| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2002: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
Background & Aims : A definitive therapy has not been developed for hepatic fibrosis. Proteolytic release and activation of latent 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 anti-fibrogenic agents. We explored this idea by employing 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. We measured cellular and hepatic levels of plasmin, TGF-β, TGF-β activity, activated HSC markers (stimulated proliferation, morphological change, and expression of α-smooth muscle actin), and fibrosis (Azan-staining and quantification of hydroxyproline content). Results : Camostat mesilate (500 μM) inhibited generation of TGF-β by suppressing plasmin activity and reduced the activity of TGF-β, which blocked in vitro activation of HSCs. In in vivo model, camostat mesilate (1-2 mg/g of diet) markedly attenuated a rise in hepatic plasmin and TGF-β levels, HSC activation, and hepatic fibrosis without apparent systemic or local side effects. Conclusion : Camostat mesilate prevents porcine serum-induced rat hepatic fibrosis via a profound reduction in TGF-β generation as well as interfering with its activity.
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