TY - JOUR
T1 - Prevention of rat hepatic fibrosis by the protease inhibitor, camostat mesilate, via reduced generation of active TGF-β
AU - Okuno, Masataka
AU - Akita, Kuniharu
AU - Moriwaki, Hisataka
AU - Kawada, Norifumi
AU - Ikeda, Kazuo
AU - Kaneda, Kenji
AU - Suzuki, Yasuhiro
AU - Kojima, Soichi
PY - 2001
Y1 - 2001
N2 - Background & Aims: Proteolytic release and activation of latent transforming growth factor β (TGF-β) by the hepatic stellate cells (HSCs) are key events for pathogenesis of hepatic fibrosis, and protease inhibitors suppress TGF-β 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-β, TGF-β activity, activated HSC markers (increased cell number, morphologic change, and expression of both α-smooth muscle actin and collagenα2[I]), and fibrosis (Azan-staining and quantification of hydroxyproline content). Results: Camostat mesilate (500 μmol/L) inhibited generation of TGF-β by suppressing plasmin activity and reduced the activity of TGF-β, 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-β 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-β generation.
AB - Background & Aims: Proteolytic release and activation of latent transforming growth factor β (TGF-β) by the hepatic stellate cells (HSCs) are key events for pathogenesis of hepatic fibrosis, and protease inhibitors suppress TGF-β 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-β, TGF-β activity, activated HSC markers (increased cell number, morphologic change, and expression of both α-smooth muscle actin and collagenα2[I]), and fibrosis (Azan-staining and quantification of hydroxyproline content). Results: Camostat mesilate (500 μmol/L) inhibited generation of TGF-β by suppressing plasmin activity and reduced the activity of TGF-β, 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-β 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-β generation.
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U2 - 10.1053/gast.2001.24832
DO - 10.1053/gast.2001.24832
M3 - Article
C2 - 11375959
AN - SCOPUS:0035022130
VL - 120
SP - 1784
EP - 1800
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 7
ER -