Page
1627
End Page
1638

Bombesin-like peptides and receptors in normal fetal baboon lung: roles in lung growth and maturation.

Previously, we have shown that bombesin-like peptide (BLP) promotes fetal lung development in rodents and humans but mediates postnatal lung injury in hyperoxic baboons. The present study analyzed the normal ontogeny of BLP and BLP receptors as well as the effects of BLP on cultured normal fetal baboon lungs. Transcripts encoding gastrin-releasing peptide (GRP), a pulmonary BLP, were detectable on gestational day 60 (ED60), peaked on approximately ED90, and then declined before term (ED180). Numbers of BLP-immunopositive neuroendocrine cells peaked from ED80 to ED125 and declined by ED160, preceding GRP-receptor mRNAs detected from ED125 until birth. BLP (0.1-10 nM) stimulated type II cell differentiation in organ cultures as assessed by [(3)H]choline incorporation into surfactant phospholipids, electron microscopy, and increased surfactant protein (SP) A- and/or SP-C-immunopositive cells and SP-A mRNA. BLP also induced neuroendocrine differentiation on ED60. Cell proliferation was induced by GRP, peaking on ED90. Similarly, blocking BLP degradation stimulated lung growth and maturation, which was completely reversed by a BLP-specific antagonist. The dissociation between GRP and GRP-receptor gene expression during ontogeny suggests that novel BLP receptors and/or peptides might be implicated in these responses.

Authors
Emanuel, RL; Torday, JS; Mu, Q; Asokananthan, N; Sikorski, KA; Sunday, ME
MLA Citation
Emanuel, RL, Torday, JS, Mu, Q, Asokananthan, N, Sikorski, KA, and Sunday, ME. "Bombesin-like peptides and receptors in normal fetal baboon lung: roles in lung growth and maturation." Am J Physiol 277.5 Pt 1 (November 1999): L1003-L1017.
PMID
10564187
Source
pubmed
Published In
The American journal of physiology
Volume
277
Issue
5 Pt 1
Publish Date
1999
Start Page
L1003
End Page
L1017

Syntaxin 1A is transiently expressed in fetal lung mesenchymal cells: potential developmental roles.

Lung development is a complex process in which epithelial-mesenchymal interactions play a key role. A conserved secretory apparatus, the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, is essential for exocytosis in many cell types. Syntaxins, located on the terminal plasma membrane (T-SNAREs), are a critical component of the secretosomal complex involved in vesicular docking, fusion, and exocytosis. We analyzed syntaxin 1A mRNA and protein in fetal rat lung ontogeny, demonstrating peak expression on about day 19 of embryonic development, immediately preceding type II pneumocyte differentiation. Syntaxin 1A is predominantly expressed by lipofibroblasts, which are required for bombesin-like peptide-induced surfactant phospholipid synthesis (choline uptake) by isolated type II cells. In organ cultures, anti-syntaxin 1A antibody HPC-1 blocks choline uptake both at baseline and when induced by bombesin-like peptide or dexamethasone. HPC-1 also promotes thymidine uptake in parallel in a dose-dependent fashion. These observations indicate a potential role for syntaxin 1A during fetal lung development, possibly through involvement in secretion of mesenchymal cell-derived factors that induce terminal type II cell differentiation.

Authors
Brimhall, BB; Sikorski, KA; Torday, J; Shahsafaei, A; Haley, KJ; Sunday, ME
MLA Citation
Brimhall, BB, Sikorski, KA, Torday, J, Shahsafaei, A, Haley, KJ, and Sunday, ME. "Syntaxin 1A is transiently expressed in fetal lung mesenchymal cells: potential developmental roles." Am J Physiol 277.2 Pt 1 (August 1999): L401-L411.
PMID
10444535
Source
pubmed
Published In
The American journal of physiology
Volume
277
Issue
2 Pt 1
Publish Date
1999
Start Page
L401
End Page
L411

Calcitonin driven v-Ha-ras induces multilineage pulmonary epithelial hyperplasias and neoplasms.

We initiated a transgenic model for primary pulmonary neuroendocrine cell (PNEC) hyperplasia/neoplasia using v-Ha-ras driven by the neural/neuroendocrine (NE)-specific calcitonin promoter (rascal). Previously, we showed that nitrosamine treated rodents develop PNEC hyperplasia but non-NE lung tumors, with variable outcomes presumably reflecting ras activation in multiple cell lineages. Interestingly, all rascal transgenic mouse lineages develop hyperplasias of NE and non-NE cells but mostly non-NE lung carcinomas, with rascal mRNA in differentiated PNECs and tumor cells. Analyses of embryonic lung demonstrate rascal mRNA in undifferentiated epithelium, consistent with expression in a common pluripotent precursor cell. These unexpected observations indicate that v-Ha-ras can lead to both NE and non-NE hyperplasia/neoplasia in vivo, opening new avenues for studies of lung carcinogenesis.

Authors
Sunday, ME; Haley, KJ; Sikorski, K; Graham, SA; Emanuel, RL; Zhang, F; Mu, Q; Shahsafaei, A; Hatzis, D
MLA Citation
Sunday, ME, Haley, KJ, Sikorski, K, Graham, SA, Emanuel, RL, Zhang, F, Mu, Q, Shahsafaei, A, and Hatzis, D. "Calcitonin driven v-Ha-ras induces multilineage pulmonary epithelial hyperplasias and neoplasms." Oncogene 18.30 (July 29, 1999): 4336-4347.
PMID
10439041
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
18
Issue
30
Publish Date
1999
Start Page
4336
End Page
4347
DOI
10.1038/sj.onc.1202810

CD10/neutral endopeptidase inhibition augments pulmonary neuroendocrine cell hyperplasia in hamsters treated with diethylnitrosamine and hyperoxia.

In previous studies, we demonstrated that pulmonary neuroendocrine cell (PNEC) hyperplasia in hamsters treated with diethylnitrosamine (DEN) plus 65% hyperoxia (DEN/O2) reflects predominantly neuroendocrine cell differentiation. Several peptides implicated in non-neoplastic PNEC hyperplasia are hydrolyzed by CD10/neutral endopeptidase 24.11 (CD10/NEP), an enzyme known to downregulate neurogenic inflammation of the lung by modulating locally effective concentrations of multiple bioactive peptides. In fetal mice, we observed that CD10/NEP inhibition by SCH32615 potentiates cell proliferation and type II cell differentiation in the lung in utero. Further, CD10/NEP messenger RNA levels parallelled relative PNEC numbers in DEN/O2-treated hamster lung, suggesting that the enzyme might mediate spontaneous regression of PNEC hyperplasia. The goals of the present study were: (1) to determine whether CD10/NEP inhibition would alter the extent of PNEC hyperplasia occurring in these hamsters, and (2) to analyze cellular mechanisms potentially involved in altering numbers of PNECs in this model. We administered SCH32615 chronically to a subset of DEN/O2-treated hamsters. Immunostaining of lungs from the CD10/ NEP-inhibited subset demonstrated significant acceleration of the development of PNEC hyperplasia, increased PNEC proliferation, and diminished PNEC apoptosis as compared with animals receiving no SCH32615. These observations indicate that PNEC hyperplasia can occur as a result of multiple cellular processes, including increased neuroendocrine cell differentiation, proliferation, and survival. CD10/NEP modulates PNEC numbers primarily by promoting cell differentiation and proliferation during lung injury, probably via increasing the half-life of bioactive peptides in the lung.

Authors
Willett, CG; Shahsafei, A; Graham, SA; Sunday, ME
MLA Citation
Willett, CG, Shahsafei, A, Graham, SA, and Sunday, ME. "CD10/neutral endopeptidase inhibition augments pulmonary neuroendocrine cell hyperplasia in hamsters treated with diethylnitrosamine and hyperoxia." Am J Respir Cell Mol Biol 21.1 (July 1999): 13-20.
PMID
10385588
Source
pubmed
Published In
American journal of respiratory cell and molecular biology
Volume
21
Issue
1
Publish Date
1999
Start Page
13
End Page
20
DOI
10.1165/ajrcmb.21.1.3389

Proliferation and differentiation defects during lung development in corticotropin-releasing hormone-deficient mice.

Corticotropin-releasing hormone-deficient (CRH-KO) mice, which as a consequence are also glucocorticoid-insufficient, exhibit neonatal lethality when derived from CRH-KO mothers. Death is due to respiratory insufficiency as a result of abnormal pulmonary development, and can be prevented by prenatal administration of glucocorticoids. In the study described here, we used CRH-KO mice as a model of genetically altered in utero glucocorticoid action to elucidate the role of endogenous glucocorticoids in lung maturation. The histologic appearance of the lungs of these mice is normal until Day 17.5 of gestation, at which point failure of septal thinning and air-space formation is observed. These morphologic alterations in the CRH-KO mouse lung are the result of continued cell division in cellular compartments that by this time in gestation have ceased proliferating in wild-type mice, rather than the result of a failure of apoptosis. In accord with this observation, the CRH-KO lung exhibits delayed induction of type II pneumocyte biochemical parameters, such as messenger RNAs (mRNAs) for surfactant protein-A (SP-A) and SP-B, and fatty acid synthase, as well as delayed Clara cell maturation. In contrast, surfactant phospholipid synthesis is not impaired during CRH-KO lung development. Our findings indicate that an essential role of endogenous glucocorticoids in pulmonary maturation in utero is to stimulate a developmental program in late gestation that affects epithelial and mesenchymal cell proliferation and differentiation throughout the parenchyma.

Authors
Muglia, LJ; Bae, DS; Brown, TT; Vogt, SK; Alvarez, JG; Sunday, ME; Majzoub, JA
MLA Citation
Muglia, LJ, Bae, DS, Brown, TT, Vogt, SK, Alvarez, JG, Sunday, ME, and Majzoub, JA. "Proliferation and differentiation defects during lung development in corticotropin-releasing hormone-deficient mice." Am J Respir Cell Mol Biol 20.2 (February 1999): 181-188.
PMID
9922208
Source
pubmed
Published In
American journal of respiratory cell and molecular biology
Volume
20
Issue
2
Publish Date
1999
Start Page
181
End Page
188
DOI
10.1165/ajrcmb.20.2.3381

Regulation of the G protein Galphai2 by growth and development in fetal airway epithelium.

Heterotrimeric guanine nucleotide-binding (G) proteins transduce a wide variety of receptor-mediated signals to effectors that are involved in numerous cellular functions, including cell proliferation and differentiation. Thrombin and bombesin/gastrin-releasing peptide mediate their effects via G protein-coupled receptors to regulate lung growth and development. The growth responses of these ligands are likely to be mediated via the Gi subfamily of G proteins, specifically via Galphai2. We hypothesized that Galphai2 is expressed in the lung during ontogeny in a growth-dependent manner, and that Galphai2 regulates cell growth. We demonstrate that Galphai2 is present in the developing lung of Sprague-Dawley rats, and that its expression is enhanced between embryonic Day 19 and postnatal Day 2. The strongest expression occurs in the fetal airway epithelium, and this expression in fetal airway cells is growth-dependent. Galphai2 is localized to the plasma membrane, a location consistent with interaction with growth factor receptors. Inhibition of Gi-family signal transduction by pertussis toxin (10 ng/ml) inhibits DNA synthesis in embryonic Day 19 in fetal airway epithelium. Galphai2 is likely to be a key mediator of growth signals in the developing lung.

Authors
Kinane, TB; Komatsuzaki, K; Aleixo, MD; Sunday, ME; Ercolani, L
MLA Citation
Kinane, TB, Komatsuzaki, K, Aleixo, MD, Sunday, ME, and Ercolani, L. "Regulation of the G protein Galphai2 by growth and development in fetal airway epithelium." Am J Respir Cell Mol Biol 20.1 (January 1999): 35-42.
PMID
9870915
Source
pubmed
Published In
American journal of respiratory cell and molecular biology
Volume
20
Issue
1
Publish Date
1999
Start Page
35
End Page
42
DOI
10.1165/ajrcmb.20.1.3297

Bombesin-like peptides and receptors in normal fetal baboon lung: Roles in lung growth and maturation

Previously, we have shown that bombesin-like peptide (BLP) promotes fetal lung development in rodents and humans but mediates postnatal lung injury in hyperoxic baboons. The present study analyzed the normal ontogeny of BLP and BLP receptors as well as the effects of BLP on cultured normal fetal baboon lungs. Transcripts encoding gastrin-releasing peptide (GRP), a pulmonary BLP, were detectable on gestational day 60 (ED60), peaked on approximately ED90, and then declined before term (ED180). Numbers of BLP- immunopositive neuroendocrine cells peaked from ED80 to ED125 and declined by ED160, preceding GRP-receptor mRNAs detected from ED125 until birth. BLP (0.1-10 nM) stimulated type II cell differentiation in organ cultures as assessed by [3H]choline incorporation into surfactant phospholipids, electron microscopy, and increased surfactant protein (SP) A- and/or SP-C- immunopositive cells and SP-A mRNA. BLP also induced neuroendocrine differentiation on ED60. Cell proliferation was induced by GRP, peaking on ED90. Similarly, blocking BLP degradation stimulated lung growth and maturation, which was completely reversed by a BLP-specific antagonist. The dissociation between GRP and GRP-receptor gene expression during ontogeny suggests that novel BLP receptors and/or peptides might be implicated in these responses.

Authors
Emanuel, RL; Torday, JS; Mu, Q; Asokananthan, N; Sikorski, KA; Sunday, ME
MLA Citation
Emanuel, RL, Torday, JS, Mu, Q, Asokananthan, N, Sikorski, KA, and Sunday, ME. "Bombesin-like peptides and receptors in normal fetal baboon lung: Roles in lung growth and maturation." American Journal of Physiology - Lung Cellular and Molecular Physiology 277.5 21-5 (1999): L1003-L1017.
Source
scival
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
277
Issue
5 21-5
Publish Date
1999
Start Page
L1003
End Page
L1017

Syntaxin 1A is transiently expressed in fetal lung mesenchymal cells: Potential developmental roles

Lung development is a complex process in which epithelial-mesenchymal interactions play a key role. A conserved secretory apparatus, the soluble N- ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, is essential for exocytosis in many cell types. Syntaxins, located on the terminal plasma membrane (T-SNAREs), are a critical component of the secretosomal complex involved in vesicular docking, fusion, and exocytosis. We analyzed syntaxin 1A mRNA and protein in fetal rat lung ontogeny, demonstrating peak expression on about day 19 of embryonic development, immediately preceding type II pneumocyte differentiation. Syntaxin 1A is predominantly expressed by lipofibroblasts, which are required for bombesin- like peptide-induced surfactant phospholipid synthesis (choline uptake) by isolated type II cells. In organ cultures, anti-syntaxin 1A antibody HPC-1 blocks choline uptake both at baseline and when induced by bombesin-like peptide or dexamethasone. HPC-1 also promotes thymidine uptake in parallel in a dose-dependent fashion. These observations indicate a potential role for syntaxin 1A during fetal lung development, possibly through involvement in secretion of mesenchymal cell-derived factors that induce terminal type II cell differentiation.

Authors
Brimhall, BB; Sikorski, KA; Torday, J; Shahsafaei, A; Haley, KJ; Sunday, ME
MLA Citation
Brimhall, BB, Sikorski, KA, Torday, J, Shahsafaei, A, Haley, KJ, and Sunday, ME. "Syntaxin 1A is transiently expressed in fetal lung mesenchymal cells: Potential developmental roles." American Journal of Physiology - Lung Cellular and Molecular Physiology 277.2 21-2 (1999): L401-L411.
Source
scival
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
277
Issue
2 21-2
Publish Date
1999
Start Page
L401
End Page
L411

Bombesin-like peptide mediates lung injury in a baboon model of bronchopulmonary dysplasia.

The etiology of bronchopulmonary dysplasia (BPD), a chronic lung disease of infants surviving respiratory distress syndrome, remains fundamentally enigmatic. BPD is decreasing in severity but continues to be a major problem in pediatric medicine, being especially prevalent among very premature infants. Increased numbers of pulmonary neuroendocrine cells containing bombesin-like peptide (BLP) have been reported to occur in human infants with BPD. We tested the hypothesis that BLP mediates BPD using the hyperoxic baboon model. Urine BLP levels increased soon after birth only in 100% O2-treated 140-d animals which developed BPD, correlating closely with severity of subsequent chronic lung disease. Similar elevations in urine BLP were observed in the 125-d baboon "interrupted gestation" model of BPD. Postnatal administration of anti-BLP antibody attenuated clinical and pathological evidence of chronic lung disease in the hyperoxic baboon model. Urine BLP could be a biological predictor of infants at risk for BPD, and blocking BLP postnatally could be useful for BPD prevention.

