κ‑阿片受体激动剂U50488H通过抑制NLRP3/Caspase‑1信号通路对体外循环致大鼠肺损伤的影响  

Effect ofκ-opioid receptor agonist U50448H on rats'lung injury induced by cardiopulmonary bypass via inhibiting the NLRP3/Caspase-1 signaling pathway

作　　者：刘晓洋 高光洁 Liu Xiao yang;Gao Guangjie(Department of Anesthesiology,the Air Force Hospital of Northern Theater PLA,Shenyang 110042,China)

机构地区：[1]北部战区空军医院麻醉科,辽宁沈阳110042

出　　处：《实用药物与临床》2024年第7期488-492,共5页Practical Pharmacy and Clinical Remedies

基　　金：辽宁省自然科学基金资助项目(2020‑MS‑043)。

摘　　要：目的观察κ-阿片受体(KOR)激动剂U50488H对体外循环诱导的大鼠肺损伤的影响,并探讨U50488H对肺保护的作用机制。方法将24只SPF级SD大鼠随机分为假手术组(Sham组)、大鼠体外循环模型组(CPB组)和KOR激动剂在体外循环(CPB)模型中的干预组(U50448H组),每组8只。U50448H组于CPB前30 min静脉注射1.5 mg/kg U50488H,分别于CPB后0 h、1 h和2 h各时点行动脉血气分析,计算肺泡-动脉氧分压差(AaDO_(2))和呼吸指数(Respiratory index,RI)。三组大鼠均在停CPB后2 h时处死,取完整右肺下叶,采用重力法测定血管外肺水(Extravascular lung water,EVLW),HE染色观察肺组织形态学变化。采用ELISA方法检测血浆脂多糖(LPS)、超氧化物歧化酶(SOD)、丙二醛(MDA)和还原型谷胱甘肽(GSH)的含量,TUNEL法检测肺组织的细胞凋亡,Western blot测定肺组织GSDMD-C、GSDMD-N、NLRP3、ASC、pro-Caspase-1和pro-IL-1β蛋白的表达。结果CPB组大鼠在CPB后0 h、1 h和2 h各时点的AaDO_(2)和RI、LPS明显高于Sham组(P<0.05);U50488H组3个时点的AaDO_(2)、RI、LPS均明显低于CPB组(P<0.05)。与Sham组比较,CPB组大鼠EVLW,血浆MDA和GSH,肺组织的凋亡指数(AI),NLRP3、ASC、pro-Caspase-1和pro-IL-1β蛋白的表达明显增高,血浆SOD含量明显降低,差异均有统计学意义(P<0.05);而U50488H组上述指标与Sham组比较,差异无统计学意义(P>0.05)。CPB组大鼠出现了严重的肺损伤和肺泡内充血/出血,并伴有广泛的炎症细胞浸润,U50448H组肺损伤明显减轻。结论κ-阿片受体激动剂U50488H通过抑制肺组织中NLRP3/Caspase-1信号通路介导的炎症和氧化应激反应,从而减轻CPB后大鼠的肺损伤。Objective To investigate the effect ofκ-opioid receptor(KOR)agonist U50488H on lung injury induced by cardiopulmonary bypass in rats,and to explore the mechanism of U50488H in lung protection.Methods Totally 24 SPF grade SD rats were randomly divided into a sham surgery group(Sham group),a rat cardiopulmonary bypass model group(CPB group),and an intervention group with KOR agonists in the cardiopulmonary bypass(CPB)model(U50448H group),with 8 rats in each group.The U50448H group received intravenous injection of 1.5 mg/kg U50488H 30 minutes before CPB.The arterial blood gas analysis was performed to calculate the value of AaDO_(2) and RI at 0 h,1 h and 2 h of CPB.The rats of the 3 groups were sacrificed at 2 h after CPB,and the complete inferior lobe of the right lung was taken to determine extra vascular lung water(EVLW)by gravimetric method.HE staining was used to observe the pathological morphology of lung tissue.ELISA was applied to test the levels of LPS,SOD,MDA and GSH in serum.The apoptosis of lung tissue was detected using TUNEL method.Western blot was performed for examining the expression of GSDMD-C,GSDMD-N,NLRP3,ASC,pro-Caspase-1and pro-IL-1βin lung tissue.Results The values of AaDO_(2),RI and LPS at 0 h,1 h and 2 h after CPB in CPB group were higher than those in Sham group(P<0.05);the values of AaDO_(2),RI and LPS in U50488H group were significantly lower than those in CPB group(P<0.05).Compared with the Sham group,the levels of EVLW,plasma MDA and GSH,lung AI and the expression of NLRP3,ASC,pro-Caspase-1and pro-IL-1βwere significantly increased while the levels of plasma SOD were significantly decreased in CPB group,the differences being statistically significant(P<0.05);the above indexes were not significantly different in U50488H group compared with the Sham group(P>0.05).The rats of CPB group had serious lung damage,intra-alveolar congestion/hemorrhage and massive inflammatory cell infiltration.The lung injury was alleviated in U50448H group.Conclusion KOR agonist U50488H inhibits inflammation

关 键 词：κ-阿片受体激动剂 U50488H 体外循环 急性肺损伤 NLRP3/Caspase-1 

分 类 号：R614[医药卫生—麻醉学]