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

Masataka Okuno, Kuniharu Akita, Hisataka Moriwaki, Norifumi Kawada, Kazuo Ikeda, Kenji Kaneda, Yasuhiro Suzuki, Soichi Kojima

Research output: Contribution to journalArticlepeer-review

120 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1784-1800
Number of pages17
JournalGastroenterology
Volume120
Issue number7
DOIs
Publication statusPublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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