help button home button
AJRCMB
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Published ahead of print on February 2, 2009, doi:10.1165/rcmb.2008-0470OC

Am. J. Respir. Cell Mol. Biol., Volume 41, Number 4, October 2009, 415-425

A more recent version of this article appeared on October 1, 2009
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2008-0470OCv1
41/4/415    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kramer, E. L
Right arrow Articles by Le Cras, T. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kramer, E. L
Right arrow Articles by Le Cras, T. D.

Submitted on December 4, 2008
Accepted on February 2, 2009

Egr-1 Suppresses EGFR-Mediated Airway Hyperresponsiveness and Lung Remodeling in Mice

Elizabeth L Kramer1, Elizabeth M Mushaben2, Patricia A Pastura2, Thomas H Acciani2, Gail H Deutsch3, Gurjit K Khurana Hershey4, Thomas R Korfhagen1, William D Hardie5, Jeffrey A Whitsett1, and Timothy D. Le Cras1*

1 Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States, 2 Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States, 3 Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States, 4 Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States, 5 Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States

* To whom correspondence should be addressed. E-mail: tim.lecras{at}cchmc.org.

Transforming growth factor-alpha (TGF-{alpha}) and its receptor, the epidermal growth factor receptor (EGFR), are induced following lung injury and are associated with remodeling in chronic pulmonary diseases such as pulmonary fibrosis and asthma. Expression of TGF-{alpha} in the lungs of adult mice causes fibrosis, pleural thickening, and pulmonary hypertension (PH) in addition to increased expression of a transcription factor, early growth response-1 (Egr-1). Egr-1 was increased in airway smooth muscle (ASM) and the vascular adventitia in the lungs of mice conditionally expressing TGF-{alpha} in airway epithelium (CCSP-rtTA+/-/(tetO)7-TGF-{alpha}+/-). The goal of this study was to determine the role of Egr-1 in TGF-{alpha} induced lung disease. To accomplish this, TGF-{alpha} transgenic mice were crossed to Egr-1 knockout (Egr-1ko/ko) mice. The lack of Egr-1 markedly increased the severity of TGF-{alpha} induced pulmonary disease, dramatically enhancing airway muscularization, increasing pulmonary fibrosis, and causing greater airway hyperresponsiveness to methacholine. Smooth muscle hyperplasia, not hypertrophy, caused the ASM thickening in the absence of Egr-1. No detectable increases in pulmonary inflammation were found. In addition to the airway remodeling disease, vascular remodeling and pulmonary hypertension were also more severe in Egr-1ko/ko mice. Thus, Egr-1 acts to suppress EGFR-mediated airway and vascular muscularization, fibrosis, and airway hyperresponsiveness in the absence of inflammation. This provides a unique model to study the processes causing pulmonary fibrosis and ASM thickening without the complicating effects of inflammation.
Key words: TGF-alpha • pulmonary fibrosis • asthma • pulmonary hypertension • vascular remodeling






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2009 American Thoracic Society. 		  The ATS Has Opened Search for New PATS Editor