Abstract
Severe cholestatic liver injury diseases, such as obstructive jaundice and the subsequent acute obstructive cholangitis, are induced by biliary tract occlusion. Heat shock protein 90 (HSP90) inhibitors have been demonstrated to be protective for various organs. The potential of HSP90 inhibitors in the treatment of cholestatic liver injury, however, remains unclear. In the present study, rat models of bile duct ligation (BDL) were established, the HSP90 inhibitor 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG) was administered, and its ability to ameliorate the cholestasis-induced liver injuries was evaluated. In the BDL rat models and clinical samples, increased HSP90 expression was observed to be associated with cholestatic liver injury. Furthermore, 17-DMAG alleviated cholestasis-induced liver injury in the rat models, as revealed by the assessment of pathological changes and liver function. In addition, 17-DMAG protected hepatocytes against cholestatic injury in vitro. Further assays indicated that 17-DMAG administration prevented cholestasis-induced liver injury in the rats by decreasing the expression of interleukin (IL)-1β and IL-18. Moreover, 17-DMAG also decreased the cholestasis-induced upregulation of IL-1β and IL-18 in liver sinusoidal endothelial cells in vitro. In conclusion, the HSP90 inhibitor 17-DMAG is able to prevent liver injury in rats with biliary obstruction, and this phenomenon is associated with the reduction of IL-1β and IL-18 expression.