沙格列汀通过调控ROS/NLRP3信号通路减轻大鼠呼吸机所致肺损伤  

Saxagliptin attenuates ventilator‑induced lung injury in rats by regulating ROS/NLRP3 signaling pathway

作　　者：王佳佳 蔚海霞 马源 李忠林 秦伟伟 马福国[1] 王明山[1] 孙立新[1] Wang Jiajia;Yu Haixia;Ma Yuan;Li Zhonglin;Qin Weiwei;Ma Fuguo;Wang Mingshan;Sun Lixin(Department of Anesthesiology,Qingdao Municipal Hospital,Qingdao 266071,China;Department of Anesthesiology,Qingdao Cheng-yang People's Hospital,Qingdao 266109,China)

机构地区：[1]青岛市市立医院麻醉科,青岛266071 [2]青岛市城阳区人民医院麻醉科,青岛266109

出　　处：《国际麻醉学与复苏杂志》2023年第10期1015-1020,共6页International Journal of Anesthesiology and Resuscitation

基　　金：青岛市医疗卫生优秀学科带头人项目。

摘　　要：目的探索活性氧(reactive oxygen species,ROS)/NOD样受体热蛋白结构域相关蛋白3(NOD‐like receptor pyrin domain containing 3,NLRP3)信号通路在沙格列汀减轻大鼠呼吸机所致肺损伤(ventilator‐induced lung injury,VILI)中的作用。方法6~8周龄SPF级健康雄性SD大鼠36只,体重240~300 g,按照随机数字表法分为对照组(C组)、VILI组(V组)及VILI+沙格列汀组(S组),每组12只。大潮气量(20 ml/kg)机械通气4 h复制大鼠VILI模型。各组于气管插管前及气管插管通气4 h后留取股动脉血行动脉血气分析检测pH、PaO2、PaCO_(2)及葡萄糖水平。处死大鼠后采用ELISA法检测血清及支气管肺泡灌洗液(bronchoalveolar lavage fluid,BALF)中IL‐1β和IL‐18浓度,取肺组织测量肺组织湿/干重比(wet/dry ratio,W/D),观察肺组织病理学改变并行肺损伤评分,Western blot法测定NLRP3、凋亡相关斑点样蛋白(apoptosis‐related speck protein,ASC)和胱天蛋白酶1(cysteinyl aspartate specific proteinase‐1,caspase‐1)的表达水平,采用2,7‐二氯荧光素二乙酸酯(2,7‐dichlorodihydro‐fluorescein diacetate,DCFHDA)荧光探针法测定肺组织ROS表达水平。结果机械通气结束时:与C组比较,V组大鼠葡萄糖水平升高(P<0.05),V组、S组大鼠PaO_(2)、PaCO_(2)降低(P<0.05),pH、W/D值、肺损伤评分、血清及BALF中IL‐1β及IL‐18浓度升高(P<0.05),肺组织中NLRP3、ASC和caspase‐1的表达上调(P<0.05),ROS表达增加(P<0.05);与V组比较,S组大鼠PaO_(2)、Pa‐CO_(2)升高(P<0.05),葡萄糖水平、pH、W/D值、肺损伤评分、血清及BALF中IL‐1β及IL‐18浓度降低(P<0.05),肺组织NLRP3、ASC、caspase‐1的表达下调(P<0.05),ROS表达减少(P<0.05)。结论沙格列汀通过抑制ROS/NLRP3信号通路在VILI中发挥保护作用。Objective To explore the effect of reactive oxygen species(ROS)/NOD‐like receptor pyrin domain containing 3(NLRP3)signaling pathway on alleviating ventilator‐induced lung injury(VILI)by saxagliptin in rats.Methods A total of 36 SPF‐grade healthy Sprague‐Dawley rats,aged 6−8 weeks,weighing 240−300 g,were selected.According to the random number table method,they were divided into three groups(n=12):a control(group C),a VILI group(group V)and a VILI+saxagliptin group(group S).Then,mechanical ventilation with high tidal volume(20 ml/kg)was performed for 4 h to simulate a model of VILI in rats.Before en‐dotracheal intubation,and 4 h after mechanical ventilation,femoral arterial blood was collected for arterial blood gas analysis to detect potential of hydrogen(pH),partial pressure of oxygen(PaO2),partial pressure of carbon dioxide(PaCO2)and glucose levels.The rats were sacrificed,and interleukin(IL)‐1βand IL‐18 concentrations in serum and bronchoalveolar lavage fluid(BALF)were determined by enzyme linked immunosorbent assay(ELISA).The wet weight/dry weight(W/D)ratio,pathologic histology changes of lung tissue and lung injury scores were examined.The protein levels of NLRP3,apoptosis‐related speck protein(ASC),and cysteinyl aspartate specific proteinase‐1(caspase‐1)were detected by Western blot.The expression of ROS in lung tissues was determined by 2,7‐dichlorodihydro‐fluorescein diacetate(DCFHDA)fluorescence probe.Results At the end of mechanical ventilation,compared with group C,group V showed elevated glucose levels(P<0.05),while both group V and group S presented decreases in PaO2 and PaCO2(P<0.05),increases in pH,W/D ratio,lung injury score,IL‐1βand IL‐18 concentrations in serum and BALF(P<0.05),up‐regulated expression of NLRP3,ASC,and caspase‐1(P<0.05),and increased ROS expression(P<0.05).Compared with group V,group S showed elevated PaO2 and Pa‐CO2,decreases in pH,glucose levels,W/D ratio,lung injury score,IL‐1βand IL‐18 concentrations(P<0.05),down‐regulated protei

关 键 词：沙格列汀 呼吸机所致肺损伤 活性氧 NOD样受体热蛋白结构域相关蛋白3 

分 类 号：R614[医药卫生—麻醉学]