Airway eptihelial compression: a stimulus for airway remodeling in asthma

摘要

The airway wall undergoes significant remodeling in asthmatic patients, characterized by airway wall thickening, subepithelial fibrosis, increased myocyte muscle mass, myofibroblast hyperplasia, and mucus metaplasia [reviewed in 1]. These changes are thought to contribute to airway hyperresponsiveness, and are widely attributed to the inflammatory environment of the asthmatic airway. We have proposed that the mechanical stress that accompanies bronchoconstriction, a characteristic of the asthmatic response, may contribute to airway remodeling. In support of this hypothesis, we have previously demonstrated that in the absence of a superimposed inflammatory stimulus, transcellular pressure applied to rat tracheal epithelial cells is capable of eliciting increased expression of TGF-β, endothelin-l, and EGR-1[2]. Identical compressive stresses applied across human bronchial epithelial cells can increase fibrotic protein synthesis in co-cultured fibroblasts [3]. Although these data demonstrate that compressive stress of bronchial epithelial cells is profibrotic, the effect of compressive stress on factors responsible for recruiting fibroblasts and smooth muscle cells, and promoting their proliferation is not well characterized. To address this question we focus here on expression of heparin binding epidermal growth factor-like growth factor (HB-EGF) and on a more detailed analysis of endothelin gene expression and protein secretion. HB-EGF, a member of the EGF family, is a potent mitogen and chemotactic factor for fibroblasts, as well as smooth muscle and epithelial cells [4]. The endothelins (Et- 1,2,3) are best known as potent bronchoconstrictors, but El- 1 and Et-2 are also mitogenic for fibroblasts and smooth muscle cells, chemotactic for fibroblasts, and pro-inflammatory [5]. These molecules therefore have the capacity to participate in many of the changes that characterize airway remodeling.