氟尿嘧啶、伊立替康和奥沙利铂诱导小鼠心肌损伤的病理生理特征及其机制

摘要

【目的】观察氟尿嘧啶（5‐FU ）、伊立替康、奥沙利铂（OXA ）诱导心肌损伤特点并分析其可能的机制。【方法】42只昆明小鼠，分为7组，每组6只，分别给予5‐Fu、伊立替康、OXA 的最大非致死量（CMAX ）和1／2CMAX给药诱导，建立小鼠心肌损伤模型，为A1、A2、B1、B2、C1、C2组，分别腹腔连续注射上述三种药物5 d，对照组（D组）注射等量生理盐水，连续注射5d。5d后，处死小鼠，取小鼠心脏组织，HE染色检测心脏组织病理学改变；提取小鼠心肌组织蛋白，检测心肌组织中丙二醛（MDA）、过氧化氢酶（CAT）、超氧化物歧化酶（SOD）水平；Western blot法检测NF‐κB和I‐κB的表达并比较。【结果】三种化疗药物均能诱导小鼠心肌损伤，心肌间质血管周围可见出血及炎性细胞大量浸润，且CMAX损伤较1／2CMAX严重。与对照组相比，化疗药物诱导的各组MDA水平显著上升，抗氧化分子 SOD和 CAT 水平显著下降，差异均有统计学意义（ P ＜0．05）；NF‐κB在三种化疗药物诱导的心肌组织中表达上升（ P ＜0．05），I‐κB表达下降（ P ＜0．05）。【结论】5‐Fu、伊立替康、OXA均能导致心肌组织损伤，氧化应激和NF‐κB活化可能是其主要机制。%[Objective] To observe the effects of fluorouracil (5‐Fu) ,irinotecan and oxaliplatin‐induced myocardial injuries and analyze their possible mechanisms .[Methods] The maximum non‐lethal doses of 5‐Fu , irinotecan and oxaliplatin were pre‐administered to Kunming mice .A total of 42 Kunming mice were divided into 7 groups (n=6 each) .The maximal non‐lethal dose injection and half of maximal non‐lethal dose injection groups were designed for each drug .The chemotherapy‐induced murine model of myocardial injury was estab‐lished .At Day 5 ,mice were sacrificed and heart tissues harvested .HE staining was used to detect the patho‐logical changes of myocardial tissues .And myocardial tissue protein was extracted for detecting the levels of malondialdehyde (MDA) ,superoxide dismutase (SOD) and catalase (CAT ) by colorimeter and the expres‐sions of NF‐κB and I‐κB by Western blot .[Results] The maximal non‐lethal doses of 5‐Fu ,irinotecan and ox‐aliplatin were 400 ,400 and 100 mg/kg respectively .All three chemotherapeutic agents could induce myocardi‐al injuries .And perivascular hemorrhage and an extensive infiltration of inflammatory cells were visible in my‐ocardial interstitium .Chemotherapeutic drugs induced oxidative damage of myocardial tissue .The levels of MDA significantly increased in maximal non‐lethal dose injection and half of maximum non‐lethal dose injection groups versus control group .And the differences were statistically significant ( P<0 .05) .The levels of SOD and CAT significantly decreased and the differences were also statistically significant ( P <0 .05) .Further‐more ,the expression of NF‐κB increased ( P <0 .05) and there is a down‐regulation of I‐κB ( P <0 .05) .It suggested that an activation of nuclear factor‐κB (NF‐κB) might be involved in chemotherapy‐induced myocar‐dial tissue injury .[Conclusion] 5‐Fu ,irinotecan and oxaliplatin may induce myocardial injuries .Oxidative stress and NF‐κB activation are probably major mechanisms .