Expression of growth factors by airway epithelial cells in a model of chronic asthma: Regulation and relationship to subepithelial fibrosis

Background: Growth factors produced by airway epithelial cells may be important in the pathogenesis of subepithelial fibrosis, a distinctive lesion of chronic human asthma. Objective: To examine the relationship between the development of subepithelial fibrosis and the expression of transforming growth factor-β1 (TGF-β1) and ligands for the epidermal growth factor receptor. Methods: BALB/c mice sensitized to ovalbumin were chronically challenged by inhalation of low levels of antigen, leading to development of subepithelial fibrosis and other changes of airway wall remodelling. Growth factor expression was assessed by immunohistochemistry and enzyme immunoassay. Results: Allergic sensitization directly correlated with airway epithelial expression of both the cleaved, potentially biologically active form of TGF-β1 and of amphiregulin in response to allergen challenge. Accumulation of TGF-β1 was related to remodelling of the airway wall in chronic asthma, whereas expression of amphiregulin did not exhibit a similar relationship. Production of epithelial cell-derived TGF-β1 appeared to be regulated by IL-13, while both IL-13 and CD4⁺ T cells regulated accumulation of TGF-β1. In contrast to results reported in high-level exposure models of airway fibrosis, eosinophils did not appear to be a significant source of TGF-β1. Conclusion: Airway epithelial cell-derived TGF-β1 has a potentially crucial role in the development of airway wall remodelling in asthma. Immunological mechanisms may regulate the release and accumulation of TGF-β1.