Prevention of rat hepatic fibrosis by the protease inhibitor, camostat mesilate, via reduced generation of active TGF-β

(Background & Aims) under bar: Proteolytic release and activation of latent transforming growth factor beta (TGF-beta) by the hepatic stellate cells (HSCs) are hey events for pathogenesis of hepatic fibrosis, and protease inhibitors suppress IGF-beta generation by cultured HSCs, suggesting their potential use as antifibrogenic agents, We explored this idea using camostat mesilate, a serine protease inhibitor, to determine its effects and mechanisms of action in vivo. (Methods) under bar: Camostat mesilate was either added to cultured rat HSCs or administered orally to rats during porcine serum treatment, followed by overexpression of urokinase. We measured cellular and hepatic levels of plasmin, TGF-beta, TGF-beta activity, activated HSC markers (increased cell number, morphologic change, and expression of both alpha -smooth muscle actin and collagen alpha2[1]), and fibrosis (Azan-staining and quantification of hydroxyproline content). (Results) under bar: Camostat mesilate (500 mu mol/L) inhibited generation of TGF-beta by suppressing plasmin activity and reduced the activity of TGF-beta, which blocked in vitro activation of HSCs, In the in vivo model, camostat mesilate (1-2 mg/g of diet) markedly attenuated an increase in hepatic plasmin and TGF-beta levels, HSC activation, and hepatic fibrosis without apparent systemic or local side effects, all of which were reverted by restoration of hepatic plasmin activity. (Conclusions) under bar: Camostat mesilate prevents porcine serum-induced rat hepatic fibrosis via a profound reduction in TGF-beta generation.