Mechanical Stress Triggers Selective Release of Fibrotic Mediators from Bronchial Epithelium

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Abstract
Transforming growth factor- (TGF-) and endothelin (ET) are forming growth factor-2 (TGF-2) protein, without an found in elevated amounts in the airways of individuals with increase in TGF-2 mRNA. These two differentially regu- asthma. The cellular source of these peptides and their role in lated mediators act synergistically to promote a profibrotic mediating the airway fibrosis of chronic asthma are unknown. microenvironment. In response to mechanical stresses similar to those occurring in vivo during airway constriction, bronchial epithelial cells in- Materials and Methods crease the steady-state level of mRNA for both ET-1 and ET-2, followed by increased release of ET protein. Mechanical stress Materials also enhances release of TGF-2 from a preformed cell-associ- Normal human bronchial epithelial (NHBE) cells were obtained ated pool. TGF-2 and ET act individually and, more impor- from Clonetics-BioWhittaker (Walkersville, MD), and human lung tantly, synergistically to promote fibrotic protein synthesis in fibroblasts (CCL-186) were obtained from the American Type reporter fibroblasts. To confirm the role of these intermediates Culture Collection (Rockville, MD). Plasmin, ET-1, ET-2, and ET in stress-induced fibrosis, conditioned medium from mechani- receptor antagonists (BQ 788 and BQ 485) were purchased from cally stressed bronchial epithelial cells was shown to elicit fi- Calbiochem (San Diego, CA). The enzyme-linked immunosorbent brotic protein synthesis in reporter fibroblasts; this effect was assay (ELISA) kit for measuring endothelin was from Peninsula significantly inhibited by combined treatment with ET receptor Laboratories (San Carlos, CA). Recombinant TGF-2, neutraliz- antagonists and a neutralizing antibody to TGF-2. These data ing antibody for TGF-2, and ELISA kits for TGF-2, TGF-1, are consistent with a primary pathogenic role for mechanical platelet-derived growth factor (PDGF) AB, and PDGF BB were stress-induced release of both TGF-2 and ET in the subepithel- from R&D Systems (Minneapolis, MN). Rabbit polyclonal anti- ial fibrosis that characterizes chronic asthma.

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