Authors
Sunday, ME; Yoder, BA; Cuttitta, F; Haley, KJ; Emanuel, RL
MLA Citation
Sunday, ME, Yoder, BA, Cuttitta, F, Haley, KJ, and Emanuel, RL. "Bombesin-like peptide mediates lung injury in a baboon model of bronchopulmonary dysplasia." J Clin Invest 102.3 (August 1, 1998): 584-594.
PMID
9691095
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
102
Issue
3
Publish Date
1998
Start Page
584
End Page
594
DOI
10.1172/JCI2329

Tumor necrosis factor induces neuroendocrine differentiation in small cell lung cancer cell lines.

We studied tumor necrosis factor (TNF)-alpha as a candidate cytokine to promote neuroendocrine cell differentiation in a nitrosamine-hyperoxia hamster lung injury model. Differential screening identified expression of the genes modulated by TNF-alpha preceding neuroendocrine cell differentiation. Undifferentiated small cell lung carcinoma (SCLC) cell lines NCI-H82 and NCI-H526 were treated with TNF-alpha for up to 2 wk. Both cell lines demonstrated rapid induction of gastrin-releasing peptide (GRP) mRNA; H82 cells also expressed aromatic-L-amino acid decarboxylase mRNA within 5 min after TNF-alpha was added. Nuclear translocation of nuclear factor-kappaB immunostaining occurred with TNF-alpha treatment, suggesting nuclear factor-kappaB involvement in the induction of GRP and/or aromatic-L-amino acid decarboxylase gene expression. We also demonstrated dense core neurosecretory granules and immunostaining for proGRP and neural cell adhesion molecule in H82 cells after 7-14 days of TNF-alpha treatment. We conclude that TNF-alpha can induce phenotypic features of neuroendocrine cell differentiation in SCLC cell lines. Similar effects of TNF-alpha in vivo may contribute to the neuroendocrine cell differentiation/hyperplasia associated with many chronic inflammatory pulmonary diseases.

Authors
Haley, KJ; Patidar, K; Zhang, F; Emanuel, RL; Sunday, ME
MLA Citation
Haley, KJ, Patidar, K, Zhang, F, Emanuel, RL, and Sunday, ME. "Tumor necrosis factor induces neuroendocrine differentiation in small cell lung cancer cell lines." Am J Physiol 275.2 Pt 1 (August 1998): L311-L321.
PMID
9700092
Source
pubmed
Published In
The American journal of physiology
Volume
275
Issue
2 Pt 1
Publish Date
1998
Start Page
L311
End Page
L321

Inflammatory cell distribution within and along asthmatic airways.

Asthmatic airways are infiltrated with inflammatory cells that release mediators and cytokines into the microenvironment. In this study, we evaluated the distribution of CD45-positive leukocytes and eosinophils in lung tissue from five patients who died with severe asthma compared with five patients with cystic fibrosis. For morphometric analysis, the airway wall was partitioned into an "inner" area (between basement membrane and smooth muscle) and an "outer" area (between smooth muscle and alveolar attachments). Large airways (with a perimeter greater than 3.0 mm) from patients with asthma or cystic fibrosis had a greater density of CD45-positive cells (p < 0.05) and eosinophils (p < 0.001) in the inner airway region compared with the same airway region in small airways. Furthermore, in small airways, asthmatic lungs showed a greater density of CD45-positive cells (p < 0.01) and eosinophils (p < 0.01) in the outer compared with the inner airway wall region. These observations indicate that there are regional variations in inflammatory cell distribution within the airway wall in patients with asthma that are not observed in airways from patients with cystic fibrosis. We speculate that this inflammatory cell density in peripheral airways in severe asthma may relate to the peripheral airway obstruction characteristic of this condition.

Authors
Haley, KJ; Sunday, ME; Wiggs, BR; Kozakewich, HP; Reilly, JJ; Mentzer, SJ; Sugarbaker, DJ; Doerschuk, CM; Drazen, JM
MLA Citation
Haley, KJ, Sunday, ME, Wiggs, BR, Kozakewich, HP, Reilly, JJ, Mentzer, SJ, Sugarbaker, DJ, Doerschuk, CM, and Drazen, JM. "Inflammatory cell distribution within and along asthmatic airways." Am J Respir Crit Care Med 158.2 (August 1998): 565-572.
PMID
9700136
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
158
Issue
2
Publish Date
1998
Start Page
565
End Page
572
DOI
10.1164/ajrccm.158.2.9705036

Macrophage-stimulating protein and its receptor in non-small-cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration.

Previously, we identified macrophage-stimulating protein (MSP) as being expressed during hamster lung injury induced by nitrosamine carcinogens. Transient, generalized epithelial-cell hyperplasia during the preneoplastic period, and eventually nonneuroendocrine (non-NE) lung tumors, are known to develop in these nitrosamine-treated hamsters. We wished to test the hypothesis that MSP and its tyrosine kinase receptor, RON, might represent an autocrine/paracrine system involved in the pathogenesis of human nonneuroendocrine lung tumors, the non-small-cell carcinomas (NSCLCs). We found that this occurred in a paracrine fashion in three of eight primary human NSCLCs that expressed messenger RNA (mRNA) for MSP at high levels in histologically normal lung adjacent to the tumor, but not in the primary tumor, together with mRNA for RON in both normal and tumor tissue. MSP and RON could also constitute an autocrine/paracrine system in human NSCLC cell lines: five of 16 cell lines (squamous and adenosquamous) expressed both MSP and RON; and an additional five of 16 cell lines expressed RON without detectable MSP. Although three cases of primary squamous-cell carcinomas expressed MSP (two of three in the tumor and one of three in nonneoplastic lung), mRNA for RON was not detectable in these cases. RON was functional in all tested RON mRNA-positive cell lines, with exogenous MSP inducing RON-mediated tyrosine phosphorylation. Treatment of a RON-positive adenosquamous carcinoma cell line with MSP additionally resulted in increased motility in a cell-migration assay, suggesting that MSP might promote cell migration of some NSCLCs. In conclusion, MSP and RON might represent an autocrine/paracrine system involved in the pathogenesis of lung cancer, although the nature of the biologic responses in different cell types might vary considerably.

Authors
Willett, CG; Wang, MH; Emanuel, RL; Graham, SA; Smith, DI; Shridhar, V; Sugarbaker, DJ; Sunday, ME
MLA Citation
Willett, CG, Wang, MH, Emanuel, RL, Graham, SA, Smith, DI, Shridhar, V, Sugarbaker, DJ, and Sunday, ME. "Macrophage-stimulating protein and its receptor in non-small-cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration." Am J Respir Cell Mol Biol 18.4 (April 1998): 489-496.
PMID
9533936
Source
pubmed
Published In
American journal of respiratory cell and molecular biology
Volume
18
Issue
4
Publish Date
1998
Start Page
489
End Page
496
DOI
10.1165/ajrcmb.18.4.2978

Expression of v-Ha-ras driven by the calcitonin/calcitonin gene-related peptide promoter: a novel transgenic murine model for medullary thyroid carcinoma.

v-Ha-ras has been demonstrated previously to induce neuroendocrine differentiation of medullary thyroid carcinoma (MTC, malignant C cell tumor) cell lines. The potential role of ras mediated signaling in neuroendocrine cells in vivo has been investigated by expressing v-Ha-ras under control of the neural/neuroendocrine specific calcitonin/calcitonin gene-related peptide (CGRP) promoter. Five independent mouse lineages were derived following germ line insertion of the transgene. Four of the five lineages consistently express the transgene; neuroendocrine expression is found in three of the five lineages as both spliced and full length messages. Phenotypically, the mice expressing rascal have shortened lifespans primarily due to the high incidence of MTCs between 6 months to a year of age. C-cell hyperplasia is demonstrated in several mice in the absence of gross evidence of tumor formation. Histopathological and ultrastructural analyses demonstrate typical features of MTCs including prominent immunohistochemical staining for calcitonin and dense-core neurosecretory-type granules. In addition, four of 22 tumors co-express thyroglobulin (a non-neuroendocrine follicular epithelial cell marker) and calcitonin (a neuroendocrine marker) in a subset of the tumor cells. The rascal transgenic mouse provides a unique model for investigating the sequential pathogenesis of MTC and possibly also for elucidating the relationship between MTC and mixed medullary-follicular carcinomas.

Authors
Johnston, D; Hatzis, D; Sunday, ME
MLA Citation
Johnston, D, Hatzis, D, and Sunday, ME. "Expression of v-Ha-ras driven by the calcitonin/calcitonin gene-related peptide promoter: a novel transgenic murine model for medullary thyroid carcinoma." Oncogene 16.2 (January 15, 1998): 167-177.
PMID
9464534
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
16
Issue
2
Publish Date
1998
Start Page
167
End Page
177
DOI
10.1038/sj.onc.1201478

Tumor necrosis factor induces neuroendocrine differentiation in small cell lung cancer cell lines

We studied tumor necrosis factor (TNF)-α as a candidate cytokine to promote neuroendocrine cell differentiation in a nitrosamine-hyperoxia hamster lung injury model. Differential screening identified expression of the genes modulated by TNF-α preceding neuroendocrine cell differentiation. Undifferentiated small cell lung carcinoma (SCLC) cell lines NCI-H82 and NCI- H526 were treated with TNF-α for up to 2 wk. Both cell lines demonstrated rapid induction of gastrin-releasing peptide (GRP) mRNA; H82 cells also expressed aromatic-L-amino acid decarboxylase mRNA within 5 min after TNF-α was added. Nuclear translocation of nuclear factor-κB immunostaining occurred with TNF-α treatment, suggesting nuclear factor-κB involvement in the induction of GRP and/or aromatic-L-amino acid decarboxylase gene expression. We also demonstrated dense core neurosecretory granules and immunostaining for proGRP and neural cell adhesion molecule in H82 cells after 7-14 days of TNF-α treatment. We conclude that TNF-α can induce phenotypic features of neuroendocrine cell differentiation in SCLC cell lines. Similar effects of TNF-α in vivo may contribute to the neuroendocrine cell differentiation/hyperplasia associated with many chronic inflammatory pulmonary diseases.

Authors
Haley, KJ; Patidar, K; Zhang, F; Emanuel, RL; Sunday, ME
MLA Citation
Haley, KJ, Patidar, K, Zhang, F, Emanuel, RL, and Sunday, ME. "Tumor necrosis factor induces neuroendocrine differentiation in small cell lung cancer cell lines." American Journal of Physiology - Lung Cellular and Molecular Physiology 275.2 19-2 (1998): L311-L321.
Source
scival
Published In
American journal of physiology. Lung cellular and molecular physiology
Volume
275
Issue
2 19-2
Publish Date
1998
Start Page
L311
End Page
L321

Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia

The thrombospondins are a family of extracellular calcium-binding proteins that modulate cellular phenotype. Thrombospondin-1 (TSP-1) reportedly regulates cellular attachment, proliferation, migration, and differentiation in vitro. To explore its function in vivo, we have disrupted the TSP-1 gene by homologous recombination in the mouse genome. Platelets from these mice are completely deficient in TSP-1 protein; however, thrombin- induced platelet aggregation is not diminished. TSP-1-deficient mice display a mild and variable lordotic curvature of the spine that is apparent from birth. These mice also display an increase in the number of circulating white blood cells, with monocytes and eosinophils having the largest percent increases. The brain, heart, kidney, spleen, stomach, intestines, aorta, and liver of TSP-1-deficient mice showed no major abnormalities. However, consistent with high levels of expression of TSP-1 in lung, we observe abnormalities in the lungs of mice that lack the protein. Although normal at birth, histopathological analysis of lungs from 4-wk-old TSP-1-deficient mice reveals extensive acute and organizing pneumonia, with neutrophils and macrophages. The macrophages stain for hemosiderin, indicating that diffuse alveolar hemorrhage is occurring. At later times, the number of neutrophils decreases and a striking increase in the number of hemosiderin-containing macrophages is observed associated with multiple-lineage epithelial hyperplasia and the deposition of collagen and elastin. A thickening and ruffling of the epithelium of the airways results from increasing cell proliferation in TSP-1-deficient mice. These results indicate that TSP-1 is involved in normal lung homeostasis.

Authors
Lawler, J; Sunday, M; Thibert, V; Duquette, M; George, EL; Rayburn, H; Hynes, RO
MLA Citation
Lawler, J, Sunday, M, Thibert, V, Duquette, M, George, EL, Rayburn, H, and Hynes, RO. "Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia." Journal of Clinical Investigation 101.5 (1998): 982-992.
PMID
9486968
Source
scival
Published In
Journal of Clinical Investigation
Volume
101
Issue
5
Publish Date
1998
Start Page
982
End Page
992
DOI
10.1172/JCI1684

Expression of heterogeneous nuclear ribonucleoprotein A2/B1 changes with critical stages of mammalian lung development

Recent reports have demostrated a link between expression of members of the family of heterogeneous nuclear ribonucleoproteins (hnRNPs) and cancer. Overexpression of hnRNP A2/B1 correlated with the eventual development of lung cancer in three different clinical cohorts. We have studied the expression of hnRNP A2/B1 messenger RNA (mRNA) and protein during mammalian development. The expression of hnRNP A2/B1 mRNA and protein are parallel but change dynamically during critical periods in mouse pulmonary development. hnRNP A2/B1 is first detected in the lung in the early pseudoglandular period, peaks at the beginning of the canalicular period, and remains high during the saccular (alveolar) period. In mouse and rat, hnRNP A2/B1 expression is first evident in the earliest lung buds. As lung development progresses, the cuboidal epithelial cells of the distal primitive alveoli show high levels of the ribonucleoprotein, which is almost undetectable in the proximal conducting airways. The expression of hnRNP A2/ B1 is restricted in mature lung. Similar dynamic pattern of expression through lung development was also found in rat and human lung. Upregulated expression of hnRNP A2/B1 at critical periods of lung development was comparable to the level of expression found in lung cancers and preneoplastic lesions and is consistent with hnRNP A2/B1 overexpression playing an oncodevelopmental role.

Authors
Montuenga, LM; Zhou, J; Avis, I; Vos, M; Martinez, A; Cuttitta, F; Treston, AM; Sunday, M; Mulshine, JL
MLA Citation
Montuenga, LM, Zhou, J, Avis, I, Vos, M, Martinez, A, Cuttitta, F, Treston, AM, Sunday, M, and Mulshine, JL. "Expression of heterogeneous nuclear ribonucleoprotein A2/B1 changes with critical stages of mammalian lung development." American Journal of Respiratory Cell and Molecular Biology 19.4 (1998): 554-562.
PMID
9761751
Source
scival
Published In
American Journal of Respiratory Cell and Molecular Biology
Volume
19
Issue
4
Publish Date
1998
Start Page
554
End Page
562

Generation and characterization of mice lacking gastrin-releasing peptide receptor.

Gastrin-releasing peptide (GRP) is a mammalian bombesin-like peptide which is widely distributed in the central nervous system as well as in the gastrointestinal tract. GRP binds to its high affinity receptor (GRPR) to elicit a wide spectrum of biological effects on behavior, digestion, and metabolism. To define the in vivo function of GRPR, we generated GRPR null mutant mice by gene targeting. The intracerebroventricular administration of GRP caused hypothermia in wild-type mice, but not in mutant mice. The GRPR deficient mice showed significantly increased locomotor activity during the dark period, and social responses scored by sniffing, mounting, and approaching behaviors against an intruder. Aggressive scores such as fighting and biting were not altered in the mutant mice. These phenotypes were observed in mice generated from two independent ES cell clones and backcrossed to a C57BL/6J background. The GRPR deficient mice should be useful for studying the bombesin system in vivo.

