伊马替尼通过Nrf2/HO-1信号通路调节脂多糖诱导的小鼠急性肺损伤的机制  

The mechanism of imatinib on the regulation of lipopolysaccharide-induced acute lung injury in mice through the Nrf2/HO-1 signaling pathway

作　　者：李端阳 刘雅茹 周芷晴 杨红 宗晓龙[3] 李真玉[1] Li Duanyang;Liu Yaru;Zhou Zhiqing;Yang Hong;Zong Xiaolong;Li Zhenyu(Department of Emergency Medicine,The Second Hospital of Tianjin Medical University,Tianjin 300211;Department of Pharmacology,School of Basic Medical Sciences,Tianjin Medical University,Tianjin 300070;Department of Clinical Laboratory,The Second Hospital of Tianjin Medical University,Tianjin 300211)

机构地区：[1]天津医科大学第二医院急诊医学科,天津300211 [2]天津医科大学基础医学院药理学系,天津300070 [3]天津医科大学第二医院检验科,天津300211

出　　处：《中华急诊医学杂志》2024年第8期1104-1109,共6页Chinese Journal of Emergency Medicine

基　　金：国家临床重点专科急诊医学科建设项目(2023283);天津市高层次人才选拔培养工程"青年医学新锐"人才项目[2018(19)];天津市卫健委中医中西医结合科研课题(2021207)。

摘　　要：目的评价伊马替尼对内毒素血症急性肺损伤小鼠的影响。方法采用随机数字表法将60只8~12周龄的SPF级雄性C57BL/6小鼠分为4组(n=15):对照组(C组)、伊马替尼组(I组)、内毒素血症组(LPS组)和伊马替尼+内毒素血症组(I+LPS组)。复制内毒素血症急性肺损伤小鼠模型,24 h后处死小鼠,观察小鼠肺组织病理学检测结果并进行肺损伤评分,测量肺组织湿/干比;ELISA法检测血清肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)和白细胞介素-6(IL-6)的表达;试剂盒检测肺组织丙二醛(malondialdehyde,MDA)、谷胱甘肽(glutathione,GSH)、过氧化氢酶(catalase,CAT)、超氧化物歧化酶(superoxide dismutase,SOD)和还原型谷胱甘肽/氧化型谷胱甘肽(GSH/GSSG)水平;Western blot法分析肺组织核转录因子κB(NF-κB)的磷酸化水平、核转录因子红系2相关因子2(nuclear factor-erythroid 2-related factor 2,Nrf2)及血红素氧合酶1(heme oxygenase-1,HO-1)的表达水平。结果与C组相比较,LPS组的肺湿/干比比值[(3.47±0.41)vs.(5.58±0.47)]及肺损伤评分[(1.25±0.89)vs.(10.25±1.75)]升高(P<0.05),血清中TNF-α和IL-6水平上调(P<0.05),SOD、CAT、GSH、GSH/GSSG水平降低(P<0.05),MDA水平增加,p-NF-κB、Nrf2和HO-1蛋白表达上调(均P<0.05);与LPS组比较,I+LPS组肺W/D比值[(5.58±0.47)vs.(4.62±0.38)]及肺损伤评分[(10.25±1.75)vs.(7.00±1.31)]下降(P<0.05),血清TNF-α和IL-6水平下降(P<0.05),SOD、CAT、GSH、GSH/GSSG水平升高(P<0.05),MDA水平下调(P<0.05),p-NF-κB蛋白表达下降,Nrf2和HO-1蛋白表达升高(P<0.05)。结论伊马替尼可改善脓毒症急性肺损伤,其机制可能与抑制氧化应激有关。Objective To evaluate the effect of imatinib on the endotoxemia-induced acute lung injury in mice.Methods Sixty SPF male,8-12 weeks,C57BL/6 mice were randomly(random)divided into 4 groups(n=15 each):control group(group C),imatinib group(groupⅠ),endotoxemia group(group LPS)and imatinib+endotoxemia group(group I+LPS).The endotoxemia model of acute lung injury was established.After 24 hours,the mice were sacrificed.The pathological changes of lung tissues were evaluated,the lung injury scores were calculated,and the wet/dry ratios of lung tissues were measured.ELISA was used to detect the levels of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)in serum.Detection kits were used to analyze the levels of malondialdehyde(MDA),glutathione(GSH),catalase(CAT),superoxide dismutase(SOD)and the ratio of reduced glutathione to oxidized glutathione(GSH/GSSG)in lung tissues;The expression levels of phosphorylated nuclear factor-kappa B(p-NF-κB),nuclear factor-erythroid 2-related factor 2(Nrf2)and heme oxygenase-1(HO-1)in lung tissues were analyzed by western blotting.Results Compared with the group C,the wet/dry(W/D)ratio of lungs[(3.47±0.41)vs.(5.58±0.47)],lung injury scores[(1.25±0.89)vs.(10.25±1.75)],and the levels of TNF-αand IL-6 in serum increased in the group LPS(P<0.05).The levels of SOD,CAT,GSH and GSH/GSSG decreased,the level of MDA increased,and the expression of p-NF-κB,Nrf2 and HO-1 protein up-regulated(P<0.05).Compared with the LPS group,the W/D ratio of lungs[(5.58±0.47)vs.(4.62±0.38)]and lung injury scores[(10.25±1.75)vs.(7.00±1.31)]in the I+LPS group decreased(P<0.05),and the levels of TNF-αand IL-6 in the serum decreased(P<0.05).In lung tissues,the levels of SOD,CAT,GSH and GSH/GSSG increased(all P<0.05),the level of MDA decreased(all P<0.05),the expression of p-NF-κB protein decreased,and the expression of Nrf2 and HO-1 protein increased(P<0.05).Conclusions Imatinib improves sepsisinduced acute lung injury in mice,and the mechanism of actions behind may be related to the inhibition of o

关 键 词：内毒素血症 急性肺损伤 伊马替尼 血红素加氧酶-1 氧化应激 脂多糖 核转录因子红系2相关因子2 核因子κB 

分 类 号：R563[医药卫生—呼吸系统]