Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2

Mast cells play a potentially important role in fibroproliferative diseases , releasing mediators including tryptase that are capable of stimulating fi broblast proliferation and procollagen synthesis. The mechanism by which tr yptase stimulates fibroblast proliferation is unclear, although recent stud ies suggest it can activate protease-activated receptor (PAR)-2. We therefo re investigated the role of PAR-2 in tryptase-induced proliferation of huma n fetal lung and adult lung parenchymal and airway fibroblasts and, for com parative purposes, adult dermal fibroblasts. Tryptase (0.7-70 mU/ml) induce d concentration-dependent increases in proliferation of all fibroblasts stu died. Antipain, bis(5-amidino-2-benzimidazolyl)methane, and benzamidine inh ibited tryptase-induced fibroblast proliferation, demonstrating that proteo lytic activity is required for the proliferative effects of tryptase. RT-PC R demonstrated the presence of PAR-2 mRNA, and immunohistochemical staining localized PAR-2 to the cell surface of lung fibroblasts. In addition, spec ific PAR-2 activating peptides, SLIGKV and SLIGRL, mimicked the proliferati ve effects of tryptase. In contrast, human dermal fibroblasts only weakly s tained with the PAR-2 antibody, PAR-2 mRNA was almost undetectable, and fib roblasts did not respond to PAR-2 activating peptides. These results sugges t that tryptase induces lung, but not dermal, fibroblast proliferation via activation of PAR-2 and are consistent with the hypothesis that the release of tryptase from activated mast cells may play an important role in the fi broproliferative response observed in asthma, chronic obstructive pulmonary disease, and patients with pulmonary fibrosis.