贝那普利对肝纤维化大鼠的保护作用及可能机制

Protective effect of benazepril on liver fibrosis in rats and its possible mechanism

目的探讨贝那普利对肝纤维化大鼠的保护作用及对肝组织核因子E2相关因子2(nuclear factor erythroid 2-related factor 2, Nrf2),血清活性氧(reactive oxygen species, ROS)的影响。方法 SD大鼠18只,随机分为对照组、模型组、贝那普利组各6只。模型组、贝那普利组皮下注射体积分数40%四氯化碳连续8周制备肝纤维化模型,对照组注射等量食用油剂;贝那普利组同时给予贝那普利10 mg/(kg·d)灌胃,连续8周,模型组、对照组给予等量生理盐水灌胃。开始试验第56天,检测3组血清ROS;处死大鼠后取肝组织行组织病理检查评估肝硬化分期,实时荧光定量PCR法检测3组肝组织Nrf2 mRNA相对表达量。结果开始试验第56天,对照组HE染色及Masson染色见肝小叶结构正常,肝细胞排列整齐(肝硬化分期S_0期6只),模型组肝细胞可见大量炎症细胞浸润,肝内有明显纤维间隔形成(肝硬化分期S_3期4例,S_4期2只),贝那普利组肝细胞炎症损伤及纤维化程度较模型组减轻(肝硬化分期S_1期3例,S_2期2只,S_3期1只);模型组、贝那普利组肝组织Nrf2 mRNA相对表达量(4.01±3.40、6.69±4.86)及血清ROS[(1.82±0.46)、(1.56±0.84)mg/L]均高于对照组[0.12±0.11、(0.78±0.44)mg/L](P<0.05),且模型组血清ROS高于贝那普利组(P<0.05),肝组织Nrf2 mRNA相对表达量低于贝那普利组(P<0.05)。结论贝那普利具有明显的抗肝纤维化作用,其机制可能与上调肝组织Nrf2表达,降低血清ROS有关。

Objective To investigate the protective role of benazepril in liver fibrosis rats and its influence on nuclear factor erythroid 2-related factor 2(Nrf2)in hepatic tissue and serum reactive oxygen species(ROS).Methods Eighteen rats were randomly divided into control group,model group and benazepril group,with 6 rats in each group.Model group and benazepril group were subcutaneously injected with 40%carbon tetrachloride(CCl4)for 8 weeks to prepare liver fibrosis models.Control group was subcutaneously injected with the same amount of oil.Benazepril group received lavage with benazepril 10 mg/(kg·d)for 8 weeks,and control group and model group received lavage with the same volume of normal saline.On the 56 th day of experiment,the level of ROS was detected in three groups.After the rats were sacrificed,the hepatic tissues were taken to evaluate the stage of liver cirrhosis by histopathological examination.Real-time quantitative PCR was used to detect the level of Nrf2 mRNA in hepatic tissues in three groups.Results On the 56 th day of experiment,HE and Masson stain showed normal structure of the hepatic lobule and arranged liver cells(cirrhosis stage S0 in 6 rats)in control group,a large number of infiltrated inflammatory liver cells and obvious fiber space in the liver(cirrhosis stage S3 in 4 rats and S4 in 2)in model group,and lighter degree of hepatic inflammatory injury and fibrosis compared with model group(cirrhosis stage S1 in 3,S2 in 2 and S3 in 1)in benazepril group.The relative expressions of Nrf2 mRNA(4.01±3.40,6.69±4.86)and ROS((1.82±0.46),(1.56±0.84)mg/L)in model group and benazepril group were significantly higher than those in control group(0.12±0.11,(0.78±0.44)mg/L)(P<0.05),the level of ROS was significantly higher in model group than that in benazepril group(P<0.05),and the relative expression of Nrf2 mRNA was significantly lower in model group than that in benazepril group(P<0.05).Conclusion Benazepril plays an anti-cirrhosis role probably by up-regulating Nrf2 level in hepatic tissue,and lowering serum ROS level.