Early growth response-1 suppresses epidermal growth factor receptor-mediated airway hyperresponsiveness and lung remodeling in mice.
Transforming growth factor (TGF)-alpha and its receptor, the epidermal growth factor receptor, are induced after 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, 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 (Clara cell secretory protein-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-1(ko/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-1(ko/ko) mice. Thus, Egr-1 acts to suppress epidermal growth factor receptor-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.
Kramer
Elizabeth L
EL
Section of Neonatology, Perinatal & Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
Mushaben
Elizabeth M
EM
Pastura
Patricia A
PA
Acciani
Thomas H
TH
Deutsch
Gail H
GH
Khurana Hershey
Gurjit K
GK
Korfhagen
Thomas R
TR
Hardie
William D
WD
Whitsett
Jeffrey A
JA
Le Cras
Timothy D
TD
D000403:Airway Resistance; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D006965:Hyperplasia; D008168:Lung / Q000473:pathology*; D008170:Lung Compliance; D016210:Methacholine Chloride / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D011651:Pulmonary Artery / Q000166:cytology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000009:adverse effects / Q000502:physiology*; D015431:Weight Loss
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha; D016210:Methacholine Chloride; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D000420:Albuterol