辛伐他汀对脓毒症大鼠心肌保护作用的实验研究

Protective Effect of Simvastatin on Myocardium in Septic Rats

目的探讨辛伐他汀对脓毒症大鼠心肌损害的保护作用及可能机制。方法将30只4周龄清洁级雄性Wistar大鼠随机分为3组:假手术对照组(Sham组)、脓毒症模型组(CLP组)和辛伐他汀干预组(Sim组)。Sham组仅开腹翻动盲肠;CLP组及Sim组行盲肠结扎穿刺术;Sim组于术后尾静脉注射辛伐他汀20 mg·kg-1+10%二甲基亚砜(DMSO)1 mL·kg-1和生理盐水2 mL·kg-1,其他各组均注射生理盐水3 mL·kg-1。Sham组于术后5 h、CLP组及Sim组分别于术后52、0 h处死6只大鼠,留血液和心肌组织标本。分别测定血清心肌酶CKMB、心肌组织肿瘤坏死因子-α(TNF-α)及心肌组织一氧化氮(NO)含量,观察心肌组织病理变化并采用免疫组织化学测定TOLL样受体4(TLR-4)蛋白表达。结果 CLP组心肌组织损伤明显,TLR-4表达明显,CKMB、TNF-α、NO水平较Sham组均显著升高(均P<0.01),其中CKMB、TNF-α水平和TLR-4表达于5 h较高,而NO水平于20 h较高。Sim组心肌病理损伤减轻,且各指标表达较CLP组均显著下降(均P<0.01)。结论辛伐他汀能减轻脓毒症大鼠心肌损害,可能与通过抑制TLR-4信号转导通路、减少TNF-α及NO炎症因子的过量表达有关。

Objective To investigate the protective effect of simvastatin on myocardium in septic rats and its possible mechanism of action.Methods Thirty 4-week-old male Wistar rats were randomly divided into three groups.Laparotomy and manipulation of the cecum were performed in sham operated group.Sepsis was induced by cecal ligation and puncture（CLP） in CLP group.Intravenous injection with simvastatin（20 mg·kg-1） dissolved in 10% dimethylsulfoxide（DMSO,1 mL·kg-1） and normal saline（2 mL·kg-1） was performed after CLP in simvastatin group.Rats in sham operated group and CLP group were injected with 3 mL·kg-1 of normal saline.Six rats were sacrificed in each group at 5 hours after CLP and in CLP group and simvastatin group at 20 hours after CLP.The blood and myocardial samples were collected,and the levels of serum CKMB,myocardial TNF-α and myocardial NO were measured.Pathological lesions in myocardial tissue was observed by light microscope and the expression of TLR-4 protein was determined by immunohistochemistry.Results In CLP group,myocardial tissue was seriously injured,and the expression of TLR4 was obviously detected.Compared with sham operated group,the levels of CKMB,TNF-α and NO significantly increased in sham operated group（P0.01）.The maximum levels of CKMB,TNF-α and TLR-4 expression were observed at 5 hours after CLP,while the maximum NO levels were observed at 20 hours after CLP.Compared with CLP group,myocardial damage was reduced and the levels of CKMB,TNF-α,NO and TLR-4 expression were decreased by simvastatin（P0.01）.Conclusion The protective effect of simvastatin on myocardial damage in septic rats may be mediated by a mechanism involving the inhibition of TLR-4 signaling pathway and the reduction of TNF-α and NO over-expression.