Authors
Wada, E; Watase, K; Yamada, K; Ogura, H; Yamano, M; Inomata, Y; Eguchi, J; Yamamoto, K; Sunday, ME; Maeno, H; Mikoshiba, K; Ohki-Hamazaki, H; Wada, K
MLA Citation
Wada, E, Watase, K, Yamada, K, Ogura, H, Yamano, M, Inomata, Y, Eguchi, J, Yamamoto, K, Sunday, ME, Maeno, H, Mikoshiba, K, Ohki-Hamazaki, H, and Wada, K. "Generation and characterization of mice lacking gastrin-releasing peptide receptor." Biochem Biophys Res Commun 239.1 (October 9, 1997): 28-33.
PMID
9345264
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
239
Issue
1
Publish Date
1997
Start Page
28
End Page
33
DOI
10.1006/bbrc.1997.7418

Differential screening of a human chromosome 3 library identifies hepatocyte growth factor-like/macrophage-stimulating protein and its receptor in injured lung. Possible implications for neuroendocrine cell survival.

Transient pulmonary neuroendocrine cell hyperplasia and non-neuroendocrine lung tumors develop in nitrosaminetreated hamsters, which we hypothesized might modulate epithelial cell phenotype by expressing gene(s) homologous to human chromosome 3p gene(s) deleted in small cell carcinoma of the lung (SCLC). We differentially screened a chromosome 3 library using nitrosamine-treated versus normal hamster lung cDNAs and identified hepatocyte growth factor-like/macrophage-stimulating protein (HGFL/MSP) in injured lung. HGFL/MSP mRNA is low to undetectable in human SCLC and carcinoid tumors, but the HGFL/MSP tyrosine kinase receptor, RON, is present and functional on many of these neuroendocrine tumors. In H835, a pulmonary carcinoid cell line, and H187, a SCLC cell line, HGFL/ MSP induced adhesion/flattening and apoptosis. Using viable cell counts to assess proliferation after 14 d of treatment with HGFL/MSP, there is growth inhibition of H835 but not H187. Nitrosamine-treated hamsters also demonstrate pulmonary neuroendocrine cell apoptosis in situ during the same time period as expression of the endogenous HGFL/ MSP gene, immediately preceding the spontaneous regression of neuroendocrine cell hyperplasia. These observations suggest that HGFL/MSP might regulate neuroendocrine cell survival during preneoplastic lung injury, which could influence the ultimate tumor cell phenotype.

Authors
Willett, CG; Smith, DI; Shridhar, V; Wang, MH; Emanuel, RL; Patidar, K; Graham, SA; Zhang, F; Hatch, V; Sugarbaker, DJ; Sunday, ME
MLA Citation
Willett, CG, Smith, DI, Shridhar, V, Wang, MH, Emanuel, RL, Patidar, K, Graham, SA, Zhang, F, Hatch, V, Sugarbaker, DJ, and Sunday, ME. "Differential screening of a human chromosome 3 library identifies hepatocyte growth factor-like/macrophage-stimulating protein and its receptor in injured lung. Possible implications for neuroendocrine cell survival." J Clin Invest 99.12 (June 15, 1997): 2979-2991.
PMID
9185522
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
99
Issue
12
Publish Date
1997
Start Page
2979
End Page
2991
DOI
10.1172/JCI119493

Comparison of the ontogeny of protein gene product 9.5, chromogranin A and proliferating cell nuclear antigen in developing human lung

Pulmonary neuroendocrine cell products, especially bombesin-like peptides, are important modulators of fetal lung growth, morphogenesis and maturation. In the present study, we describe the ontogeny of protein gene product 9.5 (PGP 9.5) in 28 midtrimester human fetal lungs, in comparison to chromogranin A (CGA), a marker of differentiated neuroendocrine cells, and proliferating cell nuclear antigen (PCNA), which is expressed by actively dividing cells. PGP 9.5 immunostaining colocalized with CGA in many cells, although the peak abundance of PGP 9.5 preceded that of CGA by 4 to 6 weeks. In addition, a novel staining pattern was noted for PGP 9.5: diffuse cytoplasmic staining of undifferentiated epithelial cells, which was demonstrated by all of the airways before 15 weeks gestation. After gestational week 15, only the smallest airways demonstrated this pattern. PCNA immunostaining demonstrated age-dependent regional variation. All samples had approximately 25% epithelial cells immunopositive for PCNA. Between 11 and 14 weeks gestation over 50% of the mesenchymal cells were PCNA positive. This mesenchymal staining decreased after 14 weeks, and was rare by week 19. There was no definite correlation between the immunostaining for PGP 9.5 and that for PCNA, although PGP 9.5 positive cells were usually PCNA negative. These observations suggest that other growth factors produced by non-neuroendocrine epithelial cells also participate in lung development.

Authors
Haley, KJ; Drazen, JM; Osathanondh, R; Sunday, ME
MLA Citation
Haley, KJ, Drazen, JM, Osathanondh, R, and Sunday, ME. "Comparison of the ontogeny of protein gene product 9.5, chromogranin A and proliferating cell nuclear antigen in developing human lung." Microscopy Research and Technique 37.1 (April 1, 1997): 62-68.
Source
scopus
Published In
Microscopy Research and Technique
Volume
37
Issue
1
Publish Date
1997
Start Page
62
End Page
68
DOI
10.1002/(SICI)1097-0029(19970401)37:1<62::AID-JEMT6>3.0.CO;2-Y

Comparison of the ontogeny of protein gene product 9.5, chromogranin A and proliferating cell nuclear antigen in developing human lung.

Pulmonary neuroendocrine cell products, especially bombesin-like peptides, are important modulators of fetal lung growth, morphogenesis and maturation. In the present study, we describe the ontogeny of protein gene product 9.5 (PGP 9.5) in 28 midtrimester human fetal lungs, in comparison to chromogranin A (CGA), a marker of differentiated neuroendocrine cells, and proliferating cell nuclear antigen (PCNA), which is expressed by actively dividing cells. PGP 9.5 immunostaining colocalized with CGA in many cells, although the peak abundance of PGP 9.5 preceded that of CGA by 4 to 6 weeks. In addition, a novel staining pattern was noted for PGP 9.5: diffuse cytoplasmic staining of undifferentiated epithelial cells, which was demonstrated by all of the airways before 15 weeks gestation. After gestational week 15, only the smallest airways demonstrated this pattern. PCNA immunostaining demonstrated age-dependent regional variation. All samples had approximately 25% epithelial cells immunopositive for PCNA. Between 11 and 14 weeks gestation over 50% of the mesenchymal cells were PCNA positive. This mesenchymal staining decreased after 14 weeks, and was rare by week 19. There was no definite correlation between the immunostaining for PGP 9.5 and that for PCNA, although PGP 9.5 positive cells were usually PCNA negative. These observations suggest that other growth factors produced by non-neuroendocrine epithelial cells also participate in lung development.

Authors
Haley, KJ; Drazen, JM; Osathanondh, R; Sunday, ME
MLA Citation
Haley, KJ, Drazen, JM, Osathanondh, R, and Sunday, ME. "Comparison of the ontogeny of protein gene product 9.5, chromogranin A and proliferating cell nuclear antigen in developing human lung." Microsc Res Tech 37.1 (April 1, 1997): 62-68.
PMID
9144622
Source
pubmed
Published In
Microscopy Research and Technique
Volume
37
Issue
1
Publish Date
1997
Start Page
62
End Page
68
DOI
10.1002/(SICI)1097-0029(19970401)37:1<62::AID-JEMT6>3.0.CO;2-Y

Comparison of the ontogeny of protein gene product 9.5, chromogranin A and proliferating cell nuclear antigen in developing human lung.

Pulmonary neuroendocrine cell products, especially bombesin-like peptides, are important modulators of fetal lung growth, morphogenesis and maturation. In the present study, we describe the ontogeny of protein gene product 9.5 (PGP 9.5) in 28 midtrimester human fetal lungs, in comparison to chromogranin A (CGA), a marker of differentiated neuroendocrine cells, and proliferating cell nuclear antigen (PCNA), which is expressed by actively dividing cells. PGP 9.5 immunostaining colocalized with CGA in many cells, although the peak abundance of PGP 9.5 preceded that of CGA by 4 to 6 weeks. In addition, a novel staining pattern was noted for PGP 9.5: diffuse cytoplasmic staining of undifferentiated epithelial cells, which was demonstrated by all of the airways before 15 weeks gestation. After gestational week 15, only the smallest airways demonstrated this pattern. PCNA immunostaining demonstrated age-dependent regional variation. All samples had approximately 25% epithelial cells immunopositive for PCNA. Between 11 and 14 weeks gestation over 50% of the mesenchymal cells were PCNA positive. This mesenchymal staining decreased after 14 weeks, and was rare by week 19. There was no definite correlation between the immunostaining for PGP 9.5 and that for PCNA, although PGP 9.5 positive cells were usually PCNA negative. These observations suggest that other growth factors produced by non-neuroendocrine epithelial cells also participate in lung development.

Authors
Haley, KJ; Drazen, JM; Osathanondh, R; Sunday, ME
MLA Citation
Haley, KJ, Drazen, JM, Osathanondh, R, and Sunday, ME. "Comparison of the ontogeny of protein gene product 9.5, chromogranin A and proliferating cell nuclear antigen in developing human lung." Microscopy research and technique 37.1 (April 1997): 62-68. (Academic Article)
Source
manual
Published In
Microscopy Research and Technique
Volume
37
Issue
1
Publish Date
1997
Start Page
62
End Page
68
DOI
10.1002/(SICI)1097-0029(19970401)37:13.0.CO;2

An intrinsic adrenergic system in mammalian heart.

We have identified a previously undescribed intrinsic cardiac adrenergic (ICA) cell type in rodent and human heart. Northern and Western blot analyses demonstrated that ICA cell isolates contain mRNA and protein of enzymes involved in catecholamine biosynthesis. Radioenzymatic catecholamine assays also revealed that the catecholamine profile of adult rat ICA cell isolates differed from that of sympathetic neurons. Unlike sympathetic neuronal cells, isolated ICA cells have abundant clear vesicles on electron microscopy. Endogenous norepinephrine and epinephrine constitutively released by ICA cells in vitro affect the spontaneous beating rate of neonatal rat cardiac myocytes in culture. Finally, ICA cells could be identified in human fetal hearts at a developmental stage before sympathetic innervation of the heart has been documented to occur. These findings support the concept that these cells constitute an ICA signaling system capable of participating in cardiac regulation that appears to be independent of sympathetic innervation.

Authors
Huang, MH; Friend, DS; Sunday, ME; Singh, K; Haley, K; Austen, KF; Kelly, RA; Smith, TW
MLA Citation
Huang, MH, Friend, DS, Sunday, ME, Singh, K, Haley, K, Austen, KF, Kelly, RA, and Smith, TW. "An intrinsic adrenergic system in mammalian heart." J Clin Invest 98.6 (September 15, 1996): 1298-1303.
PMID
8823294
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
98
Issue
6
Publish Date
1996
Start Page
1298
End Page
1303
DOI
10.1172/JCI118916

Embryonic mouse lung epithelial progenitor cells co-express immunohistochemical markers of diverse mature cell lineages.

Developmental expression of marker genes representative of different mature cell types can be used to study differentiation of cell lineages. We used immunohistochemistry to study expression in developing mouse lung of calcitonin gene-related peptide (CGRP), Clara cell 10-KD protein (CC10), and surfactant protein-A (SP-A), markers that are differentially expressed in neuroendocrine cells, Clara cells, and Type II alveolar cells. Two distinct developmental phases were revealed. The earlier phase (embryonic days 13-15; E13-E15) was characterized by CGRP, CC10, and SP-A immunostaining in all epithelial cells of the distal airways, with the three patterns being virtually identical in adjacent sections. The later phase (E16-E18) was characterized by emergence of staining of the differentiated cell types. These expression patterns were recapitulated in serumless organ culture, demonstrating that information necessary to generate both phases of gene expression is present within the lung analage by E11. We conclude that CGRP, CC10, and SP-A are co-expressed in most or all cells of the distal lung epithelium at E13-E15 and later become restricted to different cell lineages. This transient expression in progenitor cells of gene products characteristic of diverse differentiated cell types may reflect an underlying mechanism of gene regulation.

Authors
Wuenschell, CW; Sunday, ME; Singh, G; Minoo, P; Slavkin, HC; Warburton, D
MLA Citation
Wuenschell, CW, Sunday, ME, Singh, G, Minoo, P, Slavkin, HC, and Warburton, D. "Embryonic mouse lung epithelial progenitor cells co-express immunohistochemical markers of diverse mature cell lineages." J Histochem Cytochem 44.2 (February 1996): 113-123.
PMID
8609367
Source
pubmed
Published In
Journal of Histochemistry and Cytochemistry
Volume
44
Issue
2
Publish Date
1996
Start Page
113
End Page
123

Pulmonary Neuroendocrine Cells and Lung Development.

Pulmonary neuroendocrine cells produce bioactive peptides such as gastrin-releasing peptide (GRP) at high levels in developing fetal lung. The role of GRP and other peptides in promoting branching morphogenesis, cell proliferation, and cell differentiation during lung organogenesis is reviewed. Possible roles for bioactive peptides derived from these cells in the pathophysiology of perinatal lung disorders are discussed.

Authors
Sunday, ME
MLA Citation
Sunday, ME. "Pulmonary Neuroendocrine Cells and Lung Development." Endocr Pathol 7.3 (1996): 173-201.
PMID
12114731
Source
pubmed
Published In
Endocrine Pathology
Volume
7
Issue
3
Publish Date
1996
Start Page
173
End Page
201

Neuroendocrine (ne) cell hyperplasia and non-ne tumors in transgenic mice with v-ha-ras driven by the calcitonin promoter

Ras mediated signalling can play a role in ME cell differentiation: transfection of v-Ha-ras into cultured NE tumor cells induces NE cell or non-NE features. We have generated transgenic mice with v-Ha-ras driven by the neural/NE-specific cjdcitonin/calcitonin gene-related peptide (CGRP) promoter. 5 "RASCAL" transgenic mouse lineages have been derived; transgene expression is strongest in thyroid and lung. Morphometric analyses of CGRP immunostained lung tissues from 23 RASCALs and 20 normal littermates demonstrated pulmonary NE cell hyperplasia, with a 3X increase in the mean number of CGRP-positive ecus per cm. of airway epithelium in RASCALs as compared to normals (65 ±17 versus 23 ±9, p = 0.04); 3 of these RASCALs had profound NE cell hyperplasia with >100 CGRP+ cells/cm. At autopsy of over 500 mice, 7 primary lung tumors were detected. 6 of these tumors were in RASCALs. Immunostaining demonstrated the type n cell marker SP-C in 4/6 tumors, the Clara cell specific antigen CC10 in 1/6, and the NE cell marker PGP9.5 in 1/6; 4/6 of the tumors were also mucin positive. Only one normal littermate had a microadenoma. Over 75% of mice also develop medullary thyroid (NE) carcinomas, 10% of which have both follicular (non-NE) and NE differentiation. In conclusion, in some animals, v-Ha-ras expression may occur in a bipotential stem cell which leads to both ME and non-NE epithelial cell hyperplasia or neoplasia.

Authors
Sunday, ME; Mu, Q; Fishman, M; Hatzis, D
MLA Citation
Sunday, ME, Mu, Q, Fishman, M, and Hatzis, D. "Neuroendocrine (ne) cell hyperplasia and non-ne tumors in transgenic mice with v-ha-ras driven by the calcitonin promoter." FASEB Journal 10.6 (1996): A1145-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
A1145

Glucose-dependent insulinotropic peptide (GIP) gene expression in the rat salivary gland.

Previous studies have indicated that following nutrient ingestion, GIP is released principally from the upper small intestine. In addition to its presence in the rat small intestine, GIP transcripts have also been localized to the submandibular salivary gland (SSG). The present studies were directed to further characterize expression of the GIP gene in the SSG. Pregnant rats were sacrificed at gestational days 18 and 20, followed by the removal of rat fetuses. The duodenum pancreas, and SSG were then excised from the fetuses, as well as from neonatal pups at ages 1, 3, 7, 10, 14, and 21 days. RNA was extracted and measured by Northern blot analysis using specific rat GIP probes. GIP transcripts were first detected in the duodenum in the 18-day fetus and reached maximum levels at birth. In contrast, GIP mRNA was not observed in the SSG until 10 days postnatally and was not detected at all in either the fetal or neonatal pancreas. In situ hybridization of the SSG using an 35S-labelled antisense GIP RNA probe demonstrated expression of the GIP gene to be limited to ductal cells, with no transcripts present in acini. In separate experiments, rats fasted overnight were given water or 10% glucose. While no changes were detected in water-fed rats following oral glucose ingestion, small, but significant increases in SSG GIP gene expression were detected at 60 and 240 min. The results of these initial studies suggest the possibility of a functional role for GIP in the rat salivary gland by the demonstration of GIP mRNA in the SSG by Northern analysis and in situ hybridization, as well as by an increase in SSG GIP gene expression following a glucose meal.

