艾司氯胺酮通过Keap1/Nrf2⁃HO⁃1减轻脓毒症肺损伤  

Esketamine alleviates septic lung injury via Keap1/Nrf2⁃HO⁃1 pathway

作　　者：张鑫宇 张建成[1] 袁世荧[1] ZHANG Xinyu;ZHANG Jiancheng;YUAN Shiying(Dept.of Critical Care Medicine,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,Hubei,China)

机构地区：[1]华中科技大学同济医学院附属协和医院重症医学科,湖北武汉430022

出　　处：《武汉大学学报(医学版)》2025年第2期147-152,共6页Medical Journal of Wuhan University

基　　金：国家重点研发计划重点专项(编号:2021YFC2501800)。

摘　　要：目的:探究艾司氯胺酮(Esketamine)调控核转录因子红系2相关因子2(Nrf2)通路减轻脓毒症小鼠急性肺损伤(ALI)。方法:雄性C57BL/6小鼠,随机分成Sham组、盲肠结扎穿孔(CLP)诱导的ALI组和CLP+Esketamine组,每组12只。CLP+Esketamine组在CLP后腹腔注射Esketamine(15 mg/kg)。CLP后24 h对小鼠评分,并记录CLP后7 d体质量。24 h取材,HE染色肺组织并评分,计算肺湿干重比;Western Blot检测各组肺的Nrf2、Kelch样环氧氯丙烷相关蛋白1(Keap1)和血红素加氧酶1(HO-1)蛋白水平;ELISA检测小鼠血清IL-6、TNF-α的水平;免疫荧光染色检测肺紧密连接蛋白。结果:与Sham组相比,CLP组肺组织损伤加重,肺湿干重比明显升高(P<0.001),血清TNF-α及IL-6水平升高(P<0.00015),肺组织紧密连接蛋白减少;肺组织HO-1与Nrf2蛋白表达降低(P<0.05,P<0.001),Keap1升高(P<0.001)。但CLP+Esketamine组能不同程度地改善小鼠状态,减轻炎症和ALI,激活Nrf2信号通路。结论:Esketamine减轻脓毒症小鼠ALI,可能激活Nrf2信号通路发挥抗氧化作用。Objective:To investigate the ability of Esketamine to attenuate acute lung injury(ALI)in septic mice through the regulation of the nuclear transcription factor red lineage 2-related factor 2(Nrf2)path-way.Methods:Male C57BL/6 mice were randomized into three groups:Sham,CLP,and CLP+Es-ketamine.The mouse model of septic ALI was prepared by cecum ligation and perforation(CLP),and the CLP+Esketamine group was injected peritoneally with Esketamine(15 mg/kg)after the CLP.The mice were scored using murine sepsis score(MSS)after 24 h of modeling,and the body weight were recorded for 7 days.Additionally,24 hours after modeling,the lungs were stained with HE staining to observe the pathological morphology and were scored.The W/D ratio of the lungs was calculated.The expressions of Nrf2,Kelch-like ECH-associated protein 1(Keap1)and heme oxy-genase-1(HO-1)in the lungs were monitored by Western Blot.ELISA assay was adopted to detect the levels of inflammatory cytokines IL-6 and TNF-αin the serum.Immunofluorescence staining was adopted to detect the expression of lung tight junction proteins.Results:Compared with those in the Sham group,body temperature and weight decreased in the CLP group.The lung tissue damage in the CLP group was greater,with a higher W/D ratio(P<0.001).The levels of TNF-αand IL-6 in the serum were increased(P<0.00015),and the tight junction proteins expression decreased.The expression of Keap1(P<0.001),HO-1,and Nrf2 in the lung tissue decreased(P<0.05,P<0.001).Compared with the CLP group,CLP+Esketamine treatment improved the state of mice in various aspects,reduced pulmonary damage,and activated the Nrf2 signaling pathway.Conclusion:Esketamine attenuates septic ALI in mice,which is related to the activation of the Nrf2 signaling pathway and antioxidant effects.

关 键 词：脓毒症 急性肺损伤 艾司氯胺酮 核转录因子红系2相关因子2 血红素加氧酶1 Kelch样环氧氯丙烷相关蛋白1 

分 类 号：R563.8[医药卫生—呼吸系统]