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

Abstract

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.

Reversible remodeling of lung tissue during hibernation in the Syrian hamster

“…EGFR controls a wide variety of biological processes, including cell proliferation, differentiation, survival and migration. EGFR is induced following lung injury and its deactivation is accompanied by suppression of remodeling in lungs (Kramer et al, 2009). High EGFR expression also leads to production of excess mucus and mucin, which contributes to the obstruction of the bronchioles, and remodeling with an asthmatic phenotype (Burgel and Nadel, 2004;Nadel, 2001) Thus, a downregulation of this protein during torpor may contribute to the reversibility of remodeling in this organ.…”

Essential Roles for Early Growth Response Transcription Factor Egr-1 in Tissue Fibrosis and Wound Healing

“…In contrast, lung fibrosis induced by transgenic TGF-␣ appeared to be exacerbated, rather than prevented, in mice lacking Egr-1. 45 The specific role of Egr-1 in promoting or attenuating lung fibrosis may be determined by the nature of the injury, the extracellular stimuli involved, and the cell types that are critical effectors of the process.…”

CXCR4 inhibitor attenuates ovalbumin-induced airway inflammation and hyperresponsiveness by inhibiting Th17 and Tc17 cell immune response

“…AHR to inhaled methacholine (Sigma-Aldrich) was measured using FlexiVent (SCIREQ Scientific Respiratory Equipment, Inc., Montréal, QC, Canada) (20). The mice were anesthetized by intraperitoneal injection of pentobarbital (50 mg/kg) (Wuhan Sanjiang Space Guge Biotech Co., Ltd., Wuhan, China), tracheotomized, and connected to the FlexiVent.…”