BACKGROUND & AIMS: Proteolytic release and activation of latent transforming growth factor beta (TGF-beta) by the hepatic stellate cells (HSCs) are key events for pathogenesis of hepatic fibrosis, and protease inhibitors suppress TGF-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: 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)[I]), and fibrosis (Azan-staining and quantification of hydroxyproline content). RESULTS: Camostat mesilate (500 micromol/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: Camostat mesilate prevents porcine serum-induced rat hepatic fibrosis via a profound reduction in TGF-beta generation.
BACKGROUND & AIMS: Proteolytic release and activation of latent transforming growth factor beta (TGF-beta) by the hepatic stellate cells (HSCs) are key events for pathogenesis of hepatic fibrosis, and protease inhibitors suppress TGF-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: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)[I]), and fibrosis (Azan-staining and quantification of hydroxyproline content). RESULTS:Camostat mesilate (500 micromol/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:Camostat mesilate prevents porcine serum-induced rathepatic fibrosis via a profound reduction in TGF-beta generation.
Authors: Angela Douglass; Karen Wallace; Matthew Koruth; Caroline Barelle; Andrew J Porter; Matthew C Wright Journal: Hepatol Int Date: 2008-09-03 Impact factor: 6.047
Authors: Olivier Bardou; Awen Menou; Charlène François; Jan Willem Duitman; Jan H von der Thüsen; Raphaël Borie; Katiuchia Uzzun Sales; Kathrin Mutze; Yves Castier; Edouard Sage; Ligong Liu; Thomas H Bugge; David P Fairlie; Mélanie Königshoff; Bruno Crestani; Keren S Borensztajn Journal: Am J Respir Crit Care Med Date: 2016-04-15 Impact factor: 21.405