Abstract

Prostaglandin E₂ (PGE₂) is a potent physiological suppressor of liver fibrosis. Because the anti-ulcer drug rebamipide can induce the formation of endogenous PGE₂, this study investigated the potential effects of rebamipide on development of a hepatic fibrosis that was inducible by carbon tetrachloride (CCl₄). Groups of Wistar rats received intraperitoneal (IP) injections of CCl₄ (0.45 ml/kg [0.72 g CCl₄/kg]) over the course of for 4 weeks. Sub-sets of CCl₄-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 PGE₂content. The results indicated that treatment with rebamipide significantly inhibited CCl₄-induced increases in serum ALT and AST and also reduced oxidative stress induced by CCl₄. 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 CCl₄. At the higher dose tested, rebamipide appeared to be able to permit the hosts to have a normal liver histology and to minimize any CCl₄-induced collagen precipitation in the liver. Lastly, the use of rebamipide was seen to be associated with significant increases in liver levels of both PGE₂ and the anti-inflammatory cytokine IL-10. Based on these findings, it is concluded that rebamipide can retard hepatic fibrosis induced by CCl₄ and that this effect may, in part, be mediated by an induction of PGE₂ and IL-10 in the liver itself.