Rebamipide retards CCl₄-induced hepatic fibrosis in rats: Possible role for PGE₂

Abstract

Prostaglandin E 2 (PGE 2 ) is a potent physiological suppressor of liver fibrosis. Because the anti-ulcer drug rebamipide can induce the formation of endogenous PGE 2 , this study investigated the potential effects of rebamipide on development of a hepatic fibrosis that was inducible by carbon tetrachloride (CCl 4 ). Groups of Wistar rats received intraperitoneal (IP) injections of CCl 4 (0.45 ml/kg [0.72 g CCl 4 /kg]) over the course of for 4 weeks. Sub-sets of CCl 4 -treated rats were also treated concurrently with rebamipide at 60 or 100 mg/kg. At 24 h after the final treatments, liver function and oxidative stress were indirectly assessed. The extent of hepatic fibrosis was evaluated using two fibrotic markers, hyaluronic acid (HA) and pro-collagen-III (Procol-III); isolated liver tissues underwent histology and were evaluated for interleukin (IL)-10 and PGE 2 content. The results indicated that treatment with rebamipide significantly inhibited CCl 4 -induced increases in serum ALT and AST and also reduced oxidative stress induced by CCl 4 . Fibrotic marker assays revealed that either dose of rebamipide decreased the host levels of Procol-III and HA that had become elevated due to the CCl 4 . At the higher dose tested, rebamipide appeared to be able to permit the hosts to have a normal liver histology and to minimize any CCl 4 -induced collagen precipitation in the liver. Lastly, the use of rebamipide was seen to be associated with significant increases in liver levels of both PGE 2 and the anti-inflammatory cytokine IL-10. Based on these findings, it is concluded that rebamipide can retard hepatic fibrosis induced by CCl 4 and that this effect may, in part, be mediated by an induction of PGE 2 and IL-10 in the liver itself. ARTICLE HISTORY

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