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Early Growth Response-1 Suppresses Epidermal Growth Factor Receptor–Mediated Airway Hyperresponsiveness and Lung Remodeling in Mice

¹ Section of Neonatology, Perinatal & Pulmonary Biology, ² Divisions of Pathology, ³ Asthma Research, ⁴ Allergy and Immunology, and ⁵ Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to Tim Le Cras, Ph.D., Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229. E-mail: tim.lecras{at}cchmc.org

Transforming growth factor (TGF)- 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- 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- in airway epithelium (Clara cell secretory protein–rtTA^+/–/[tetO]₇–TGF-^+/–). The goal of this study was to determine the role of Egr-1 in TGF-–induced lung disease. To accomplish this, TGF-–transgenic mice were crossed to Egr-1 knockout (Egr-1^ko/ko) mice. The lack of Egr-1 markedly increased the severity of TGF-–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.

Key Words: transforming growth factor- • pulmonary fibrosis • asthma • pulmonary hypertension • vascular remodeling

CLINICAL RELEVANCE This study demonstrates that loss of early growth response-1 exacerbates transforming growth factor-–induced lung disease in mice, characterized by dramatic airway smooth muscle (ASM) hyperplasia, hyperresponsiveness, and fibrosis. This noninflammatory model of lung remodeling may facilitate the testing of experimental therapies to inhibit airway and vascular smooth muscle remodeling without the complicating effects of inflammation. This is pertinent, as recent clinical studies have suggested that targeted elimination of ASM improves outcome in asthma.