熊果酸对四氯化碳所致大鼠肝纤维化及门静脉高压的影响

目的 研究熊果酸(UA)对四氯化碳(CCl4)所致大鼠肝纤维化及门静脉高压的影响及其机制.方法 取120只实验用大鼠运用随机数字表法分为正常对照组、模型对照组、UA(10、20、40 mg·kg-1)组和秋水仙碱(0.1 mg·kg-1)组,每组20只;采用CCl4复合法复制肝纤维化门静脉高压大鼠模型;自造模第1天各组开始腹腔注射给药(正常对照组和模型对照组均给予等体积生理盐水),每天1次.6周后,测定血清中转氨酶和总胆红素(TBIL)含量,测定血清中肝纤维化四项指标透明质酸(HA)、层黏蛋白(LN)、Ⅳ型胶原(CⅣ)、Ⅲ型前胶原(PCⅢ)]含量和肝组织中羟脯氨酸(HYP)水平;通过生理记录仪测定门静脉压(PVP)、门静脉血流量(PVF)、平均动脉压(MAP)并测定心率(HR);HE染色法观察肝脏组织形态结构变化;硝酸还原酶法测定肝脏组织中一氧化氮(NO)含量、放射免疫法测定环鸟苷酸(cGMP)含量;测定肝脏组织中抗氧化酶活性和丙二醛(MDA)含量.结果 较模型组对照组大鼠,UA(20、40 mg·kg-1)组血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)和TBIL含量显著降低,血清中CⅣ、PCⅢ、HA、HYP含量显著降低,其中UA 40 mg·kg-1组LN含量显著降低;UA(20、40 mg·kg-1)组PVP、PVF均显著降低,40 mg·kg-1组MAP显著升高、HR显著降低;UA(10、20、40 mg·kg-1)组肝纤维化门静脉高压大鼠肝脏组织病理性形态学变化呈不同程度改善,呈一定剂量依赖性;UA(20、40 mg·kg-1)组肝脏组织NO含量和超氧化物歧化酶(SOD)、过氧化氢酶(CAT)活性显著升高,40 mg·kg-1组cGMP含量和谷胱甘肽过氧化物酶(GSH-Px)活性显著升高,上述均差异有统计学意义(P<0.05或P<0.01).结论 UA对CCl4所致大鼠肝纤维化及门静脉高压具有一定的抑制作用,机制可能与UA能够有效保肝降酶,抑制氧化应激损伤,提高NO含量有关.

Effects of ursolic acid on liver fibrosis and portal hypertensionof CCl4-induced cirrhosis rats

Objective To investigate the effects of ursolic acid (UA) on liver fibrosis and portal hypertension of CCl4-induced cirrhosis rats.Methods One hundred and twenty experimental rats were randomly assigned into six groups:normal control group,model control group,UA (10,20,40 mg·kg-1) groups and colchicine 0.1 mg·kg-1group (positive control group).Except the normal control group,all of the model rats were made by injecting CCl4.The drugs were given by intraperitoneal injection at the same time,once a day.The contents of ALT,AST,TBIL in serum were determined;the contents of CⅣ,PCⅢ,LN,HA in serum and the level of HYP in hepatic tissue were determined;the PVP,PVF,MAP,HR were detected;the histopathological changes of the hepatic tissue were observed by HE staining;the contents of NO and cGMP in hepatic tissue were determined;the activities of SOD,GSH-Px,CAT and the content of MDA in hepatic tissue were determined.Results Compared with the model control group,the contents of ALT,AST,TBIL in serum of UA 20,40 mg·kg-1groups were significantly decreased (P<0.05,P<0.01);the contents of CⅣ,PCⅢ,HA,HYP in serum were significantly decreased and LN in 40 mg·kg-1 group was significantly decreased (P<0.05,P<0.01);the PVP,PVF in UA 20,40 mg·kg-1 groups were significantly decreased (P<0.05),and the MAP in 40 mg·kg-1 group was significantly increased and HR was significantly decreased (P<0.05);the histopathological changes in hepatic tissue of UA treatment groups were significantly improved,especially the UA 40 mg·kg-1 group;the content of NO in hepatic tissue and the activities of SOD and CAT of UA 20,40 mg·kg-1 groups were significantly increased,and the content of cGMP in UA 40 mg·kg-1 group and the activity of GSH-Px were significantly increased (P<0.05,P<0.01).Conclusions UA had inhibitory effects on liver fibrosis and portal hypertension in CCl4 induced cirrhosis rats,the function of which is likely related to its effects of protecting hepatic tissue and inhibiting enzyme activity,inhibiting the damage of oxidative stress,upregulating eNOS expression,and enhancing the content of NO.