辛伐他汀保护小鼠急性肝衰竭肝损伤  

Administration of simvastatin protects against acute live failure in mice

作　　者：雷延昌[1] 罗盼[1] 李雯[1] 

机构地区：[1]南昌大学附属感染病医院,江西省南昌市330006

出　　处：《世界华人消化杂志》2013年第35期3940-3946,共7页World Chinese Journal of Digestology

基　　金：国家自然科学基金资助项目;No.81160065~~

摘　　要：目的:了解辛伐他汀对急性肝衰竭肝损伤的保护作用及其机制.方法:D-氨基半乳糖(D galactosamine,D-GaIN)和细菌脂多糖(lipopolysaccharide,LPS)腹腔注射建立小鼠急性肝衰竭模型.♂6-8周龄Balb/c随机分为正常组、肝衰竭对照组和辛伐他汀组,每组18只.Kaplan-Meier法分析小鼠生存率,生化检测6、12、24和48 h血清丙氨酸转氨酶(alanine aminotransferase,ALT)和24 h肝脏超氧化物水平.HE染色分析24 h肝脏形态学变化,免疫组织化学分析12h肝脏高迁移率族蛋白1(high mobility group box-1 protein,HMGB1)表达.ELISA检测血清HMGB1、白介素-1(interleukin-1,IL-1、肿瘤坏死因子-(tumor necrosis factor-,T N F-)、I L-6和I L-10水平,免疫印迹分析内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)、磷酸化内皮型一氧化氮合酶(P-eNOS)和LC3Ⅱ表达.结果:辛伐他汀组1 wk生存率为83.3%显著高于肝衰竭对照组的33.3%(P<0.01);6、12、24和48 h血清ALT水平显著低于急性肝衰竭组(P<0.01).辛伐他汀组6和12 h的HMGB1水平以及24 h的IL-1水平显著低于肝衰竭对照组(P<0.01),肝脏炎症坏死和HMGB1胞浆移位较对照明显减轻.辛伐他汀增加急性肝衰竭动物肝脏eNOS、P-eNOS和LC3Ⅱ表达水平,降低肝组织超氧化物水平.结论:辛伐他汀对急性肝衰竭具有保护作用,其机制与改善内皮细胞功能障碍、氧化应激和促进肝细胞自噬有关.AIM： To explore the effects of simvastatin on acute live failure in mice and the underlying mechanism. METHODS： D-galactosamine （D-GaIN） and lipopolysaccharide （LPS） were used to induce acute liver failure in Balb/c mice. Male mice （6-8 wk） were randomly assigned to three groups （n = 18）, a normal group, an acute liver failure group and a simvastatin treatment group. Ka-plan-meier method was sis. Serum ALT levels used for survival analy- at different time point （6, 12, 24, 48 h） and hepatic superoxide level at 24 h were measured by biochemical methods. Hepatic morphological changes at 24 h were as-sessed by HE staining and hepatocyte HMGB1 cytoplasmic translocation was detected by im-munohistochemistry. Serum levels of HMGB1, IL-1β, TNF-α, IL-6 and IL-10 were detected by ELISA. Expression of eNOS, P-eNOS and LC3 Ⅱ in liver tissues was analyzed by Western blot. RESULTS： The survival rate at one week was significantly higher in the simvastatin treatment group than in the acute liver failure group （83.3% vs 33.3%, P 〈 0.01）. Simvastatin treatment sig-nificantly decreased ALT levels at 6, 12, 24, and 48 h compared with the acute liver failure group （all P 〈 0.01）. Serum levels of HMGB1 at 6 and 12 h and IL-1β at 12 h were also decreased sig-nificantly in the simvastatin group （all P 〈 0.01）, and the inflammation or necrosis and hepato-cyte HMGB1 cytoplasmic translocation in liver tissues were decreased in the simvastatin group. In simvastatin-treated mice, eNOS, P-eNOS and LC3 Ⅱ expression in liver tissue was increased compared to the acute liver failure group. How-ever, hepatic superoxide level at 24 h was de-creased in the simvastatin group.CONCLUSION： Simvastatin protects against acute live failure possibly by improving endo-thelial dysfunction, oxide stress and hepatocyte autophagy in mice.

关 键 词：辛伐他汀 内皮细胞功能障碍 自噬 急性肝衰竭 

分 类 号：R965[医药卫生—药理学]