SMAC类似物Birinapant对大鼠肝脏缺血再灌注损伤的保护作用及机制研究  

Protective effects and mechanisms of SMAC mimetic birinapant on liver ischemia reperfusion injury in rats

作　　者：高宏 易竹君[2] 李培志[2] 朱稀雯[2] 龚建平[2] 陈翔(指导) GAO Hong;YI Zhu-Jun;LI Pei-Zhi;ZHU Xi-Wen;GONG Jian-Ping;CHEN Xiang(Department of Hepatobiliary Surgery,the Fourth People′s Hospital of Chongqing,Chongqing 400010,China)

机构地区：[1]重庆市第四人民医院肝胆外科,重庆400014 [2]重庆医科大学附属第二医院肝胆外科,重庆400010

出　　处：《中国免疫学杂志》2020年第8期910-913,918,共5页Chinese Journal of Immunology

基　　金：国家自然科学基金青年基金资助(81601715)。

摘　　要：目的:探讨SMAC类似物Birinapant预处理对大鼠肝脏缺血再灌注损伤(I/RI)的保护作用及分子机制。方法:将大鼠分为空白对照组(Blank)、对照组(Control)和Birinapant预处理组(Birinapant)。Blank组不做任何处理,Control组腹腔注射30 mg/kg体重的生理盐水,1 h后构建大鼠肝脏I/RI模型,Birinapant组腹腔注射30 mg/kg体重的Birinapant,1 h后构建大鼠肝脏I/RI模型。各组在模型建立4 h后取下肝脏组织,HE染色检测各组肝脏大体形态及炎症反应;收集大鼠外周血,ELISA检测血清中TNF-α、IL-6及IL-1β炎症因子水平;提取肝脏库普弗细胞(KCs),免疫荧光检测KCs中cIAP1和TRAF3的表达;Western blot检测cIAP1和TRAF3与MAPK信号通路密切相关的JNK、p-JNK、p38及p-p38的蛋白表达。结果:与Control组相比,Birinapant预处理可以显著抑制肝脏I/RI诱导的肝组织损伤和炎症反应;Birinapant预处理也可显著降低血清中TNF-α、IL-6及IL-1β炎症因子水平;Birinapant预处理可抑制KCs中cIAP1的表达进而抑制TRAF3的降解;Birinapant预处理可抑制KCs中p-JNK和p-p38的表达进而抑制MAPK信号通路的激活。结论:预处理Birinapant可以通过抑制cIAP1的表达抑制TRAF3的降解,进而通过抑制MAPK信号通路的激活,发挥对肝脏I/RI的保护作用。Objective:To investigate the protective effects and mechanisms of SMAC mimetic Birinapant on liver ischemia reperfusion injury in rats.Methods:The rats were divided into blank group(Blank),control group(Control)and Birinapant pretreatment group(Birinapant).Blank group did not do any treatment.Control group received intraperitoneal injection of 30 mg/kg body weight of saline,and Birinapant group received 30 mg/kg of Birinapant,and rat liver I/RI model was established after 1 h.The liver tissues were removed after the model was established,and HE staining detected the morphology and inflammatory reaction of the liver tissues in each group.ELISA detected the levels of TNF-α,IL-6 and IL-1βin serum.Immunofluorescence detected the expression of cIAP1 and TRAF3 in KCs.Western blot detected the protein expression of cIAP1,TRAF3,JNK,p-JNK,p38 and p-p38.Results:Compared with the Control group,Birinapant pretreatment could significantly inhibit liver injury and inflammatory reaction which induced by liver I/RI.Besides,Birinapant pretreatment could also significantly reduce the levels of TNF-α,IL-6 and IL-1βin serum.Further,Birinapant pretreatment could inhibited the expression of cIAP1 and then inhibit the degradation of TRAF3 and inhibit the expression of p-JNK and p-p38,thus inhibited the activation of MAPK signal pathway.Conclusion:Pretreatment of Birinapant can inhibit the degradation of TRAF3 by inhibiting the expression of cIAP1,and then protect liver I/RI by inhibiting the activation of MAPK signaling pathway.

关 键 词：Birinapant 肝缺血再灌注损伤 枯否细胞 肿瘤坏死因子受体相关因子3 

分 类 号：R363[医药卫生—病理学]