Authors
Tseng, CC; Boylan, MO; Jarboe, LA; Williams, EK; Sunday, ME; Wolfe, MM
MLA Citation
Tseng, CC, Boylan, MO, Jarboe, LA, Williams, EK, Sunday, ME, and Wolfe, MM. "Glucose-dependent insulinotropic peptide (GIP) gene expression in the rat salivary gland." Mol Cell Endocrinol 115.1 (November 30, 1995): 13-19.
PMID
8674860
Source
pubmed
Published In
Molecular and Cellular Endocrinology
Volume
115
Issue
1
Publish Date
1995
Start Page
13
End Page
19

Differential display RT-PCR for identifying novel gene expression in the lung.

The unique identity of each cell is the result of differential gene expression. A new strategy for differential cDNA screening introduced by Liang and Pardee utilizes anchored oligo-dT primers and random 5' oligonucleotide 10-mers to carry out polymerase chain reaction (PCR) on reverse-transcribed RNA from different cell populations. The amplified cDNAs are displayed on a standard sequencing gel as 100-500 bands per lane on the resulting autoradiograms and comparisons are drawn between the different cell populations. The major advantages of this method over previous differential screening approaches are its high sensitivity, the small amounts of tissue required, and the ability to carry out rapid mRNA analyses using total RNA and to test multiple tissues in parallel. Its limitations are the need for many primer combinations for adequate representation of mRNAs and the large number of bands displayed. A screening strategy should include multiple positive and negative control samples and Northern blots to identify cDNAs differentially expressed. This approach should facilitate the identification of many novel genes expressed in a variety of physiological and pathological conditions.

Authors
Sunday, ME
MLA Citation
Sunday, ME. "Differential display RT-PCR for identifying novel gene expression in the lung." Am J Physiol 269.3 Pt 1 (September 1995): L273-L284. (Review)
PMID
7573459
Source
pubmed
Published In
The American journal of physiology
Volume
269
Issue
3 Pt 1
Publish Date
1995
Start Page
L273
End Page
L284

Histochemical characterization of non-neuroendocrine tumors and neuroendocrine cell hyperplasia induced in hamster lung by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone with or without hyperoxia.

Lung tumors induced by 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) with or without hyperoxia have frequent K-ras mutations but only rare p53 mutations, suggesting that this may be a model for non-small cell lung cancers. The goals of the present study were (1) to characterize the histopathology of lung tumors induced in hamsters by NNK with or without O2 and (2) as a corollary, to quantitate the pulmonary neuroendocrine cell hyperplasia in the different treatment groups early and late in the treatment period. Lung tumors induced by NNK with or without O2 were 71% adenomas, 22% adenocarcinomas, approximately 4% bronchoalveolar carcinomas, and approximately 4% squamous/adenosquamous carcinomas. One-half of all tumors were positive for the Clara cell antigen CC10 and 21% of NNK-induced tumors were mucin positive, compared with 2% of NNK/O2-induced tumors (P = 0.003). Immunostaining for PGP9.5 was positive in 5% of tumors induced by NNK alone, but in none of NNK/O2-induced tumors (P = 0.024). Abundant proliferating cell nuclear antigen occurred in 55% of NNK-induced tumors, compared with 19% of NNK/O2-induced tumors (P = 0.009). These data indicate that NNK with or without O2 induces non-neuroendocrine lung tumors. Hyperoxia appears to inhibit cell proliferation and suppress mucinous and partial neuroendocrine differentiation in some of these tumors.

Authors
Sunday, ME; Willett, CG; Graham, SA; Oreffo, VI; Linnoila, RI; Witschi, H
MLA Citation
Sunday, ME, Willett, CG, Graham, SA, Oreffo, VI, Linnoila, RI, and Witschi, H. "Histochemical characterization of non-neuroendocrine tumors and neuroendocrine cell hyperplasia induced in hamster lung by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone with or without hyperoxia." Am J Pathol 147.3 (September 1995): 740-752.
PMID
7677185
Source
pubmed
Published In
The American journal of pathology
Volume
147
Issue
3
Publish Date
1995
Start Page
740
End Page
752

Bombesin and [Leu8]phyllolitorin promote fetal mouse lung branching morphogenesis via a receptor-mediated mechanism.

Pulmonary neuroendocrine cells are localized predominantly at airway branchpoints. Previous work showed that gastrin-releasing peptide (GRP), a major pulmonary bombesin-like peptide, occurred in neuroendocrine cells exclusively in branching human fetal airways. We now demonstrate that GRP and GRP receptor genes are expressed in fetal mouse lung as early as embryonic day 12 (E12), when lung buds are beginning to branch. By in situ hybridization, GRP receptor transcripts were at highest levels in mesenchymal cells at cleft regions of branching airways and blood vessels. To explore the possibility that bombesin-like peptides might play a role in branching morphogenesis, E12 lung buds were cultured for 48 hr in serum-free medium. In the presence of 0.10-10 microM bombesin, branching was significantly augmented as compared with control cultures, with a peak of 94% above control values at 1 microM (P < 0.005). The bombesin receptor antagonist [Leu13- psi(CH2NH)Leu14]bombesin alone (100 nM) had no effect on baseline branching but completely abolished bombesin-induced branching. A bombesin-related peptide, [Leu8]phyllolitorin also increased branching (65% above control values at 10 nM, P < 0.005). [Leu8]Phyllolitorin also significantly augmented thymidine incorporation in cultured lung buds. Fibronectin, which is abundant at branchpoints, induces GRP gene expression in undifferentiated cell lines. These observations suggest that BLPs secreted by pulmonary neuroendocrine cells may contribute to lung branching morphogenesis. Furthermore, components of branchpoints may induce pulmonary neuroendocrine cell differentiation as part of a positive feedback loop, which could account in part for the high prevalence of these cells at branchpoints.

Authors
King, KA; Torday, JS; Sunday, ME
MLA Citation
King, KA, Torday, JS, and Sunday, ME. "Bombesin and [Leu8]phyllolitorin promote fetal mouse lung branching morphogenesis via a receptor-mediated mechanism." Proc Natl Acad Sci U S A 92.10 (May 9, 1995): 4357-4361.
PMID
7753811
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
92
Issue
10
Publish Date
1995
Start Page
4357
End Page
4361

Primary and Secondary Prevention of Lung Cancer: an International Association for the Study of Lung Cancer workshop.

Authors
Battey, JF; Brown, PH; Gritz, ER; Hong, WK; Johnson, BE; Karp, DD; Mulshine, JL; Shaw, GL; Shopland, DR; Sunday, ME
MLA Citation
Battey, JF, Brown, PH, Gritz, ER, Hong, WK, Johnson, BE, Karp, DD, Mulshine, JL, Shaw, GL, Shopland, DR, and Sunday, ME. "Primary and Secondary Prevention of Lung Cancer: an International Association for the Study of Lung Cancer workshop." Lung Cancer 12.1-2 (March 1995): 91-103.
PMID
7600036
Source
pubmed
Published In
Lung Cancer
Volume
12
Issue
1-2
Publish Date
1995
Start Page
91
End Page
103

Differential display RT-PCR for identifying novel gene expression in the lung

The unique identity of each cell is the result of differential gene expression. A new strategy for differential cDNA screening introduced by Liang and Pardee utilizes anchored oligo-dT primers and random 5' oligonucleotide 10-mers to carry out polymerase chain reaction (PCR) on reverse-transcribed RNA from different cell populations. The amplified cDNAs are displayed on a standard sequencing gel as 100-500 bands per lane on the resulting autoradiograms and comparisons are drawn between the different cell populations. The major advantages of this method over previous differential screening approaches are its high sensitivity, the small amounts of tissue required, and the ability to carry out rapid mRNA analyses using total RNA and to test multiple tissues in parallel. Its limitations are the need for many primer combinations for adequate representation of mRNAs and the large number of bands displayed. A screening strategy should include multiple positive and negative control samples and Northern blots to identify cDNAs differentially expressed. This approach should facilitate the identification of many novel genes expressed in a variety of physiological and pathological conditions.

Authors
Sunday, ME
MLA Citation
Sunday, ME. "Differential display RT-PCR for identifying novel gene expression in the lung." American Journal of Physiology - Lung Cellular and Molecular Physiology 269.3 13-3 (1995): L273-L284.
Source
scival
Published In
American Journal of Physiology - Lung Cellular and Molecular Physiology
Volume
269
Issue
3 13-3
Publish Date
1995
Start Page
L273
End Page
L284

Stromelysin-3 is overexpressed by stromal elements in primary non-small cell lung cancers and regulated by retinoic acid in pulmonary fibroblasts

Stromelysin-3 (STR-3) is a recently characterized matrix metalloproteinase (MMP) that was cloned on the basis of differential expression in benign and malignant breast tumors. This MMP has a unique processing mechanism and substrate specificity. Unlike previously characterized MMPs that are secreted as inactive zymogens, STR-3 is processed within the constitutive secretory pathway and secreted as an active enzyme. Although STR-3 has a characteristic MMP structure, the enzyme does not hydrolyze many of the extracellular matrix components that are substrates for other MMPs. However, STR-3 cleaves certain serine protease inhibitors (serpins), including the α1 proteinase inhibitor (α1 anti-trypsin). Because α1 proteinase inhibitor deficiency has a known pathogenetic role in pulmonary disease, the role of STR-3 in non-small cell lung carcinomas (NSCLC) is of great interest. STR-3, transcripts and protein were significantly more abundant in primary NSCLC than in adjacent normal lung specimens in an extensive panel of stage I-III squamous cell and adenocarcinomas. The major form of STR-3 detectable in the primary NSCLC was the mature fully processed active enzyme. STR-3 transcripts and protein were primarily localized to NSCLC stromal elements, prompting analysis of STR-3 induction in normal pulmonary fibroblasts. Although STR-3 could be induced in normal pulmonary fibroblasts with growth factors (basic fibroblast growth factor and platelet-derived growth factor) and/or 12-O-tetradecanoylphorbol- 13-acetate, STR-3 induction was inhibited by all-trans retinoic acid, a commonly used chemopreventive agent for aerodigestive tract malignancies. Taken together, these data suggest that STR-3 may be a novel marker and potential therapeutic target in NSCLC.

Authors
Anderson, IC; Sugarbaker, DJ; Ganju, RK; Tsarwhas, DG; Richards, WG; Sunday, M; Kobzik, L; Shipp, MA
MLA Citation
Anderson, IC, Sugarbaker, DJ, Ganju, RK, Tsarwhas, DG, Richards, WG, Sunday, M, Kobzik, L, and Shipp, MA. "Stromelysin-3 is overexpressed by stromal elements in primary non-small cell lung cancers and regulated by retinoic acid in pulmonary fibroblasts." Cancer Research 55.18 (1995): 4120-4126.
PMID
7664289
Source
scival
Published In
Cancer Research
Volume
55
Issue
18
Publish Date
1995
Start Page
4120
End Page
4126

Modulation of oncogene and tumor suppressor gene expression in a hamster model of chronic lung injury with varying degrees of pulmonary neuroendocrine cell hyperplasia.

BACKGROUND: Intense pulmonary neuroendocrine cell (PNEC) hyperplasia occurs during preneoplastic lung injury in hamsters treated with diethylnitrosamine (DEN) plus hyperoxia. Alterations in oncogene and tumor suppressor gene expression during this process have not been explored. EXPERIMENTAL DESIGN: Our goals were: (a) to analyze expression of genes potentially involved in growth and differentiation of PNECs and/or nonneuroendocrine pulmonary epithelial cells (non-PNECs) in hamsters treated for up to 20 weeks with hyperoxia and DEN or the major tobacco-derived nitrosamine, 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK); and (b) as a corollary, to determine which cells were most mitotically active by immunostaining for c-myc and proliferating cell nuclear antigen. RESULTS: Immunohistochemical analyses demonstrated intense PNEC hyperplasia after treatment with either DEN/O2 or NNK/O2. Whereas DEN/O2-induced PNEC hyperplasia spontaneously regressed, NNK/O2-induced PNEC hyperplasia continued to increase up to 20 weeks. Rb transcripts were decreased similarly in lungs from all treatment groups (NNK/O2 = DEN/O2 = DEN alone) in spite of large differences in PNEC hyperplasia between these groups. c-myc was overexpressed in lungs from animals treated with NNK/O2, DEN/O2 and DEN alone, in which c-myc protein immunostaining occurred predominantly in non-PNECs. Proliferating cell nuclear antigen immunostaining confirmed that non-PNECs were most mitotically active. CONCLUSIONS: These data indicate that PNEC hyperplasia is primarily due to PNEC differentiation, suggesting that this model is ideal for studying mechanisms of neuroendocrine differentiation. Paracrine effects of PNEC-derived growth factors may then contribute to dysregulation of non-PNEC growth preceding the ultimate development of non-neuroendocrine lung tumors in nitrosamine-treated hamsters.

Authors
Sunday, ME; Willett, CG; Patidar, K; Graham, SA
MLA Citation
Sunday, ME, Willett, CG, Patidar, K, and Graham, SA. "Modulation of oncogene and tumor suppressor gene expression in a hamster model of chronic lung injury with varying degrees of pulmonary neuroendocrine cell hyperplasia." Lab Invest 70.6 (June 1994): 875-888.
PMID
8015292
Source
pubmed
Published In
Laboratory Investigation
Volume
70
Issue
6
Publish Date
1994
Start Page
875
End Page
888

CD10/NEP in non-small cell lung carcinomas: Relationship to cellular proliferation

The cell surface metalloproteinase CD10/neutral endopeptidase 24.11 (NEP) hydrolyzes a variety of peptide substrates and reduces cellular responses to specific peptide hormones. Because CD10/NEP modulates peptide-mediated proliferation of small cell carcinomas of the lung (SCLC) and normal fetal bronchial epithelium, we evaluated the enzyme's expression in non-small cell lung carcinomas (NSCLC). Bronchoalveolar and large cell carcinoma cell lines had low levels of CD10/NEP expression whereas squamous, adenosquamous, and adenocarcinoma cell lines had higher and more variable levels of the cell surface enzyme. Regional variations in CD10/NEP immunostaining in primary NSCLC specimens prompted us to correlate CD10/NEP expression with cell growth. In primary carcinomas of the lung, clonal NSCLC cell lines and SV40-transformed fetal airway epithelium, subsets of cells expressed primarily CD10/NEP or the proliferating cell nuclear antigen (PCNA). Cultured airway epithelial cells had the lowest levels of CD10/NEP expression when the highest percentage of cells were actively dividing; in addition, these cells grew more rapidly when cell surface CD10/NEP was inhibited. NSCLC cell lines had receptors for a variety of mitogenic peptides known to be CD10/NEP substrates, underscoring the functional significance of growth-related variability in CD10/NEP expression.

Authors
Ganju, RK; Sunday, M; Tsarwhas, DG; Card, A; Shipp, MA
MLA Citation
Ganju, RK, Sunday, M, Tsarwhas, DG, Card, A, and Shipp, MA. "CD10/NEP in non-small cell lung carcinomas: Relationship to cellular proliferation." Journal of Clinical Investigation 94.5 (1994): 1784-1791.
PMID
7962523
Source
scival
Published In
Journal of Clinical Investigation
Volume
94
Issue
5
Publish Date
1994
Start Page
1784
End Page
1791
DOI
10.1172/JCI117526

CD10/neutral endopeptidase 24.11 regulates fetal lung growth and maturation in utero by potentiating endogenous bombesin-like peptides.

