阿托伐他汀对肝纤维化的改善作用及其机制  

Ameliorative effect of atorvastatin on hepatic fibrosis and its mechanism

作　　者：汪楠 陆晔[1] 郝风节 王俊青[1] WANG Nan;LU Ye;HAO Feng-jie;WANG Jun-qing(Department of General Surgery,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China)

机构地区：[1]上海交通大学医学院附属瑞金医院普外科,上海200025

出　　处：《上海交通大学学报（医学版）》2021年第12期1618-1626,共9页Journal of Shanghai Jiao tong University:Medical Science

基　　金：上海市教育委员会高峰高原学科建设计划(20191901);上海市浦江人才计划(18PJD029);上海交通大学医工交叉研究基金(YG2021QN21)。

摘　　要：目的·探讨阿托伐他汀在肝纤维化患者和动物模型中的作用及其机制。方法·检索PubMed上他汀类药物治疗不同慢性肝病的文献,起止时间为2010年1月—2020年6月。对肝纤维化发生率、肝功能失代偿发生率及患者总体死亡率进行meta分析。将16只雄性C57BL/6小鼠随机分为对照组、阿托伐他汀组、四氯化碳(CCl_(4))注射组、CCl_(4)注射联合阿托伐他汀组,每组4只。CCl_(4)注射组小鼠以20%体积分数的CCl_(4)按1 mL/kg的剂量,每周行2次腹腔注射;对照组使用同剂量玉米油进行腹腔注射;阿托伐他汀组小鼠每日以15 mg/kg剂量的阿托伐他汀灌胃1次;CCl_(4)注射联合阿托伐他汀组联合采用上述CCl_(4)和阿托伐他汀的处理方式。4周后处死小鼠,检测血清谷丙转氨酶(glutamicpyruvictransaminase,GPT)、谷草转氨酶(glutamicoxaloacetictransaminase,GOT)浓度;采用天狼星红染色检测小鼠肝内纤维化程度;采用免疫荧光染色检测肝纤维化标志物ⅠA型胶原蛋白(collagenⅠA)的表达;采用实时荧光定量PCR检测肝组织α平滑肌肌动蛋白(α-smoothmuscleactin,α-SMA)、collagenⅠ、collagenⅢ,以及白介素(interleukin,IL)-1b、IL-6、转化生长因子β(transforminggrowthfactor-β,TGF-β)的表达;采用免疫印迹法检测肝组织α-SMA蛋白和磷酸化Smad4(pSmad4)蛋白的表达。结果·最终选取9篇文献进行meta分析,结果显示他汀类药物可降低肝病患者肝纤维化、肝功能失代偿的发生率及总体死亡率。在动物实验中,4周处理后,与对照组比较,CCl_(4)注射组和CCl_(4)注射联合阿托伐他汀组小鼠体质量均显著下降(均P=0.000);而CCl_(4)注射联合阿托伐他汀组小鼠体质量与CCl_(4)注射组比较,下降程度较轻,组间差异有统计学意义(P=0.040)。与对照组比较,CCl_(4)注射组和CCl_(4)注射联合阿托伐他汀组小鼠GPT、GOT浓度均显著上升(均P=0.000);而CCl_(4)注射联合阿托伐他汀组小鼠肝酶与CCl_(4)注射�Objective·To investigate the role of atorvastatin and its mechanisms in patients and animal models of hepatic fibrosis.Methods·The literatures in PubMed were searched for statins for different chronic liver diseases from January 2010 to June 2020.Meta analysis was performed based on the occurrence of liver fibrosis,liver failure and overall patient mortality.Sixteen male C57BL/6 mice were randomly divided into control group,atorvastatin group,CCl4 injection group,and CCl4 injection combined with atorvastatin group with 4 mice in each group.The mice in the CCl4 injection group were administered intraperitoneally twice a week with 20%volume fraction of CCl4 at a dose of 1 mL/kg;the control group was administered intraperitoneally by using the same dose of corn oil;the mice in the atorvastatin group were gavaged once daily with a dose of 15 mg/kg of atorvastatin;the mice in the CCl4 injection combined with atorvastatin group were treated with a combination of CCl4 and atorvastatin.After 4 weeks,the animals were euthanized,and serum glutamic pyruvic transaminase(GPT)and glutamic oxaloacetic transaminase(GOT)were detected;the degree of intrahepatic fibrosis in the mice was detected by Sirius red staining;immunofluorescence staining was used to detect the expression of collagenⅠA;the mRNA expressions ofα-smooth muscle actin(α-SMA),collagenⅠ,collagenⅢ,interleukin(IL)-1b,IL-6,and transforming growth factor-β(TGF-β)were detected by real-time fluorescence quantitative PCR;the expressions ofα-SMA protein and phosphorylated Smad4(pSmad4)protein were detected by Western blotting.Results·Finally 9 papers were selected for meta analysis,and the results showed that statins reduced the incidence of liver fibrosis,liver failure and overall mortality in patients with liver disease.In the animal experiments,the weight of mice in both the CCl4 injection group and the CCl4 injection combined with atorvastatin group decreased significantly compared with that in the control group(P=0.000);while the weight of mice in the CC

关 键 词：阿托伐他汀 肝纤维化 炎症 转化生长因子Β 信号通路 

分 类 号：R575.2[医药卫生—消化系统]