司曲替尼对四氯化碳诱导的肝纤维化小鼠模型的影响及其作用机制OA

Objective To investigate the therapeutic effect of sitravatinib on carbon tetrachloride(CCl4)-induced liver fibrosis in mice.Methods A total of 30 male C57BL/6J mice,aged 8 weeks,were randomly divided into control group,CCl4 model group,and low-(5 mg/kg),middle-(10 mg/kg),and high-dose(20 mg/kg)sitravatinib groups.All mice except those in the control group were given intraperitoneal injection of CCl4 for 4 consecutive weeks to induce liver fibrosis,and since the first day of modeling,the mice in the low-,middle-,and high-dose sitravatinib groups were given sitravatinib at the corresponding dose by gavage every day.The serum levels of total cholesterol(TC),triglyceride(TG),and alanine aminotransferase(ALT)were measured for the mice in each group;hepatic hydroxyproline content was measured;HE staining,Masson staining,and Sirius Red staining were used to observe liver histopathological changes;quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression levels of α-smooth muscle actin(α-SMA)and collagen type I alpha 1(Col1a1)in liver tissue.The therapeutic effect of sitravatinib was assessed based on the above results.A one-way analysis of variance was used for comparison of continuous data between multiple groups,and the least significant difference t-test was used for further comparison between two groups.Results Compared with the control group,the model group had significant increases in the levels of TC,TG,and ALT(all P<0.05),and there were no significant differences in the levels of TC,TG,and ALT between the model group and the low-,middle-,and high-dose sitravatinib groups(all P>0.05).Hepatic hydroxyproline content decreased after sitravatinib intervention,with a significant difference between the middle-/high-dose sitravatinib groups and the CCl4 model group(both P<0.05).Histopathological staining showed that the sitravatinib treatment groups had a reduction in collagen deposition,along with thinning and fragmentation of fibrous septa,and in the high-dose sitravatinib group,4 mice had a fibrosis stage of S0—S1 and 2 mice had a fibrosis stage of S2—S3,suggesting a certain degree of alleviation of liver fibrosis degree compared with the CCl4 model group(mainly S3—S4).The measurement of related molecules showed that sitravatinib downregulated the mRNA and protein expression levels of α-SMA and Col1a1(all P<0.05).Conclusion Sitravatinib can effectively alleviate CCl4-induced liver fibrosis in mice,possibly by inhibiting hepatic stellate cell activation and collagen synthesis.