右美托咪定联用青蒿琥酯调控PERK/ATF4/CHOP信号通路对缺血再灌注肺损伤大鼠的保护作用  

Protective effect of dexmedetomidine combined with artesunate modulation of PERK/ATF4/CHOP signaling pathway in ischemia⁃reperfusion lung injury rats

作　　者：徐乾 梁威 李鹏[1] 彭晓红[1] 余丹 XU Qian;LIANG Wei;LI Peng;PENG Xiaohong;YU Dan(Dept.of Anesthesiology,Wuhan Fourth Hospital,Wuhan 430035,Hubei,China)

机构地区：[1]武汉市第四医院麻醉科,湖北武汉430035

出　　处：《武汉大学学报（医学版）》2024年第11期1291-1296,共6页Medical Journal of Wuhan University

基　　金：武汉市卫健委医学科研项目(编号:WX21B10)。

摘　　要：目的探究右美托咪定(Dex)联合青蒿琥酯(ART)对缺血再灌注肺损伤大鼠的保护作用及其调控机制。方法60只SD大鼠随机分为假手术(Sham)组、模型对照组、Dex组(30μg/kg)、ART组(100 mg/kg)、联合用药组(30μg/kg Dex+100 mg/kg ART)、尼莫地平组(200 mg/kg),每组10只。除Sham组外其余5组建立缺血再灌注肺损伤(IR)模型,Sham组只开胸不结扎。实验结束后取动脉血检测动脉血气指标:二氧化碳分压(PaCO_(2))和氧分压(PaO_(2));试剂盒检测肺组织氧化还原指标超氧化物歧化酶(SOD)、丙二醛(MDA)、髓过氧化酶(MPO)以及肺组织和血清炎性因子肿瘤坏死因子α(TNF⁃α)、白细胞介素(IL)⁃1β、IL⁃18水平;HE检测肺组织的病理学变化以及TUNEL染色检测细胞凋亡情况;Western Blot法检测肺组织中内质网应激信号通路蛋白激酶R样内质网激酶(PERK)、活化转录因子4(ATF4)、CCAAT/增强子结合蛋白同源蛋白(CHOP)通路相关蛋白的表达。结果与Sham组比较,模型对照组细胞凋亡率、PaCO_(2)及MDA含量、MPO活性、TNF⁃α、IL⁃1β、IL⁃18含量及PERK、ATF4、CHOP蛋白表达升高,PaO_(2)、SOD活性明显下降(P<0.05)。与模型组比较,ART组、Dex组、联合用药组及尼莫地平组细胞凋亡率、PaCO_(2)、MDA含量、MPO活性、TNF⁃α、IL⁃1β、IL⁃18含量、PERK、ATF4、CHOP表达降低,PaO_(2)、血清SOD活性升高,且联合用药组上述指标的改变优于单一用药(P<0.05)。结论Dex联合ART能够保护IR大鼠缺血再灌注肺损伤,可能通过抑制PERK/ATF4/CHOP信号通路而实现。Objective To explore the protective effect of dexmedetomidine(Dex)combined with artesunate(ART)on ischemia⁃reperfusion lung injury in rats and its regulatory mechanism.Methods A total of sixty SD rats were randomly divided into Sham operation group,model control group,ART(100 mg/kg),Dex(30μg/kg),combination(30μg/kg Dex+100 mg/kg ART),and nimodipine groups(200 mg/kg),with 10 rats in each group.Except for the Sham group,the rats in the remaining five groups were established in the ischemia⁃reperfusion lung injury model.The Sham group only opened the chest without ligation.After the experiment,the arterial blood was taken to detect the arterial blood gas indicators:Carbon dioxide partial pressure(PaCO_(2))and oxygen partial pressure(PaO_(2));The kits were used to detect the redox indicators malondialdehyde(MDA),superoxide dismutase(SOD)and myeloperoxidase(MPO)in lung tissue,and the levels of inflammatory factors tumor necrosis factor⁃α(TNF⁃α),interleukin(IL)⁃1β,and IL⁃18 in serum and lung tissue;Hematoxylin⁃eosin staining was used to detect the pathological changes of lung tissue;TUNEL staining was used to detect cell apoptosis;Western Blot method was used to detect the expression of PERK/ATF4/CHOP pathway⁃related proteins in lung tissue.Results Compared with those in the Sham group,PaCO_(2) and MDA content,MPO activity,the contents of TNF⁃α,IL⁃1β,and IL⁃18,and the expression of PERK,ATF4,CHOP protein were significantly increased,the PaO_(2),serum SOD activity were reduced in the model control group(P<0.05).Compared with those in the model group,the apoptosis rate,PaCO_(2) and MDA content,MPO activity,the contents of TNF⁃α,IL⁃1β,IL⁃18,and the expression of PERK,ATF4,CHOP proteins were reduced in the ART group,Dex group,combination group and nimodipine group,the PaO_(2) and SOD activity were increased,and the changes of above indexes in the combination group were better than those in the monotherapy group(P<0.05).Conclusion Dex combined with ART can protect rat ischemia⁃reperfus

关 键 词：右美托咪定 肺缺血再灌注 肺损伤 铁死亡 青蒿琥酯 

分 类 号：R614[医药卫生—麻醉学]