中文摘要：

目的 证明四氯化碳（CCl4）诱导的肝纤维化能够保护小鼠抵抗致死性对乙酰氨基酚（APAP）攻击,并初步探讨其发挥保护作用的机制. 方法 建立CCl4诱导的肝纤维化小鼠模型,于纤维化6周时以致死剂量的APAP（1 g/kg）进行攻击,以同样处理的正常小鼠作为对照.即实验共分为4组：对照组、急性损伤组（APAP组）、肝纤维化组（Fib组）、肝纤维化＋急性攻击组（Fib＋APAP组）,每组5只.根据攻击前后小鼠生存率、转氨酶水平及肝组织学的变化来评估正常和纤维化小鼠对致死性APAP损伤的耐受性.免疫组织化学法分析各组小鼠肝组织中高迁移率族蛋白1（HMGB1）的表达.组间差异的比较采用One-way ANOVA分析和Newman-Keuls检验. 结果 接受APAP攻击的纤维化小鼠的肝损害程度明显轻于同样处理的正常小鼠,表现为：（1） Fib＋APAP组小鼠的生存率明显高于APAP组（80％对比0）; （2） Fib＋APAP组小鼠的sALT升高水平显著低于APAP组[（6437±1 913） U/L对比（12 456±3 441） U/L],P=0.022,攻击前后,正常小鼠的sALT水平升高了257.4倍,而纤维化小鼠则仅升高了12.2倍;（3） Fib＋APAP组的肝组织学检查结果较APAP组明显改善.免疫组织化学分析结果表明,APAP组小鼠肝组织中HMGB1呈高表达,并且可见明显的HMGB1由胞核向胞质转位,而Fib＋APAP组HMGB1的表达明显弱于APAP组,且胞质转位少见.结论 CCl4诱导的肝纤维化可能通过限制HMGB1的胞质转位及其所触发的损伤效应而保护小鼠抵抗致死性APAP的攻击.

英文摘要：

Objective To investigate the protective effects of hepatic fibrosis against a lethal dose ofacetaminophen （APAP） and its underlying mechanisms using a carbon tetrachloride （CCl4）-induced mouse model of fibrosis.Methods The experimental model of hepatic fibrosis was established by intraperitoneal injection of CC14 （in mineral oil）,twice a week for 6 weeks; mice given a 6-week course of mineral oil injections served as normal controls.At the end of fibrosis induction,the expmimental （Fib group） and control （Norm group） mice were challenged with APAP （1 g/kg）.Sera and liver tissues were harvested for analyses.To assess tolerance of the normal and fibrotic mice to the lethal dose of APAP,the survival rate,serum alanine aminotransferase （sALT） levels and hepatic histopathological changes were compared before and after the acute APAP challenge.HMGB 1 expression was analyzed by immunohistochemistry.One-way ANOVA test and Newman-Keuls test were used in statistical analysis.Results The fibrotic liver was tolerant to the lethal dose of APAP,as evidenced by：（1） significantly higher survival rate in the Fib±APAP group （80% vs.Norm＋APAP group：0%）; （2） markedly lower sALT levels in the Fib＋APAP group （6 437±1 913 U/L vs.12 456± 3 441 U/L）,P =0.022; （3） remarkably well-preserved liver architecture in the Fib＋APAP group.Immunohistochemical analysis showed high HMGB1 expression and cytoplasmic translocation in the Norm＋APAP group,which was absent in the Fib＋APAP group.Conclusions CCl4-induced liver fibrosis protects mice against lethal dose of APAP,possibly by a mechanism involving inhibition of the cytoplasmic translocation of HMGB1.