NLRP3炎症小体介导细胞焦亡在急性胰腺炎肺损伤中的作用机制研究  

Mechanism of NLRP3 Inflammasome Mediated Pyroptosis in Acute Pancreatitis⁃related Lung Injury

作　　者：冯颖 陈醒 郭美霞 徐浩宇 孙博 周俊明 李敏利 FENG Ying;CHEN Xing;GUO Meixia;XU Haoyu;SUN Bo;ZHOU Junming;LI Minli(Department of Gastroenterology,Eastern Theater Command General Hospital,Nanjing 210002;Drug Instrument Supervision and Inspection Station,Wuxi Joint Logistics Support Center,Wuxi,Jiangsu Province)

机构地区：[1]东部战区总医院干部消化内科,210002 [2]无锡联勤保障中心药品仪器监督检验站

出　　处：《胃肠病学》2023年第5期257-263,共7页Chinese Journal of Gastroenterology

基　　金：东部战区总医院基础研究计划重点项目(22JCYYZD6)。

摘　　要：细胞焦亡参与了急性胰腺炎的发生,但其在远隔器官损伤中的作用尚未明确。目的:探讨NLRP3炎症小体依赖性细胞焦亡在急性胰腺炎相关肺损伤中的作用和机制。方法:32只雄性Sprague-Dawley大鼠随机分为4组:对照组、重症急性胰腺炎(SAP)组、Z-WEHD-FMK(caspase-1抑制剂)组和双硫仑(GSDMD抑制剂)组,后3组以5%牛磺胆酸钠构建SAP模型。检测血清淀粉酶、脂肪酶、降钙素原水平和髓过氧化物酶(MPO)活性;通过组织病理学检查和肺湿/干重比评估胰腺和肺损伤程度;分别以ELISA法和免疫组化染色、蛋白质印迹法检测血清细胞焦亡相关炎症因子水平和肺组织细胞焦亡通路相关蛋白表达。结果:与对照组相比,SAP组血清生化指标、MPO活性、白细胞介素(IL)-1β、IL-18水平显著升高,胰腺和肺组织损伤明显,肺组织NLRP3、caspase-1、GSDMD表达显著上调(P均<0.05);与SAP组比较,caspase-1抑制剂和GSDMD抑制剂预处理组胰腺和肺损伤程度减轻,血清生化指标、MPO活性降低,细胞焦亡相关炎症因子水平和焦亡通路相关蛋白表达下凋(P均<0.05)。结论:NLRP3/caspase-1/GSDMD通路介导的细胞焦亡在急性胰腺炎相关肺损伤中发挥重要作用,抑制相关通路可能为其治疗提供新的方向。Background:Pyroptosis is involved in the occurrence of acute pancreatitis,but its role in remote organ injury remains unclear.Aims:To investigate the role and mechanism of NLRP3 inflammasome⁃dependent pyroptosis in acute pancreatitis⁃related lung injury.Methods:Thirty⁃two male Sprague⁃Dawley rats were randomly divided into four groups:control group,severe acute pancreatitis(SAP)group,Z⁃WEHD⁃FMK(caspase⁃1 inhibitor)group and disulfiram(GSDMD inhibitor)group.Experimental SAP was constructed by using 5%sodium taurocholate in the latter 3 groups.Serum levels of amylase,lipase,procalcitonin,and the myeloperoxidase(MPO)activity were determined;the severity of pancreatic and lung injuries was assessed by histopathology and lung wet/dry weight ratio;serum levels of pyroptosis⁃related inflammatory cytokines and the expressions of proteins involved in pyroptosis pathway in lung tissue were measured by ELISA method and immunohisto⁃chemistry and Western blotting,respectively.Results:Compared with the control group,the serum biochemical indices,MPO activity,and interleukin(IL)⁃1β,IL⁃18 levels in SAP group were significantly increased with aggravated pancreatic and lung tissue injuries;meanwhile,the expressions of NLRP3,caspase⁃1 and GSDMD in lung tissue were significantly up⁃regulated(all P<0.05).Pretreatment with caspase⁃1 or GSDMD inhibitors reduced the severity of pancreatic and lung tissue injuries,improved the serum biochemical indices and MPO activity,and ameliorated the increased pyroptosis⁃related inflammatory cytokines and pyroptosis pathway⁃related proteins(all P<0.05).Conclusions:NLRP3/caspase⁃1/GSDMD pathway mediated pyroptosis plays an important role in acute pancreatitis⁃related lung injury,and inhibition of pyroptosis pathways might be a new direction for its treatment.

关 键 词：急性胰腺炎 急性肺损伤 细胞焦亡 NLRP3炎症小体 

分 类 号：R576[医药卫生—消化系统]