Bombesin-like peptides (BLPs) are mitogens for bronchial epithelial cells and small cell lung carcinomas, and increase fetal lung growth and maturation in utero and in organ cultures. BLPs are hydrolyzed by the enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP) which is expressed in bronchial epithelium and functions to inhibit BLP-mediated growth of small cell lung carcinomas. To determine whether CD10/NEP regulates peptide-mediated lung development, we administered a specific CD10/NEP inhibitor, SCH32615, to fetal mice in utero from gestational days e15-17. Fetal lung tissues were evaluated on e18 for: (a) growth using [3H]thymidine incorporation into nuclear DNA; and (b) maturation using: [3H]-choline incorporation into surfactant phospholipids, electron microscopy for type II pneumocytes, and Northern blot analyses for surfactant apoproteins A, B, and C. Inhibition of CD10/NEP stimulated [3H]thymidine incorporation into DNA (70% above baseline, P < 0.005), [3H]choline incorporation into surfactant phospholipids (38% above baseline, P < 0.005), increased numbers of type II pneumocytes (36% above baseline, P = 0.07), and fivefold higher surfactant protein A transcripts (P < 0.05). CD10/NEP-mediated effects were completely blocked by the specific bombesin receptor antagonist, [D-Phe12, Leu14]bombesin. These observations suggest that CD10/NEP regulates fetal lung growth and maturation mediated by endogenous BLPs.

Authors
King, KA; Hua, J; Torday, JS; Drazen, JM; Graham, SA; Shipp, MA; Sunday, ME
MLA Citation
King, KA, Hua, J, Torday, JS, Drazen, JM, Graham, SA, Shipp, MA, and Sunday, ME. "CD10/neutral endopeptidase 24.11 regulates fetal lung growth and maturation in utero by potentiating endogenous bombesin-like peptides." J Clin Invest 91.5 (May 1993): 1969-1973.
PMID
8486767
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
91
Issue
5
Publish Date
1993
Start Page
1969
End Page
1973
DOI
10.1172/JCI116417

Anti-bombesin monoclonal antibodies modulate fetal mouse lung growth and maturation in utero and in organ cultures.

Fetal pulmonary neuroendocrine cells (PNECs) contain abundant gastrin-releasing peptide (GRP, mammalian bombesin-like peptide [BLP]). Previously, addition of bombesin resulted in increased fetal lung growth and maturation in utero and in organ cultures. A monoclonal antibody (mAb) to bombesin (2A11) blocked baseline automaturation of lung organ cultures in serum-free medium. In the present study, we analyze lung development following daily in utero administration of 2A11 from gestational days 15-18. Fetal lung treated with 2A11 and then harvested on day 18 demonstrated a dose-dependent decrease in surfactant phospholipid synthesis compared to controls treated with MOPC, an unreactive mAb. However, 2A11-treated fetal lung harvested on day 17 showed paradoxical increases in 3H-choline incorporation into saturated phosphatidylcholine, 3H-thymidine incorporation into DNA, and relative numbers of differentiated type II pneumocytes. In serum-containing day 17 lung organ cultures, 2A11 stimulated choline and thymidine incorporation. Since epidermal growth factor (EGF) is the only agent besides bombesin known to stimulate both fetal lung growth and maturation, we added EGF to serum-free cultures and reconstituted the stimulatory effects. A murine EGF receptor mAb (ERA) blocked 2A11-induced lung growth and maturation in serum-containing cultures, and this effect was overcome by adding EGF. In vivo, ERA also blocked stimulatory effects of 2A11 in fetal lung on day 17. These observations suggest that EGF receptor up-regulation may maintain lung growth and maturation if BLP levels are diminished on day 17. Nonetheless, BLPs appear to be involved in lung maturation on day 18, supporting a role for PNECs in normal lung development.

Authors
Sunday, ME; Hua, J; Reyes, B; Masui, H; Torday, JS
MLA Citation
Sunday, ME, Hua, J, Reyes, B, Masui, H, and Torday, JS. "Anti-bombesin monoclonal antibodies modulate fetal mouse lung growth and maturation in utero and in organ cultures." Anat Rec 236.1 (May 1993): 25-32.
PMID
8507013
Source
pubmed
Published In
Anatomical Record
Volume
236
Issue
1
Publish Date
1993
Start Page
25
End Page
32
DOI
10.1002/ar.1092360107

Role of airway smooth muscle in asthma: Possible relation to the neuroendocrine system

Though not yet firmly established, it appears likely that the neuroendocrine system (NES) regulates airway smooth muscle function. As it is the latter which is altered in asthma, the importance of the role of the NES in this disease is clear. The fact that transmitters from the NE cells are released from their basal aspect, and are in close proximity to the subjacent airway smooth muscle, further indicates an interaction. The question then arises as to what are the experimental desiderata for conducting studies of the ASM. As human tissues from asthmatics are difficult to obtain, animal models have been developed. The requirements are that, in these animals, the allergy be IgE based, that a congenital or familial factor be operative, that a noncholinergic nonadrenergic inhibitory system be a component of the neural regulatory system, and that the antigen for immunization be of a type commonly found in human asthmatics. Ideally, evidence of clinical asthma and exercise-induced asthma and nocturnal attacks should also be present. If in vitro research is to be conducted, there are additional requirements. The tissue should be from a relevant location. For the early asthmatic attack, central bronchi (3-5 mm diameter) should be used. Muscle strips obtained from them should be parallel-fibred and the cartilage plaques should be carefully dissected away, otherwise they contribute unwanted frictional forces when velocity is measured. Care should be taken to ensure that the epithelial cell layer is intact, as evidence indicates that it may regulate airway muscle function, though this has not been established for all the animal species used in asthma research.

Authors
Stephens, NL; Jiang, H; Halayko, A; Johnson, DE; Sorokin, SP; Jr, RFH; Cutz, E; Aguayo, SM; Scheuermann, DW; Polak, JM; McDowell, EM; Linnoila, RI; Sunday, ME; Gail, DB; Gosney, JR
MLA Citation
Stephens, NL, Jiang, H, Halayko, A, Johnson, DE, Sorokin, SP, Jr, RFH, Cutz, E, Aguayo, SM, Scheuermann, DW, Polak, JM, McDowell, EM, Linnoila, RI, Sunday, ME, Gail, DB, and Gosney, JR. "Role of airway smooth muscle in asthma: Possible relation to the neuroendocrine system." Anatomical Record 236.1 (1993): 152-167.
Source
scival
Published In
Anatomical Record
Volume
236
Issue
1
Publish Date
1993
Start Page
152
End Page
167

Paracrine effects of bombesin/gastrin-releasing peptide and other growth factors on pulmonary neuroendocrine cells in vitro

Pulmonary neuroendocrine cells (PNEC) are numerous in the fetus where they have been implicated to have a role in fetal lung development. We assessed the effects of putative growth factors, gastrin releasing peptide (GRP), cholecystokinin (CCK), gastrin (GN), serotonin (5-HT), and epidermal growth factor (EGF), some of which are produced by PNEC, either alone or in combination, on cultured fetal rabbit PNEC from 20, 24, and 28 day fetuses. GRP increased the total protein of the cultures over a 7 day period in an age-dependent manner, with greatest effect in cultures from the 24 day fetus, no effect with the 28 day fetus, and an inhibitory effect on 20 day cultures. This was accompanied by an increase in PNEC, which could be blocked by treatment of the cultures with a monoclonal antibody to GRP (2A11). There was no increase in 3H-thymidine labeling of PNEC in GRP treated cultures but an increase in numbers of cells partially stained for 5-HT, suggesting the induction of a precursor cell. Other growth factors had neither an inhibitory nor a stimulatory effect either alone or in combination with GRP. Preliminary studies with 125I-GRP receptor localization suggests that the GRP receptor is mostly expressed on pulmonary fibroblasts, and less on epithelial cells, so that the role for GRP in fetal lung development, at least in the rabbit, is probably indirect, acting via a paracrine mechanism.

Authors
Speirs, V; Bienkowski, E; Wong, V; Cutz, E; Polak, JM; Scheuermann, DW; Sunday, ME; Linnoila, RI; Gail, DB; Aguayo, SM; Stephens, NL; Becker, KL; Sorokin, SP; Miller, YE; Jr, RFH; McDowell, EM; Gosney, JR; Hung, K-S; Springall, DR
MLA Citation
Speirs, V, Bienkowski, E, Wong, V, Cutz, E, Polak, JM, Scheuermann, DW, Sunday, ME, Linnoila, RI, Gail, DB, Aguayo, SM, Stephens, NL, Becker, KL, Sorokin, SP, Miller, YE, Jr, RFH, McDowell, EM, Gosney, JR, Hung, K-S, and Springall, DR. "Paracrine effects of bombesin/gastrin-releasing peptide and other growth factors on pulmonary neuroendocrine cells in vitro." Anatomical Record 236.1 (1993): 53-67.
Source
scival
Published In
Anatomical Record
Volume
236
Issue
1
Publish Date
1993
Start Page
53
End Page
67

Pulmonary neuroendocrine cells in species at high altitude

Ever since pulmonary neuroendocrine cells were first described, a chemoreceptor function has been attributed to them. This hypothesis proposes that the innervated clusters of these cells, which are known to degranulate when the oxygen tension around them is reduced, respond to hypoxia to initiate activity in a reflex arc and ultimately adjust some aspect of pulmonary function. If this were true, one might expect to see changes in the pulmonary neuroendocrine system in species exposed to the unremitting hypoxia at natural high altitude. Whilst evidence from some studies suggests that such changes do occur, others have been unable to demonstrate any effect. To some extent this may be attributable to species variability, but might also reflect whether the organism is genetically adapted or merely acclimatized to life in an oxygen-poor environment.

Authors
Gosney, JR; Nylen, ES; Jr, RFH; Linnoila, RI; Springall, DR; Polak, JM; Sorokin, SP; McDowell, EM; Keith, IM; Scheuermann, DW; Stephens, NL; Cuttitta, F; Sunday, ME; Aguayo, SM; Johnson, DE; Hung, K-S
MLA Citation
Gosney, JR, Nylen, ES, Jr, RFH, Linnoila, RI, Springall, DR, Polak, JM, Sorokin, SP, McDowell, EM, Keith, IM, Scheuermann, DW, Stephens, NL, Cuttitta, F, Sunday, ME, Aguayo, SM, Johnson, DE, and Hung, K-S. "Pulmonary neuroendocrine cells in species at high altitude." Anatomical Record 236.1 (1993): 105-112.
Source
scival
Published In
Anatomical Record
Volume
236
Issue
1
Publish Date
1993
Start Page
105
End Page
112

Neuroepithelial bodies and growth of the airway epithelium in developing hamster lung

Clusters of small-granule endocrine cells, neuroepithelial bodies (NEBs), appear in the airway lining of pseudoglandular lungs, but their prenatal function has remained obscure. Transplacental labeling of S-phase cells in Syrian golden hamsters has allowed us to relate NEBs to patterns of replication in the surrounding endoderm. Two methods were used: 1) continuous exposure to 3H-thymidine for the last 25% (4 days) of gestation, and 2) 2- hr exposure to 5-bromo-2'-deoxyuridine (BrdU) on fetal day 15. 3H-thymidine incorporation was assessed in autoradiographs of neonatal lung by grain counting from 923 nonendocrine and 251 endocrine cells in 28 airway epithelial terrains, each centered on a NEB: 12 in the perihilar, 8 in the middle, and 8 in the distal third of the left axial bronchus. Grain densities for 10-25 nonendocrine cells on either side of the NEB were plotted vs. position relative to the endocrine cell cluster and analyzed by rank-order correlation and linear regression. Label was highest in cells closest to NEBs in all 12 terrains (P < 0.05-0.001) in the perihilar airway, in 3 of 8 terrains (P < 0.025-0.001) in the middle third of the bronchus, and in respective, pooled populations (P < 0.001). The effect was not demonstrable in the distal third of the airway. In the 15-day fetus 243 mm of airway perimeter were measured and 3,218 BrdU-labeled epithelial cells counted from sections through the entire length of the left axial airway and the lobar bronchus, intermediate, and terminal bronchioles of the infracardiac (IC) lobe. Overall, 43% of BrdU-labeled cells and only 24% of epithelium lay within 20 μm of NEBs. Preferential concentration of S-phase cells around NEBs was significant (P < 0.001) by X2 test at all airway levels. Net density of NEB-associated BrdU+ cells was 10/mm of basal lamina in the trachea, rose distally along the left axial airway to 22/mm at the end of the undivided bronchus, and fell to 15/mm in the terminal channels. It was 9 cells/mm in terminal bronchioles of the infracardiac lobe. Regional differences in 3H-thymidine and BrdU labeling patterns can be correlated with differences in the age of NEBs. We conclude that NEBs regulate local cell proliferation in developing hamster airway, probably activated in a proximal-to-distal wave reflecting maturational changes in the NEBs along the same gradient.

Authors
Jr, RFH; Sorokin, SP; McDowell, EM; McNelly, NA; Polak, JM; Scheuermann, DW; Johnson, DE; Becker, KL; Keith, IM; Cutz, E; Stephens, NL; Mossman, BT; Cuttitta, F; Sunday, ME
MLA Citation
Jr, RFH, Sorokin, SP, McDowell, EM, McNelly, NA, Polak, JM, Scheuermann, DW, Johnson, DE, Becker, KL, Keith, IM, Cutz, E, Stephens, NL, Mossman, BT, Cuttitta, F, and Sunday, ME. "Neuroepithelial bodies and growth of the airway epithelium in developing hamster lung." Anatomical Record 236.1 (1993): 15-24.
Source
scival
Published In
Anatomical Record
Volume
236
Issue
1
Publish Date
1993
Start Page
15
End Page
24

Lung endocrine cell markers, peptides, and amines

Authors
Polak, JM; Becker, KL; Cutz, E; Gail, DB; Goniakowska-Witalinska, L; Gosney, JR; Lauweryns, JM; Linnoila, RI; McDowell, EM; Miller, YE; Scheuermann, DW; Springall, DR; Sunday, ME; Zaccone, G
MLA Citation
Polak, JM, Becker, KL, Cutz, E, Gail, DB, Goniakowska-Witalinska, L, Gosney, JR, Lauweryns, JM, Linnoila, RI, McDowell, EM, Miller, YE, Scheuermann, DW, Springall, DR, Sunday, ME, and Zaccone, G. "Lung endocrine cell markers, peptides, and amines." Anatomical Record 236.1 (1993): 169-171.
PMID
8507003
Source
scival
Published In
Anatomical Record
Volume
236
Issue
1
Publish Date
1993
Start Page
169
End Page
171

Pulmonary neuroendocrine cells in pediatric lung disease: Alterations in airway structure in infants with bronchopulmonary dysplasia

Despite four decades of investigation, the function of pulmonary neuroendocrine cells (NEC) remains unclear. Since NEC secretory products3 may influence airway growth or differentiation or alter airway smooth muscle tone, increased numbers of NEC seen in bronchopulmonary dysplasia (BPD) may be partially responsible for the genesis of the structural and pathophysiological alterations seen in this disease state. Changes in airway structure were studied in six infants dying with BPD and six conceptional age-matched control infants dying of noncardiopulmonary disease. Changes in bombesin-, calcitonin-, and serotonin-immunoreactive NEC were quantified in lung specimens from three infants who died at 2 months of age with severe BPD and three conceptional age-matched controls. There were no differences in either bronchiolar or bronchial airway epithelial areas, but significant increases in bronchiolar (1.8-fold) (P < 0.001) and especially bronchial smooth muscle (2.5-fold) (P < 0.001) were documented in infants with BPD. Few bombesin-, calcitonin-, and serotonin-immunoreactive cells were identified in cartilaginous airways; however, there was a clear increase in the total number of bronchiolar immunoreactive cells in infants with severe BPD (28.5 ± 11.2 cells/mm airway epithelium) compared to control infants (4.5 ± 4.9) (P < 0.05). Our results confirm that airway wall composition does change in BPD, but there is either no or an inverse correlation between NEC number and airway epithelial and smooth muscle areas and cell numbers. The role of NEC secretory products in airway smooth muscle growth and function requires further investigation.

