THROMBIN STIMULATES FIBROBLAST PROCOLLAGEN PRODUCTION VIA PROTEOLYTICACTIVATION OF PROTEASE-ACTIVATED RECEPTOR-1

Thrombin is a multifunctional serine protease that has a crucial role in blood coagulation. It is also a potent mesenchymal cell mitogen and chemoattractant and might therefore have an important role in the rec ruitment and local proliferation of mesenchymal cells at sites of tiss ue injury. We hypothesized that thrombin might also affect the deposit ion of connective tissue proteins at these sites by directly stimulati ng fibroblast procollagen production. To address this hypothesis, the effect of thrombin on procollagen production and gene expression by hu man foetal lung fibroblasts was assessed over 48 h. Thrombin stimulate d procollagen production at concentrations of 1nM and above, with maxi mal increases of between 60 and 117 % at 10 nM thrombin. These effects of thrombin were, at least in part, due to increased steady-state lev els of alpha(1)(I) procollagen mRNA, They could furthermore be reprodu ced with thrombin receptor-activating peptides for the protease-activa ted receptor 1 (PAR-1) and were completely abolished when thrombin was rendered proteolytically inactive with the specific inhibitors DPhe-P ro-ArgCH(2)Cl and hirudin, indicating that thrombin is mediating these effects via the proteolytic activation of PAR-1. These results sugges t that thrombin might influence the deposition of connective tissue pr oteins during normal wound healing and the development of tissue fibro sis by stimulating fibroblast procollagen production.