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
(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.