Authors
Johnson, DE; Anderson, WR; Burke, BA; Polak, JM; Jr, RFH; Becker, KL; Stephens, NL; Sunday, ME; Cutz, E
MLA Citation
Johnson, DE, Anderson, WR, Burke, BA, Polak, JM, Jr, RFH, Becker, KL, Stephens, NL, Sunday, ME, and Cutz, E. "Pulmonary neuroendocrine cells in pediatric lung disease: Alterations in airway structure in infants with bronchopulmonary dysplasia." Anatomical Record 236.1 (1993): 115-121.
Source
scival
Published In
Anatomical Record
Volume
236
Issue
1
Publish Date
1993
Start Page
115
End Page
121

Neuroendocrine cells and nerves of the lung

Authors
Adriaensen, D; Scheuermann, DW; Cutz, E; Sorokin, SP; Linnoila, RI; Polak, JM; Jr, RFH; Aguayo, SM; Sunday, ME
MLA Citation
Adriaensen, D, Scheuermann, DW, Cutz, E, Sorokin, SP, Linnoila, RI, Polak, JM, Jr, RFH, Aguayo, SM, and Sunday, ME. "Neuroendocrine cells and nerves of the lung." Anatomical Record 236.1 (1993): 70-86.
Source
scival
Published In
Anatomical Record
Volume
236
Issue
1
Publish Date
1993
Start Page
70
End Page
86

CD10/neutral endopeptidase 24.11 in developing human fetal lung. Patterns of expression and modulation of peptide-mediated proliferation.

The cell membrane-associated enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP) functions in multiple organ systems to downregulate responses to peptide hormones. Recently, CD10/NEP was found to hydrolyze bombesin-like peptides (BLP), which are mitogens for normal bronchial epithelial cells and small cell lung carcinomas. Growth of BLP-responsive small cell lung carcinomas was potentiated by CD10/NEP inhibition, implicating CD10/NEP in regulation of BLP-mediated tumor growth. BLP are also likely to participate in normal lung development because high BLP levels are found in fetal lung, and bombesin induces proliferation and maturation of human fetal lung in organ cultures and murine fetal lung in utero. To explore potential roles for CD10/NEP in regulating peptide-mediated human fetal lung development, we have characterized temporal and cellular patterns of CD10/NEP expression and effects of CD10/NEP inhibition in organ cultures. Peak CD10/NEP transcript levels are identified at 11-13 wk gestation by Northern blots and localized to epithelial cells and mesenchyme of developing airways by in situ hybridization. CD10/NEP immunostaining is most intense in undifferentiated airway epithelium. In human fetal lung organ cultures, inhibition of CD10/NEP with either phosphoramidon or SCH32615 increases thymidine incorporation by 166-182% (P < 0.025). The specific BLP receptor antagonist, [Leu13-psi(CH2NH)Leu14]bombesin abolishes these effects on fetal lung growth, suggesting that CD10/NEP modulates BLP-mediated proliferation. CD10/NEP expression in the growing front of airway epithelium and the effects of CD10/NEP inhibitors in lung explants implicate the enzyme in the regulation of peptide-mediated fetal lung growth.

Authors
Sunday, ME; Hua, J; Torday, JS; Reyes, B; Shipp, MA
MLA Citation
Sunday, ME, Hua, J, Torday, JS, Reyes, B, and Shipp, MA. "CD10/neutral endopeptidase 24.11 in developing human fetal lung. Patterns of expression and modulation of peptide-mediated proliferation." J Clin Invest 90.6 (December 1992): 2517-2525.
PMID
1469102
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
90
Issue
6
Publish Date
1992
Start Page
2517
End Page
2525
DOI
10.1172/JCI116145

Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease.

Authors
Aguayo, SM; Miller, YE; Waldron, JA; Bogin, RM; Sunday, ME; Staton, GW; Beam, WR; King, TE
MLA Citation
Aguayo, SM, Miller, YE, Waldron, JA, Bogin, RM, Sunday, ME, Staton, GW, Beam, WR, and King, TE. "Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease." N Engl J Med 327.18 (October 29, 1992): 1285-1288.
PMID
1406819
Source
pubmed
Published In
The New England journal of medicine
Volume
327
Issue
18
Publish Date
1992
Start Page
1285
End Page
1288
DOI
10.1056/NEJM199210293271806

Induction and spontaneous regression of intense pulmonary neuroendocrine cell differentiation in a model of preneoplastic lung injury.

Pulmonary neuroendocrine cell (PNEC) hyperplasia is associated with chronic lung diseases in humans, where it is thought to play a role in reparative responses to lung injury. To investigate the kinetics of strongly induced PNEC hyperplasia in an animal model, we exposed hamsters to a combination of hyperoxia (60% O2) and diethylnitrosamine (DEN) for up to 20 weeks. We thus demonstrate not only the induction but also spontaneous regression of intense PNEC differentiation and growth, which are much more intense than those observed with DEN alone. Lung tissues were immunostained for serotonin, calcitonin gene-related peptide (CGRP), calcitonin (CT), and gastrin-releasing peptide (GRP) (mammalian bombesin). Between 9 and 12 weeks of treatment, the number of CGRP- and serotonin-positive neuroepithelial bodies per cm airway epithelium increased over 10-fold, and CT became detectable. The number of neuroepithelial bodies immunostained for CGRP, serotonin, and CT peaked at 12-14 weeks of treatment, thereafter regressing to near-control levels by 20 weeks, in spite of continued DEN/O2 treatment. Simultaneously, by 6-7 weeks of treatment, there was a significant increase in the mean number of CGRP-positive cells per neuroepithelial body, which continued to rise up to double control levels, with a plateau at 13-20 weeks. GRP and pro-GRP immunostaining were not detectable at any time point. Polymerase chain reaction analyses of neuroendocrine-specific mRNAs demonstrated that CGRP, CT, and GRP mRNAs (normalized for beta-actin) peaked in lung tissues from most animals at 9-14 weeks after the beginning of DEN/O2 treatment, with decreased expression at 16-20 weeks. These data suggest that regulation of levels of these neuropeptides may be primarily transcriptional. This model may be a valuable system for analyzing mechanisms of induction and regression of normal PNEC differentiation and growth.

Authors
Sunday, ME; Willett, CG
MLA Citation
Sunday, ME, and Willett, CG. "Induction and spontaneous regression of intense pulmonary neuroendocrine cell differentiation in a model of preneoplastic lung injury." Cancer Res 52.9 Suppl (May 1, 1992): 2677s-2686s.
PMID
1314133
Source
pubmed
Published In
Cancer Research
Volume
52
Issue
9 Suppl
Publish Date
1992
Start Page
2677s
End Page
2686s

Induction and spontaneous regression of pulmonary neuroendocrine cell hyperplasia in a hamster model.

Authors
Sunday, ME; Willett, CG
MLA Citation
Sunday, ME, and Willett, CG. "Induction and spontaneous regression of pulmonary neuroendocrine cell hyperplasia in a hamster model." Chest 101.3 Suppl (March 1992): 21S-.
PMID
1541190
Source
pubmed
Published In
Chest
Volume
101
Issue
3 Suppl
Publish Date
1992
Start Page
21S

Isoform-specific thyroid hormone receptor antibodies detect multiple thyroid hormone receptors in rat and human pituitaries.

There are three known isoforms of the thyroid hormone receptor (TR) in the rat: TR alpha-1, TR beta-1, and TR beta-2. The TR alpha-1 and TR beta-1 mRNAs are found in many tissues, whereas TR beta-2 mRNA is detected only in the pituitary gland. Thus far, TR alpha-1 and TR beta-1 mRNAs have been found in humans and are highly homologous to their counterparts in rats; however, TR beta-2 mRNA has not yet been demonstrated in humans. To examine the expression of these TRs at the protein level, we have raised isoform-specific polyclonal antibodies in female New Zealand White rabbits against the rat TRs and c-erbA alpha-2, a carboxy-terminal variant of TR alpha-1 that does not bind thyroid hormone. The rabbits were immunized with synthetic peptides that contained the following amino acid sequences: TR alpha-common-(10-31), c-erbA alpha-2-(428-442), TR beta-1-(73-93), and TR beta-2-(86-101, 113-133). All immune sera could bind specifically to their respective immunizing peptides on enzyme-linked immunosorbent assay as well as immunoprecipitate specifically in vitro translated rat and human TRs. Anti-TR beta-1 and anti-TR alpha-common antibodies could immunoprecipitate TR beta-1 or TR alpha-1, respectively, in transfected COS-7 cells. We also immunostained normal adult rat and human pituitary glands. Each isoform-specific antibody could immunostain almost all of the anterior pituitary cells, suggesting that TR alpha-1, TR beta-1, TR beta-2, and c-erbA alpha-2 are most likely expressed in all anterior pituitary cell types in rats and humans. The staining of rat pituitary glands by the anti-TR beta-2 antibodies demonstrates for the first time that TR beta-2 is expressed as a protein in pituitary cells. Furthermore, the staining of human pituitary glands by the anti-TR beta-2 antibodies suggests that there is a human homolog of the rat pituitary-specific TR beta-2 that shares similar epitopes with the rat TR beta-2. In summary, we have prepared isoform-specific antibodies against TRs that can recognize in vitro translated, transiently transfected, and in situ rat and human pituitary TRs. These antibodies will be useful in examining tissue- and cell type-specific expression of rat and human TRs at the protein level.

Authors
Yen, PM; Sunday, ME; Darling, DS; Chin, WW
MLA Citation
Yen, PM, Sunday, ME, Darling, DS, and Chin, WW. "Isoform-specific thyroid hormone receptor antibodies detect multiple thyroid hormone receptors in rat and human pituitaries." Endocrinology 130.3 (March 1992): 1539-1546.
PMID
1537303
Source
pubmed
Published In
Endocrinology
Volume
130
Issue
3
Publish Date
1992
Start Page
1539
End Page
1546
DOI
10.1210/endo.130.3.1537303

Induction and spontaneous regression of intense pulmonary neuroendocrine cell differentiation in a model of preneoplastic lung injury

Pulmonary neuroendocrine cell (PNEC) hyperplasia is associated with chronic lung diseases in humans, where it is thought to play a role in reparative responses to lung injury. To investigate the kinetics of strongly induced PNEC hyperplasia in an animal model, we exposed hamsters to a combination of hyperoxia (60% O2) and diethylnitrosamine (DEN) for up to 20 weeks. We thus demonstrate not only the induction but also spontaneous regression of intense PNEC differentiation and growth, which are much more intense than those observed with DEN alone. Lung tissues were immunostained for serotonin, calcitonin gene-related peptide (CGRP), calcitonin (CT), and gastrin-releasing peptide (GRP) (mammalian bombesin). Between 9 and 12 weeks of treatment, the number of CGRP- and serotonin-positive neuroepithelial bodies per cm airway epithelium increased over 10-fold, and CT became detectable. The number of neuroepithelial bodies immunostained for CGRP, serotonin, and CT peaked at 12-14 weeks of treatment, thereafter regressing to near-control levels by 20 weeks, in spite of continued DEN/O2 treatment. Simultaneously, by 6-7 weeks of treatment, there was a significant increase in the mean number of CGRP-positive cells per neuroepithelial body, which continued to rise up to double control levels, with a plateau it 13-20 weeks. GRP and pro-GRP immunostaining were not detectable at any time point. Polymerase chain reaction analyses of neuroendocrine-specific mRNAs demonstrated that CGRP, CT, and GRP mRNAs (normalized for β-actin) peaked in lung tissues from most animals at 9-14 weeks after the beginning of DEN/O2 treatment, with decreased expression at 16-20 weeks. These data suggest that regulation of levels of these neuropeptides may be primarily transcriptional. This model may be a valuable system for analyzing mechanisms of induction and regression of normal PNEC differentiation and growth.

Authors
Sunday, ME; Willett, CG
MLA Citation
Sunday, ME, and Willett, CG. "Induction and spontaneous regression of intense pulmonary neuroendocrine cell differentiation in a model of preneoplastic lung injury." Cancer Research 52.9 SUPPL. (1992): 2677s-2686s.
Source
scival
Published In
Cancer Research
Volume
52
Issue
9 SUPPL.
Publish Date
1992
Start Page
2677s
End Page
2686s

Induction and spontaneous regression of pulmonary neuroendocrine cell hyperplasia in a hamster model

Authors
Sunday, ME; Willett, CG
MLA Citation
Sunday, ME, and Willett, CG. "Induction and spontaneous regression of pulmonary neuroendocrine cell hyperplasia in a hamster model." Chest 101.3 SUPPL. (1992): 21S-.
Source
scival
Published In
Chest
Volume
101
Issue
3 SUPPL.
Publish Date
1992
Start Page
21S

CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung.

Bombesin-like peptides are essential autocrine growth factors for many small cell carcinomas (SCCas) of the lung. Herein, we demonstrate that these malignant pulmonary neuroendocrine cells express low levels of the cell surface metalloendopeptidase CD10/neutral endopeptidase 24.11 (CD10/NEP, common acute lymphoblastic leukemia antigen) and that this enzyme hydrolyzes bombesin-like peptides. The growth of bombesin-like peptide-dependent SCC as is inhibited by CD10/NEP and potentiated by CD10/NEP inhibition. The results provide evidence that CD10/NEP is involved in the regulation of tumor cell proliferation. Since SCCa of the lung occurs almost exclusively in cigarette smokers and cigarette smoke inactivates CD10/NEP, decreased cell surface CD10/NEP enzymatic activity may be causally related to the development of SCCa of the lung.

Authors
Shipp, MA; Tarr, GE; Chen, CY; Switzer, SN; Hersh, LB; Stein, H; Sunday, ME; Reinherz, EL
MLA Citation
Shipp, MA, Tarr, GE, Chen, CY, Switzer, SN, Hersh, LB, Stein, H, Sunday, ME, and Reinherz, EL. "CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung." Proc Natl Acad Sci U S A 88.23 (December 1, 1991): 10662-10666.
PMID
1660144
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
88
Issue
23
Publish Date
1991
Start Page
10662
End Page
10666

Gastrin-releasing peptide gene expression in small cell and large cell undifferentiated lung carcinomas.

Gastrin-releasing peptide (GRP; mammalian bombesin) is present in the neuroendocrine cells of human fetal lung and in small cell lung carcinomas (SCLCs), where it may act as a growth factor. Considering the potential importance of GRP as a tumor marker, we have conducted a retrospective immunohistochemical analysis of 176 lung tumors for markers of GRP gene expression, as well as several other markers of neuroendocrine cell differentiation: chromogranin A, neuron-specific enolase, and calcitonin. The majority of carcinoids contained mature GRP, in contrast to only a minority of SCLCs and large cell lung carcinomas (LCLCs). However, a majority of SCLCs and LCLCs contained proGRP immunoreactivity. In situ hybridization did not add any information beyond what was obtained using proGRP antisera. In spite of sharing these neuroendocrine cell markers, SCLCs are associated with a graver prognosis than LCLCs. No prognostic significance was associated with immunostaining for GRP or several other markers of neuroendocrine cell differentiation.

Authors
Sunday, ME; Choi, N; Spindel, ER; Chin, WW; Mark, EJ
MLA Citation
Sunday, ME, Choi, N, Spindel, ER, Chin, WW, and Mark, EJ. "Gastrin-releasing peptide gene expression in small cell and large cell undifferentiated lung carcinomas." Hum Pathol 22.10 (October 1991): 1030-1039.
PMID
1668786
Source
pubmed
Published In
Human Pathology
Volume
22
Issue
10
Publish Date
1991
Start Page
1030
End Page
1039

Suppression of tumor formation in vivo by expression of the JE gene in malignant cells.

The early growth response gene JE encodes a monocyte chemoattractant, MCP-1. The JE/MCP-1 protein attracts and stimulates human monocytes and induces monocyte-mediated inhibition of tumor cell growth in vitro. Expression of human or murine JE/MCP-1 in Chinese hamster ovary (CHO) cells completely suppressed their ability to form tumors in nude mice. Coinjection of JE/MCP-1-expressing cells with nonexpressing CHO cells or with HeLa cells also prevented tumor formation. Since JE/MCP-1 expression had no discernible effect on the tranformed phenotype of these cells in vitro, the suppressive effect depends on host animal factors. These factors are likely to be components of the inflammatory response, because JE/MCP-1-expressing cells elicited a predominantly monocytic infiltrate at the site of injection. Our results suggest that JE/MCP-1 protein may be useful in cancer therapy.

Authors
Rollins, BJ; Sunday, ME
MLA Citation
Rollins, BJ, and Sunday, ME. "Suppression of tumor formation in vivo by expression of the JE gene in malignant cells." Mol Cell Biol 11.6 (June 1991): 3125-3131.
PMID
2038321
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
11
Issue
6
Publish Date
1991
Start Page
3125
End Page
3131

Bombesin may play a role in fetal lung growth and maturation in utero and in lung organ culture.

