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
Effect of sitravatinib on a mouse model of carbon tetrachloride-induced liver fibrosis and its mechanism
摘要
Abstract
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.关键词
肝纤维化/司曲替尼/治疗学/小鼠,近交C57BLKey words
Hepatic Fibrosis/Sitravatinib/Therapeutics/Mice,Inbred C57BL引用本文复制引用
张欢,吴翔宇,赵倩雯,芮法娟,耿楠,靳睿,李婕..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[J].临床肝胆病杂志,2026,42(3):600-607,8.基金项目
北京肝胆相照公益基金会力肝专项研究项目(iGandanF-1082024-LG004,iGandanF-1082025-LG034,iGandanF-1082025-LG019) （iGandanF-1082024-LG004,iGandanF-1082025-LG034,iGandanF-1082025-LG019）
南京鼓楼医院临床研究专项资金项目(2024-LCYJ-PY-52,2025-LCYJ-PY-02) （2024-LCYJ-PY-52,2025-LCYJ-PY-02）
南京鼓楼医院国家自然科学基金青年培育项目(2025-JCYJ-QP-016,2025-JCYJ-QP-017) （2025-JCYJ-QP-016,2025-JCYJ-QP-017）
南京大学中医研究院课题项目和南京鼓楼医院医学发展医疗救助基金会资助项目(ICM2024002,ICM2024032) （ICM2024002,ICM2024032）
中国博士后科学基金(2024M761417) Beijing iGandan Foundation(iGandanF-1082024-LG004,iGandanF-1082025-LG034,iGandanF-1082025-LG019) （2024M761417）
Nanjing Drum Tower Hospital Clinical Research Special Fund Project(2024-LCYJ-PY-52,2025-LCYJ-PY-02) （2024-LCYJ-PY-52,2025-LCYJ-PY-02）
Nanjing Drum Tower Hospital Youth Cultivation Fund(2025-JCYJ-QP-016,2025-JCYJ-QP-017) （2025-JCYJ-QP-016,2025-JCYJ-QP-017）
Project of Institute of Chinese Medicine,Nanjing University and Aid Project of Nanjing Drum Tower Hospital Health,Education&Research Foundation(ICM2024002,ICM2024032) （ICM2024002,ICM2024032）
China Postdoctoral Science Foundation(2024M761417) （2024M761417）
