Triggering the induction of myofibroblast and fibrogenesis by airway epithelial shedding

Myofibroblasts have been thought to participate in subepithelial fibrosis i n asthma, but the mechanism of myofibroblast induction has not been fully u nderstood. In this study we investigated injury-related myofibroblast induc tion in a coculture system of guinea-pig epithelial cells and fibroblasts c ocultured in a human amnion chamber. After pseudostratified epithelial cell s were mechanically scraped, migrated flat epithelial cells differentiated into cuboidal appearances on Day 4 and then returned to their original shap es on Day 8, During the course of the epithelial redifferentiation, it was found by Northern blot analysis, immunohistochemistry for alpha -smooth mus cle actin, and electron microscopic observation that the myofibroblasts wer e transiently induced on Day 4. The myofibroblast induction was inhibited b y the blocking of transforming growth factor (TGF)-beta1 and thrombospondin (TSP)-1, indicating that the activation of TGF-beta1 by TSP-1 would induce myofibroblasts, This finding was also supported by a transient upregulatio n of TSP immunoreactivity and TSP-1 messenger RNA (mRNA) in fibroblasts. In terestingly, epithelial injury reduced TGF-beta1 immunoreactivity in the am nion membrane but did not affect TGF-beta1 mRNA in epithelial cells and fib roblasts, indicating that TGF-beta1 supplied from the extracellular matrix can participate in myofibroblast induction. Concurrently with myofibroblast induction, procollagen type I and III mRNAs were upregulated in fibroblast s, and obvious collagen deposition was observed ultrastructurally around th e myofibroblasts compared with the fibroblasts. These results indicate that induced myofibroblasts can be functionally more active in producing collag en than are resting fibroblasts. The present study suggests that epithelial injury stimulates TGF-beta1 release from the extracellular matrix and its activation via TSP-1 production, causing collagen synthesis through myofibr oblast induction.