Authors
Sunday, ME; Hua, J; Torday, J
MLA Citation
Sunday, ME, Hua, J, and Torday, J. "Bombesin may play a role in fetal lung growth and maturation in utero and in lung organ culture." Chest 99.3 Suppl (March 1991): 21S-.
PMID
1997265
Source
pubmed
Published In
Chest
Volume
99
Issue
3 Suppl
Publish Date
1991
Start Page
21S

Cell-Specific Localization of Neuropeptide Gene Expression: Gastrin-Releasing Peptide or Mammalian Bombesin

Authors
Sunday, ME
MLA Citation
Sunday, ME. "Cell-Specific Localization of Neuropeptide Gene Expression: Gastrin-Releasing Peptide or Mammalian Bombesin." Methods in Neurosciences 5.C (January 1, 1991): 123-136.
Source
scopus
Published In
Methods in Neurosciences
Volume
5
Issue
C
Publish Date
1991
Start Page
123
End Page
136
DOI
10.1016/B978-0-12-185259-7.50013-2

Bombesin may play a role in fetal lung growth and maturation in utero and in lung organ culture

Authors
Sunday, ME; Hua, J; Torday, J
MLA Citation
Sunday, ME, Hua, J, and Torday, J. "Bombesin may play a role in fetal lung growth and maturation in utero and in lung organ culture." Chest 99.3 SUPPL. (1991): 21S-.
Source
scival
Published In
Chest
Volume
99
Issue
3 SUPPL.
Publish Date
1991
Start Page
21S

Bombesin increases fetal lung growth and maturation in utero and in organ culture.

Pulmonary neuroendocrine cells (PNECs) in fetuses synthesize gastrin-releasing peptide (GRP, or mammalian bombesin) at high levels, but the role of this hormone in lung development has been obscure. The present study demonstrates that bombesin administered for 2 to 4 d toward the end of gestation in utero led to increased DNA (days 17 and 18) and saturated phosphatidylcholine (SPC) synthesis (day 18) in a dose-dependent fashion in fetal lung. These kinetics coincide with the timing of endogenous GRP gene activation in untreated fetal mouse lung, where GRP mRNA is detectable on day 16 and peaks at day 18. Electron microscopy on in vivo bombesin-treated fetal lung showed an increase in the number of cells containing lamellar bodies on both days 17 and 18, consistent with increased growth and/or maturation of type II cells. In mouse fetal lung organ cultures, the addition of bombesin led to accelerated uptake of [3H]thymidine into DNA, [3H]leucine into protein, and [3H]choline into SPC, indicating that increased growth and maturation may be direct effects. Extending these observations to another species, bombesin was found to induce growth and maturation of human fetal lung in organ culture. A monoclonal antibody to bombesin (2A11) prevented bombesin-induced increases in choline and thymidine incorporation in lung organ cultures and also blocked baseline automaturation of control lung organ cultures in serum-free medium. These data suggest that bombesin, and thus PNECs, play a role in normal lung development.

Authors
Sunday, ME; Hua, J; Dai, HB; Nusrat, A; Torday, JS
MLA Citation
Sunday, ME, Hua, J, Dai, HB, Nusrat, A, and Torday, JS. "Bombesin increases fetal lung growth and maturation in utero and in organ culture." Am J Respir Cell Mol Biol 3.3 (September 1990): 199-205.
PMID
2390263
Source
pubmed
Published In
American journal of respiratory cell and molecular biology
Volume
3
Issue
3
Publish Date
1990
Start Page
199
End Page
205
DOI
10.1165/ajrcmb/3.3.199

Altered growth of a human neuroendocrine carcinoma line after transfection of a major histocompatibility complex class I gene.

The major histocompatibility complex (MHC) class I molecules are known to serve as recognition elements for cytotoxic T cells in mediating the rejection of transplanted tumors. We demonstrate that MHC molecules may have nonimmune functions in modulating tumor cell growth in addition to their classical role in antitumor immunity. A human neuroendocrine carcinoma cell line, COLO 320, with low levels of endogenous class I expression was transfected with the murine H-2Ld gene. Eleven independent stable clones were established, four containing only pRSV-neo and seven also containing varying copy numbers of the transfected Ld gene. The ability of the different clones to grow as colonies in soft agar correlated strongly with the relative amounts of Ld antigen expression (r = 0.89; P less than 0.001). There was a weaker correlation between increased clonogenic ability and higher levels of Ld mRNA (r = 0.67; P less than 0.05). There was no correlation between clonogenic ability and relative expression of amplified c-myc gene or of integrated pRSV-neo. Furthermore, in nude mice, Ld antigen expression was associated with increased formation of metastatic lung colonies 6 weeks after intravenous injection of 10(5) cells. These observations are consistent with the concept that MHC class I antigens may have a role in modulating the growth potential of certain tumor cells independent of their involvement in immune responses.

Authors
Sunday, ME; Isselbacher, KJ; Gattoni-Celli, S; Willett, CG
MLA Citation
Sunday, ME, Isselbacher, KJ, Gattoni-Celli, S, and Willett, CG. "Altered growth of a human neuroendocrine carcinoma line after transfection of a major histocompatibility complex class I gene." Proc Natl Acad Sci U S A 86.12 (June 1989): 4700-4704.
PMID
2660144
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
86
Issue
12
Publish Date
1989
Start Page
4700
End Page
4704

Galanin is an estrogen-inducible, secretory product of the rat anterior pituitary.

Galanin is a peptide widely distributed throughout vertebrate central and peripheral nervous systems. Although its precise physiologic role is unknown, it can stimulate the pituitary secretion of prolactin and growth hormone. We examined the control of rat galanin (rGal) gene expression in the anterior pituitary using RNA blot and in situ hybridization analyses and using specific RIA. Pituitaries of normal male and ovariectomized female rats contained little detectable rGal mRNA. Treatment of these animals with 17 beta-estradiol increased pituitary rGal mRNA up to 4000-fold. These increases depended on time and dose of estrogen administration and correlated with up to 50-fold increases in pituitary galanin-like immunoreactivity. Galanin-like immunoreactivity was detectable in the plasma of estrogen-treated animals. Pituitary levels of rGal mRNA in female rats varied greater than 30-fold during the estrous cycle, with a peak on estrus and a nadir on diestrus. Estrogen-induced rGal gene expression was also observed in transplantable MtTW15 prolactin- and growth hormone-containing tumors but not in neuronal tissues expressing this gene. These data demonstrate that rGal is a secreted product of rat anterior pituitary cells, where its gene expression is strongly affected by physiologic levels of circulating estrogen.

Authors
Kaplan, LM; Gabriel, SM; Koenig, JI; Sunday, ME; Spindel, ER; Martin, JB; Chin, WW
MLA Citation
Kaplan, LM, Gabriel, SM, Koenig, JI, Sunday, ME, Spindel, ER, Martin, JB, and Chin, WW. "Galanin is an estrogen-inducible, secretory product of the rat anterior pituitary." Proc Natl Acad Sci U S A 85.19 (October 1988): 7408-7412.
PMID
2459706
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
85
Issue
19
Publish Date
1988
Start Page
7408
End Page
7412

Gastrin-releasing peptide (mammalian bombesin) gene expression in health and disease.

Authors
Sunday, ME; Kaplan, LM; Motoyama, E; Chin, WW; Spindel, ER
MLA Citation
Sunday, ME, Kaplan, LM, Motoyama, E, Chin, WW, and Spindel, ER. "Gastrin-releasing peptide (mammalian bombesin) gene expression in health and disease." Lab Invest 59.1 (July 1988): 5-24. (Review)
PMID
2839735
Source
pubmed
Published In
Laboratory Investigation
Volume
59
Issue
1
Publish Date
1988
Start Page
5
End Page
24

Gastrin-releasing peptide gene expression in developing, hyperplastic, and neoplastic human thyroid C-cells.

Gastrin-releasing peptide (GRP), the mammalian homolog of bombesin, is often studied as a prototypic neuroregulatory hormone and growth factor, but its own regulation and physiological roles remain to be fully defined. We now demonstrate that the GRP gene is expressed in human thyroidal calcitonin (CT)-containing neuroendocrine cells (C-cells) in an ontogenic pattern similar to its expression in pulmonary neuroendocrine cells and is also expressed at high levels in C-cell hyperplasias and neoplasias (medullary carcinomas of the thyroid). Mean GRP-like immunoreactivity is 20 times higher in 3-week-old to 5-month-old infants than in normal adults, with six of seven infants having GRP levels 6- to 67-fold higher than those in normal adults, the highest levels occurring at 2-2.5 months. CT levels are about 100 times greater than GRP levels at all time intervals, with levels of GRP and CT being linearly correlated (r = 0.98). By RNA blot analysis, GRP mRNAs are increased in neonatal thyroids compared to adult thyroids. In situ hybridization and immunoperoxidase analyses localize GRP mRNAs and peptide to a majority of C-cells in fetuses and neonates, but to only 5-18% of C-cells in normal adults. The majority of developing C-cells have a dendritic morphology, suggesting a paracrine role, although this morphology is not observed in adult C-cells. In addition, for unknown reasons, an increased percentage of C-cells positive for GRP occurs in normal thyroid adjacent to GRP-negative follicular adenomas and papillary carcinomas, an association that we term perineoplastic. We hypothesize that GRP gene expression may play a role in both normal and neoplastic growth processes.

Authors
Sunday, ME; Wolfe, HJ; Roos, BA; Chin, WW; Spindel, ER
MLA Citation
Sunday, ME, Wolfe, HJ, Roos, BA, Chin, WW, and Spindel, ER. "Gastrin-releasing peptide gene expression in developing, hyperplastic, and neoplastic human thyroid C-cells." Endocrinology 122.4 (April 1988): 1551-1558.
PMID
3345727
Source
pubmed
Published In
Endocrinology
Volume
122
Issue
4
Publish Date
1988
Start Page
1551
End Page
1558
DOI
10.1210/endo-122-4-1551

Tissue-specific expression of the mammalian bombesin gene.

Authors
Sunday, ME
MLA Citation
Sunday, ME. "Tissue-specific expression of the mammalian bombesin gene." Ann N Y Acad Sci 547 (1988): 95-113.
PMID
3071227
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
547
Publish Date
1988
Start Page
95
End Page
113

Transient elevation of messenger RNA encoding gastrin-releasing peptide, a putative pulmonary growth factor in human fetal lung.

Gastrin-releasing peptide (GRP), the mammalian homologue of the amphibian peptide bombesin, is present in pulmonary neuroendocrine cells and appears to be a growth factor for both normal and neoplastic pulmonary cells. Previously we have reported the cloning of the messenger RNAs (mRNAs) and gene that encode human GRP. We now report that GRP mRNAs are markedly elevated in human fetal lung during the canalicular phase of pulmonary development (from approximately 16 to 30 wk gestation). By RNA blot and in situ hybridization analyses, GRP mRNAs were first detectable in fetal lung at 9-10 wk, plateaued at levels 25-fold higher than in adult lungs from 16 to approximately 30 wk and then declined to near adult levels by 34 wk gestation. By contrast, GRP peptide levels remain elevated until several months after birth. Consistent with this, in situ hybridization and immunohistochemical studies showed that GRP mRNA and peptide consistently colocalized in early gestation lung but that in neonatal lung, many cells that contained GRP peptide no longer contained GRP mRNA. The transient expression of high levels of GRP mRNAs during an approximately 12-wk phase of fetal lung development suggests that the secretion of GRP or its COOH-terminal peptides from pulmonary neuroendocrine cells may play a role in normal lung development.

Authors
Spindel, ER; Sunday, ME; Hofler, H; Wolfe, HJ; Habener, JF; Chin, WW
MLA Citation
Spindel, ER, Sunday, ME, Hofler, H, Wolfe, HJ, Habener, JF, and Chin, WW. "Transient elevation of messenger RNA encoding gastrin-releasing peptide, a putative pulmonary growth factor in human fetal lung." J Clin Invest 80.4 (October 1987): 1172-1179.
PMID
3654977
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
80
Issue
4
Publish Date
1987
Start Page
1172
End Page
1179
DOI
10.1172/JCI113176

Platelet-derived growth factor receptors form a high affinity state in membrane preparations. Kinetics and affinity cross-linking studies.

The specific binding of 125I-PDGF (platelet-derived growth factor) to intact fibroblasts becomes relatively nondissociable during incubation at 37 degrees C. To characterize the interaction of PDGF with its receptors under conditions in which there is no receptor internalization, we have studied the binding of 125I-PDGF to membrane preparations derived from mouse 3T3 cells and rat liver. The binding sites had the affinity and specificity characteristics expected of PDGF receptors. At 37 degrees C (but not at 4 degrees C) the specific binding of 125I-PDGF to membranes gradually became nondissociable as assessed by either dilution or by addition of excess unlabeled PDGF. This tight binding was not due to a covalent interaction since the polyanionic compound suramin readily dissociated specifically bound 125I-PDGF. This property of suramin was used to expose rat liver PDGF receptors which were occupied by endogenous PDGF. Affinity cross-linking studies demonstrated that the formation of the nondissociable state of 125I-PDGF binding was associated with the binding of 125I-PDGF to a 160,000-dalton protein and to a 110,000-dalton species. The cross-linked binding sites could be adsorbed to wheat germ agglutinin and to anion exchange resins. The isoelectric point of both cross-linked species determined by two-dimensional gel electrophoresis was approximately 4.7. These data demonstrate that in membrane preparations, PDGF binds to an anionic 160,000-dalton glycoprotein which is likely to be the receptor. A high affinity state of PDGF binding, which is formed rapidly at 37 degrees C, can be dissociated by suramin.

Authors
Williams, LT; Tremble, PM; Lavin, MF; Sunday, ME
MLA Citation
Williams, LT, Tremble, PM, Lavin, MF, and Sunday, ME. "Platelet-derived growth factor receptors form a high affinity state in membrane preparations. Kinetics and affinity cross-linking studies." J Biol Chem 259.8 (April 25, 1984): 5287-5294.
PMID
6325430
Source
pubmed
Published In
The Journal of biological chemistry
Volume
259
Issue
8
Publish Date
1984
Start Page
5287
End Page
5294

Induction of immune responses by schistosome granuloma macrophages.

In mice, granuloma formation after Schistosomiasis mansoni infection is known to be a T cell-dependent response to schistosome eggs that peaks at 6 to 8 wk after infection (early) then regresses to a minimum by 20 to 32 wk (late). This decline in host responsiveness, termed modulation, has been attributed to T cell-mediated suppression. We now have investigated the macrophages from either Early or Late schistosome granulomas phenotypically and found no difference in expression of I-A subregion encoded antigens. We also tested granuloma macrophage (Gm) populations in their capacity to induce positive and negative antigen-specific immune responses to the hapten 4-hydroxy-3-nitrophenyl acetyl (NP). As few as 10(3) to 10(4) NP-coupled Early or Late Gm given s.c. were equally capable of inducing MHC-restricted NP-specific delayed-type hypersensitivity (DTH) responses and this DTH-inducing capability was equivalent to that of splenic adherent cell (SAC) controls. Further, both Early and Late Gm were able to generate NP-specific induction-phase suppressor cells (Ts1) when as few as 10(2) NP-coupled Gm were given i.v., the same as NP-SAC controls. Finally, NP-specific effector-phase suppressor cells (Ts3) were equally induced by Early Gm, Late Gm, or SAC controls. Therefore, macrophages derived from Early or Late schistosome granulomas or normal spleens are apparently phenotypically indistinguishable and equally capable, in extremely small quantities, of inducing NP-specific DTH, Ts1, and Ts3 immune responses.

Authors
Sunday, ME; Stadecker, MJ; Wright, JA; Aoki, I; Dorf, ME
MLA Citation
Sunday, ME, Stadecker, MJ, Wright, JA, Aoki, I, and Dorf, ME. "Induction of immune responses by schistosome granuloma macrophages." J Immunol 130.5 (May 1983): 2413-2417.
PMID
6187855
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
130
Issue
5
Publish Date
1983
Start Page
2413
End Page
2417

Anti-receptor antibody-induced H-Y-specific delayed-type hypersensitivity responses in nonresponder mice.

