1. ¹Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, Izumo, Japan
2. ²Department of Medicine, Institute of Hepatology, University College of London, London, UK
3. ³Department of Biochemistry, Faculty of Medicine, Shimane University, Izumo, Japan

Correspondence: Dr S Hattori, MD, Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, Enya-cho 89-1, Izumo 693-8501, Shimane, Japan. E-mail: shinji-h@med.shimane-u.ac.jp

Received 9 September 2006; Accepted 21 January 2007; Published online 5 March 2007.

Abstract

Liver cirrhosis remains a difficult-to-treat disease with a substantial morbidity and mortality rate. There is an emerging body of data purporting a pivotal role of the activated p38 mitogen-activated protein kinase (MAPK) in the process of cirrhosis. Several anticirrhotic agents have been developed over the past few years, and most of them exert their effects by indirectly inhibiting the p38 pathway. Effect of a selective p38 inhibitor is yet to be reported. In this study, we evaluated the salutary effect of FR-167653 (FR), a selective p38 inhibitor, in a carbon tetrachloride (CCl₄)-induced rat cirrhotic model. Twenty rats were assigned into four groups: Sham, olive oil only; Control, CCl₄ in olive oil; FR50, FR 50 mg/kg/day and CCl₄; and FR100, FR 100 mg/kg/day and CCl₄. FR dose-dependently inhibited activation of p38 and had an ameliorating effect on cirrhosis formation. Significant dose-dependent reduction in -smooth muscle actin immunostaining and hydroxyproline content of the liver was noticed in the FR-treated rats. Also densitometric analysis showed a significant reduction in azan-stained area in the FR-treated rats. These fibrotic changes were observed in the myofibroblasts including the hepatic stellate cells and portal fibroblasts. mRNA expression of runt-related protein 2 (Runx2), a profibrogenic transcription factor, was significantly low in FR-treated livers, indicating that Runx2 might be a key downstream regulator of the p38 pathway. A similar reduction in expression of Smad4 and tissue inhibitor of metalloproteinase-1 was noticed in the FR-treated rats. In conclusion, FR treatment exerted a significant beneficial effect in a CCl₄-induced rat cirrhotic model. The ameliorating effect of FR could be partially attributable to an inhibition of the Smad4/p38/Runx2 axis in the cirrhotic liver.