Praziquantel Suppresses Liver Fibrosis And Inflammation In Mice Infected With Schistosomiasis Japonica

The main damage caused by schistosomiasis japonica is granuloma around the egg and the liver fibrosis caused by excessive tissues repair in chronic infection. It is reported that the hepatic inflammation in acute stage of schistosomiasis not only mediates the egg granuloma response but is also the priming of activation in fibrosis associated cells. Like other diseases of liver fibrosis, chronic schistosomiasis induces persistent inflammation in liver to activate hepatic stellate cells (HSCs). Activated HSCs express excessive collagen and, while the ability of collagen degradation is reduced. The deposition of excessive extracellular matrix in liver leads to fibrotic liver. Therefore, after the anti-parasite treatment, it is necessary to continue the treatment of anti-inflammation and anti-fibrosis to attenuate the response of egg granuloma and subsequent fibrogenesis in liver.Praziquantel as a safe and effective anti-parasite drug has been used for several years. Recently, some researches suggest that praziquantel may have the effect of anti-inflammation and others suggest that praziquantel may have the effect of immune regulation. However, whether praziquantel can directly inhibit the inflammation and fibrogenesis in liver is not reported, and the potential mechanism of action by praziquantel on cells and tissues of hosts is not clear. If the cheap and safe praziquantel has the effect of anti-inflammation or anti-fibrosis, new strategy of therapy by praziquantel will be benefit for schistosomiasis and praziquantel will become a promising drug in treatment of other diseases of inflammation and fibrosis.In our study, we detected the dynamic gene expression of HSCs in different stages of schistosomiasis mice by microarray in order to find the key genes in liver fibrosis of schistosomiasis. Meanwhile, we established acute and chronic schistosomiasis of mice model and treated them with praziquantel to evaluate the anti-inflammation and anti-fibrosis effect of praziquantel. We also established CCL4–induced liver fibrosis model to further comfier the anti-fibrosis effect of praziquantel. In addition, we investigated the effect of praziquantel on HSCs and macrophage to reveal the probable mechanism.To find the key genes in development of schistosomiasis, we described the dynamic gene expression of HSCs in different stages of mice schistosomiasis by microarray and focused on members of chemokines family expressed on HSCs. Quantigene Plex System was used to validate some gene expression and the dynamic expression was analyzed by bioinformatics to describe the probable role of chemokines in different stages of schistosomiasis. We also detected the gene expression of HSCs in pathogenic cure groups of schistosomiasis mice and compared the results with untreated groups in order to reveal the probable role of chemokines in reversion of liver fibrosis in schistosomiasis. Our results showed that most of chemokine members, such as CXCL5,CCL5,CXCR2,CCR9,CCR7,CCL22,CCR1,CCR2,CCL8,CCL17 were up-regulated in HSCs of 3 weeks group compared with control group. This upregulation suggested that chemokines mediated the infiltration of immune cells and development of inflammatory microenvironment in liver in acute schistosomiasis. Chemokines, such as CXCL9, CXCL10, CXCL11, CCR2, CCR5, CXCR3 were down-regulated in HSCs of 6 weeks group compared with control group. This result suggested that in the stage of severe granuloma response, some chemokines exhibited the down-regulation and this might be due to the antigen released from the egg. While in chronic stages, CCL5, CCL8, CCL9, CCL21, CXCL5 and CCR1 were consistently upregulated and corralted with liver fibrosis of schistosomiasis. After the PZQ treatment, most of the chemokines, such as CXCL9 and CXCL10 were upregulated and they might be involved in resolution of liver fibrosis. In addition, CCL8 and CXCL12, which were considered as pro-fibrosis chemokines were down-regulated. This study will produce some useful clue for anti-fibrosis therapy. In addition, in our vitro experiment we showed the anti-fibrosis effect of CXCL9 and CXCL10 and demonstrated that they inhibited the expression of fibrosis-assciated genes, such as collagens in both the nonparenchymal cell and LX-2. Therefore, this is also a priming to further investigate the therapy of schistosomiasis based on chemokines.In order to investigate the anti-fibrosis effect of praziquantel, we established the mouse schistosomiasis model of liver fibrosis and demonstrated that anti-fibrosis treatment with PZQ significantly improved the hepatic fibrosis of schistosomiasis japonica at both 8 weeks and 15 weeks post-infection of the mouse models, as measured by Sirius Red staining areas and hydroxyproline content. Clinical parameters, such as spleen weight, portal venous pressure and serum ALT were also improved. The activation of HSCs was inhibited too by praziquantel treatment. Praziquantel treatment also significantly reduced liver collagen areas and hydroxyproline content in CCL4–induced liver fibrosis mice. Our study demonstrated that praziquantel has the direct anti-fibrosis effect on fibrotic liver and this effect may be mediated by inhibition of HSCs activation.In order to investigate the anti-inflammation effect of praziquantel, we established the mouse schistosomiasis model of acute infection and demonstrated that expressions of inflammation associated genes were significantly reduced in liver by praziquantel for 7 days. In vitro experiment, we demonstrated that praziquantel inhibited the expression of inflammatory factors and chemokines on hepatic nonparenchymal cells and splenocyte. In further investigation, we found that expressions of inflammatory factors on macrophage were inhibited by praziquantel and this may be one of the mechanisms for anti-inflammation effect of praziquantel. In conclusion, our study described the dynamic expression of HSCs in different stages of schistosomiasis mice by microarray and focused on the role of some chemokines in inflammation and fibrogenesis. Meanwhile, we raised the new insight of praziquantel and revealed that praziquantel has the effect of anti-inflammation and anti-fibrosis. Accurate mechanisms of these effects were needed further investigated.