The present study examines an antiserum prepared against antigen-reactive T cells that induces murine H-Y-specific delayed-type hypersensitivity (DTH) responses. This anti-H-Y receptor antibody (ARA) was raised in C57BL/6 male mice against splenic T lymphocytes from H-Y immune syngeneic females. Subcutaneous administration of ARA to cyclophosphamide-pretreated C57BL/6 females is able to induce H-Y-specific delayed-type footpad swelling responses. The DTH inducing capacity in ARA was selectively retained on rabbit anti-mouse immunoglobulin columns and was absorbed completely by H-Y immune lymphoid cells from C57BL/6 females. The induction of H-Y DTH reactivity was due at least in part to the activation of H-Y antigen-specific T lymphocytes that could adoptively transfer DTH-like responses to naive female mice. ARA induces DTH responses in strains with the same lgh regions, including selected strains of H-Y nonresponders. Therefore, MHC-linked lr genes do not appear to be as critical when responses are triggered by ARA instead of by antigen. Possible mechanisms for the induction of immune responses by ARA are discussed.

Authors
Sunday, ME; Dorf, ME
MLA Citation
Sunday, ME, and Dorf, ME. "Anti-receptor antibody-induced H-Y-specific delayed-type hypersensitivity responses in nonresponder mice." J Immunol 130.4 (April 1983): 1604-1609.
PMID
6187817
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
130
Issue
4
Publish Date
1983
Start Page
1604
End Page
1609

H-2K-, H-21- and H-2D-restricted hybridoma contact sensitivity effector cells.

Authors
Minami, M; Okuda, K; Sunday, ME; Dorf, ME
MLA Citation
Minami, M, Okuda, K, Sunday, ME, and Dorf, ME. "H-2K-, H-21- and H-2D-restricted hybridoma contact sensitivity effector cells." Nature 297.5863 (May 20, 1982): 231-233.
PMID
6978996
Source
pubmed
Published In
Nature
Volume
297
Issue
5863
Publish Date
1982
Start Page
231
End Page
233

Hapten-specific T cell response to 4-hydroxy-3-nitrophenyl acetyl. X. Characterization of distinct T cell subsets mediating cutaneous sensitivity responses.

NP-O-Succinimide-induced cutaneous sensitivity (CS) responses can be adoptively transferred by NP-primed lymphoid cells into naive K-, I-, or D-compatible recipients. The distinct fine specificities of I- versus D-restricted T cell clones from various strains of mice suggested that presence of different idiotypic receptors on these T cell subsets. We now demonstrate that NP-O-Su immune lymphoid cells are composed of 2 T cell subsets with distinct antigen recognition patterns, as well as different Lyt 2 phenotypes. Thus, I-restricted cells respond to NP-coupled to a protein carrier but not to NP-coupled cells, whereas D-restricted clones react to NP-cells, but not to NP-protein conjugates.

Authors
Sunday, ME; Dorf, ME
MLA Citation
Sunday, ME, and Dorf, ME. "Hapten-specific T cell response to 4-hydroxy-3-nitrophenyl acetyl. X. Characterization of distinct T cell subsets mediating cutaneous sensitivity responses." J Immunol 127.2 (August 1981): 766-768.
PMID
6972973
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
127
Issue
2
Publish Date
1981
Start Page
766
End Page
768

Anti-receptor antibody-induced suppression of murine H-Y-specific delayed-type hypersensitivity responses.

A putative anti-H-Y receptor antiserum (ARA) was raised in C57BL/6 male mice against splenic T lymphocytes from syngeneic females immunized against H-Y antigen. When this antiserum is given i.v. to C57BL/6 females it prevents the expression of H-Y-specific delayed-type hypersensitivity (DTH). The suppressive activity in ARA was selectively retained on rabbit anti-mouse immunoglobulin columns, and could be absorbed by H-Y-immune spleen cells from C57BL/6 female mice. The abrogation of H-Y DTH reactivity was at least in part due to the generation of suppressor T cells which are generated by ARA in naive female mice. ARA-generated suppressor cells specifically inhibit the induction phase of DTH responses to the H-Y antigen, having no effect on (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific cutaneous sensitivity responses or on DTH responses to minor histocompatibility antigens. Furthermore, there is a requirement for Igh gene homology between the strain producing the ARA and the strain in which the DTH response is induced. Thus, C57BL/6 ARA given to A.BY (H-2b, Igh-1e) or to B.C-8 (H-2b, Igh-1a) mice was unable to suppress homologous H-Y DTH responses in these strains. However, C57BL/6 ARA induced suppressor cells in B.C-8 mice which were capable of inhibiting H-Y DTH responses when adoptively transferred to C57BL/6 females.

Authors
Sunday, ME; Weinberger, JZ; Wolff, S; Dorf, ME
MLA Citation
Sunday, ME, Weinberger, JZ, Wolff, S, and Dorf, ME. "Anti-receptor antibody-induced suppression of murine H-Y-specific delayed-type hypersensitivity responses." Eur J Immunol 11.8 (August 1981): 626-631.
PMID
6168472
Source
pubmed
Published In
European Journal of Immunology
Volume
11
Issue
8
Publish Date
1981
Start Page
626
End Page
631
DOI
10.1002/eji.1830110807

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. VIII. Suppressor cell pathways in cutaneous sensitivity responses.

In the current study, we examine the mechanism of suppression of cutaneous sensitivity (CS) responses to 4-hydroxy-3-nitrophenyl acetyl succinimide ester. Intravenous administration of haptenated syngeneic spleen cells induces a state of hapten-specific tolerance involving I-J bearing suppressor T cells that function at either the induction phase or the effector phase of the CS response. The effective phase suppressor cells (Tse) are genetically restricted by both Igh and H-2 region genes. However, a third cell population is also required in he immune lymphocyte population for immune suppression. This third cell population, termed Ts3, is an I-J+, cyclophosphamide-sensitive T cell, as shown by reconstitution experiments. Further, the Tse-Ts3 interaction is restricted by genes in he H-2 and Igh gene complexes. The results are discussed with respect to the pathway of cellular interactions leading to immuno suppression.

Authors
Sunday, ME; Benacerraf, B; Dorf, ME
MLA Citation
Sunday, ME, Benacerraf, B, and Dorf, ME. "Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. VIII. Suppressor cell pathways in cutaneous sensitivity responses." J Exp Med 153.4 (April 1, 1981): 811-822.
PMID
6454741
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
153
Issue
4
Publish Date
1981
Start Page
811
End Page
822

Increased adhesion of erythrocytes to endothelial cells in diabetes mellitus.

Authors
Sunday, ME
MLA Citation
Sunday, ME. "Increased adhesion of erythrocytes to endothelial cells in diabetes mellitus." New England Journal of Medicine 305.22 (1981): 1350-1351.
PMID
7290164
Source
scival
Published In
New England Journal of Medicine
Volume
305
Issue
22
Publish Date
1981
Start Page
1350
End Page
1351

Suppressor cell pathways in cutaneous sensitivity responses to 4-hydroxy-3-nitrophenyl, acetyl (NP)

Authors
Sunday, ME; Benacerraf, B; Dorf, ME
MLA Citation
Sunday, ME, Benacerraf, B, and Dorf, ME. "Suppressor cell pathways in cutaneous sensitivity responses to 4-hydroxy-3-nitrophenyl, acetyl (NP)." Federation Proceedings 40.3 II (1981): No.-4697.
Source
scival
Published In
Federation Proceedings
Volume
40
Issue
3 II
Publish Date
1981
Start Page
No.
End Page
4697

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. VI. Evidence for different T cell receptors in cells that mediate H-21-restricted and H-2D-restricted cutaneous sensitivity responses.

We have previously shown that cross-reactive sensitivity (CS) responses induced by 4-hydroxy-3-nitrophenyl acetyl-O-succinimide (NP-O-Su) and elicited by its 5-iodo analogue, 4-hydroxy-5-iodo-3-nitrophenyl acetyl-O-succinimide were observed in strains of mice possessing the Igh-1b allotype, but not in strains bearing allotypes Igh-1c or Igh-1j. These CS responses are mediated by T cells and can be transferred to naive recipients that are homologous at either the H-2K, H-2I, or H-2D regions of the major histocompatibility complex. We now extend our analysis of cross-reactive 4-hydroxy-3-nitrophenyl-acetyl (NP)-induced CS responses to inbred strains of mice expressing additional Igh-1 allotypes. In contrast to NP-induced delayed-type hypersensitivity responses, which only display 4-hydroxy-5-iodo-3-nitrophenyl acetyl (NIP) cross-reactivity in Igh-1b-bearing mice, cross-reactive CS responses can also be elicited in NP-primed mice carrying the Igh-1d, Igh-1e, or Igh-1f allotypes. Moreover, cross-reactive NP-induced CS responses could be transferred by NP-O-Su-primed lymph node cells from the AKR (Igh-1d) strain, into naive recipients homologous at the H-2D region, but only non-cross-reactive NP responses could be transferred into strains homologous at the H-2I region. Furthermore, the lack of cross-reactivity in the Igh-1j-bearing C3H strain was not the result of an inability of these mice to recognize NP in association with H-2K/D products, because NP-O-Su-primed cells from C3H donors transferred NP-specific CS responses into both H-2D and H02I homologous recipients. The results are discussed with respect to the nature of the T cell receptors that control NP responses.

Authors
Sunday, ME; Benacerraf, B; Dorf, ME
MLA Citation
Sunday, ME, Benacerraf, B, and Dorf, ME. "Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. VI. Evidence for different T cell receptors in cells that mediate H-21-restricted and H-2D-restricted cutaneous sensitivity responses." J Exp Med 152.6 (December 1, 1980): 1554-1562.
PMID
6969772
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
152
Issue
6
Publish Date
1980
Start Page
1554
End Page
1562

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl.

The primary anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibody response is known to have a heteroclitic fine specificity, i.e., anti-NP antibodies bind (4-hydroxy-5-iodo-3-nitrophenyl)acetyl (NIP) with greater affinity than NP itself. Past studies of NP-specific DTH responses and NP-specific T cell-mediated suppression have demonstrated sharing of fine specificity patterns and idiotypic structure between receptors on NP-specific T cells and anti-NP antibodies. We now analyze the fine specificity of NP-specific cutaneous sensitivity (CS) reactions to NP-O-succinimide (NP-O-Su) and NIP-O-succinimide (NIP-O-Su). The specificity of these responses is shown to be controlled by genes in the Igh gene complex. Cross-reactive CS responses induced by NP-O-Su elicited by NIP-O-Su were observed in strains of mice possessing the Igh-1b allotype but not in strains bearing the Igh-1c or Igh-1j allotypes. The CS reactivity could be adoptively transferred to naive recipients, and the ability of transfer CS reactivity was T cell dependent. In contrast to the genetic requirement for I-A region homology to adoptively transfer DTH reactions, compatibility at either the H-2K, H-21, or H-2D regions was sufficient to transfer NP-specific CS reactivity to naive recipients. Furthermore, in contrast to DTH responses, cyclophosphamide pretreatment was not required to induce CS responsiveness. Thus, the specificity of NP-O-Su-induced CS responses is controlled by both H-2- and Igh-linked genes.

Authors
Sunday, ME; Weinberger, JZ; Benacerraf, B; Dorf, ME
MLA Citation
Sunday, ME, Weinberger, JZ, Benacerraf, B, and Dorf, ME. "Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl." J Immunol 125.4 (October 1980): 1601-1605.
PMID
6967910
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
125
Issue
4
Publish Date
1980
Start Page
1601
End Page
1605

Genetics of hapten specific contact sensitivity to 4-hydroxy-3-nitrophenyl succinimide ester in the mouse

Authors
Sunday, ME; Weinberger, JZ; Dorf, ME; Benacerraf, B
MLA Citation
Sunday, ME, Weinberger, JZ, Dorf, ME, and Benacerraf, B. "Genetics of hapten specific contact sensitivity to 4-hydroxy-3-nitrophenyl succinimide ester in the mouse." Federation Proceedings 39.3 II (1980): 4871--.
Source
scival
Published In
Federation Proceedings
Volume
39
Issue
3 II
Publish Date
1980
Start Page
4871-

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. IV. Specificity of cutaneous sensitivity responses

The primary anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibody response is known to have a heteroclitic fine specificity, i.e., anti-NP antibodies bind (4-hydroxy-5-iodo-3-nitrophenyl)acetyl (NIP) with greater affinity than NP itself. Past studies of NP-specific DTH responses and NP-specific T cell-mediated suppression have demonstrated sharing of fine specificity patterns and idiotypic structure between receptors on NP-specific T cells and anti-NP antibodies. The authors now analyze the fine specificity of NP-specific cutaneous sensitivity (CS) reactions to NP-O-succinimide (NP-O-Su) and NIP-O-succinimide (NIP-O-Su). The specificity of these responses is shown to be controlled by genes in the Igh gene complex. Cross-reactive CS responses induced by NP-O-Su elicited by NIP-O-Su were observed in strains of mice possessing the Igh-1(b) allotype but not in strains bearing the Igh-1(c) or Igh-1(j) allotypes. The CS reactivity could be adoptively transferred to naive recipients, and the ability of transfer CS reactivity was T cell dependent. In contrast to the genetic requirement for I-A region homology to adoptively transfer DTH reactions, compatibility at either the H-2K, H-2I, or H-2D regions was sufficient to transfer NP-specific CS reactivity to naive recipients. Furthermore, in contrast to DTH responses, cyclophosphamide pretreatmemt was not required to induce CS responsiveness. Thus, the specificity of NP-O-Su-induced CS responses is controlled by both H-2- and Igh-linked genes.

Authors
Sunday, ME; Wienberger, JZ; Benacerraf, B; Dorf, ME
MLA Citation
Sunday, ME, Wienberger, JZ, Benacerraf, B, and Dorf, ME. "Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. IV. Specificity of cutaneous sensitivity responses." Journal of Immunology 125.4 (1980): 1601-1605.
Source
scival
Published In
Journal of Immunology
Volume
125
Issue
4
Publish Date
1980
Start Page
1601
End Page
1605
Show More

Research Areas:

  • Actins
  • Adult
  • Airway Remodeling
  • Amino Acid Sequence
  • Amphibian Proteins
  • Animals
  • Animals, Genetically Modified
  • Animals, Newborn
  • Antibodies, Monoclonal
  • Antibody Specificity
  • Antigens, Differentiation
  • Antioxidants
  • Apoptosis
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Western
  • Bombesin
  • Bronchi
  • Bronchoalveolar Lavage
  • Bronchopulmonary Dysplasia
  • Calcitonin Gene-Related Peptide
  • Capillary Permeability
  • Carcinoma, Small Cell
  • Cell Culture Techniques
  • Cell Differentiation
  • Cell Division
  • Cell Line
  • Cell Lineage
  • Cell Movement
  • Cell Proliferation
  • Culture Techniques
  • Cytokines
  • Diethylnitrosamine
  • Embryonic and Fetal Development
  • Endothelial Cells
  • Epithelial Cells
  • Epithelium
  • Female
  • Fetus
  • Fibroblasts
  • Fibrosis
  • Flow Cytometry
  • Gastrin-Releasing Peptide
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Expression Regulation, Developmental
  • Gene Targeting
  • Gestational Age
  • Homeostasis
  • Humans
  • Hyperoxia
  • Hyperplasia
  • Hypersensitivity, Delayed
  • Immunity, Innate
  • Immunoenzyme Techniques
  • Immunohistochemistry
  • Infant
  • Infant, Newborn
  • Infant, Premature
  • Infant, Premature, Diseases
  • Interleukin-13
  • Kinetics
  • Leukocytes
  • Lung
  • Lung Diseases
  • Lung Injury
  • Lymphocyte Activation
  • Macrophages
  • Mast Cells
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Confocal
  • Models, Animal
  • Models, Biological
  • Molecular Sequence Data
  • Morphogenesis
  • Muscle, Smooth
  • Neprilysin
  • Neuroendocrine Cells
  • Neurosecretory Systems
  • Organ Culture Techniques
  • Oxygen
  • Phosphorylation
  • Polymerase Chain Reaction
  • Proliferating Cell Nuclear Antigen
  • Pulmonary Alveoli
  • Pulmonary Fibrosis
  • Radiation Injuries
  • Receptors, Bombesin
  • Respiratory System
  • Respiratory Tract Diseases
  • Risk Factors
  • Sensitivity and Specificity
  • Signal Transduction
  • T-Lymphocytes
  • Trachea
  • Vascular Endothelial Growth Factors