Sorafenib and praziquantel synergistically attenuate Schistosoma japonicum-induced liver fibrosis in mice.

Abstract

Liver fibrosis is an important process that occurs in most types of chronic liver diseases and often results in the end stage of liver diseases, such as cirrhosis, portal hypertension, and hepatocellular carcinoma. Sorafenib, a multiple tyrosine kinase inhibitor, has been shown to inhibit liver fibrosis in multiple experimental fibrosis mouse and rat models. The aim of this study was to test the therapeutic effect of sorafenib on liver fibrosis induced by infection with a parasite, Schistosoma japonicum, in mice. Mice were percutaneously infected through the abdomen with Schistosoma cercariae to develop a schistosomula liver fibrosis model. Eight weeks after infection, infected mice were treated with the anti-parasitic agent praziquantel for 2days and sorafenib for 2weeks. Hepatic histopathological changes were assessed using hematoxylin and eosin (HE) and Masson's trichome staining. The hepatic expression levels of collagen I, collagen III, alpha-smooth muscle actin (α-SMA), platelet-derived growth factor (PDGF), and PDGF receptor-beta (PDGFR-β) were analyzed by immunohistochemistry and western blot. Praziquantel administration alone but not sorafenib reduced liver fibrosis, and the combination of praziquantel and sorafenib significantly attenuated liver fibrosis in S. japonicum-infected mice. Moreover, sorafenib plus praziquantel markedly decreased the hepatic deposition of collagen and expression of fibrogenic genes in these mice. In conclusion, the use of sorafenib following praziquantel treatment may represent a potential therapeutic strategy for liver fibrosis induced by S. japonicum in patients.