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

Citation
M. Okuno et al., Prevention of rat hepatic fibrosis by the protease inhibitor, camostat mesilate, via reduced generation of active TGF-beta, GASTROENTY, 120(7), 2001, pp. 1784-1800
Citations number
61
Categorie Soggetti
Gastroenerology and Hepatology","da verificare
Journal title
GASTROENTEROLOGY
ISSN journal
00165085 → ACNP
Volume
120
Issue
7
Year of publication
2001
Pages
1784 - 1800
Database
ISI
SICI code
0016-5085(200106)120:7<1784:PORHFB>2.0.ZU;2-L
Abstract
(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 inh ibitors suppress IGF-beta generation by cultured HSCs, suggesting their pot ential use as antifibrogenic agents, We explored this idea using camostat m esilate, a serine protease inhibitor, to determine its effects and mechanis ms of action in vivo. (Methods) under bar: Camostat mesilate was either add ed to cultured rat HSCs or administered orally to rats during porcine serum treatment, followed by overexpression of urokinase. We measured cellular a nd hepatic levels of plasmin, TGF-beta, TGF-beta activity, activated HSC ma rkers (increased cell number, morphologic change, and expression of both al pha -smooth muscle actin and collagen alpha2[1]), and fibrosis (Azan-staini ng and quantification of hydroxyproline content). (Results) under bar: Camo stat mesilate (500 mu mol/L) inhibited generation of TGF-beta by suppressin g plasmin activity and reduced the activity of TGF-beta, which blocked in v itro 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 le vels, HSC activation, and hepatic fibrosis without apparent systemic or loc al side effects, all of which were reverted by restoration of hepatic plasm in activity. (Conclusions) under bar: Camostat mesilate prevents porcine se rum-induced rat hepatic fibrosis via a profound reduction in TGF-beta gener ation.