七氟烷通过信号转导和转录激活因子5A/髓系细胞触发受体1轴激活NOD样受体热蛋白结构域相关蛋白3炎症小体介导小胶质细胞焦亡在衰老小鼠术后认知功能障碍中的作用OA
Sevoflurane activates the NLRP3 inflammasome via the STAT5A/TREM1 axis to mediate microglial pyroptosis in postoperative cognitive dysfunction in aged mice
目的:探讨七氟烷通过信号转导和转录激活因子5A(STAT5A)/髓系细胞触发受体1(TREM1)轴激活NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症小体介导海马小胶质细胞焦亡参与衰老小鼠术后认知功能障碍(POCD)的发生机制.方法:将18～20月龄C57BL/6衰老小鼠随机分为假手术组、七氟烷组、七氟烷+STAT5A抑制剂组、七氟烷+TREM1抑制剂组及七氟烷+NLRP3抑制剂组.七氟烷麻醉后,通过Morris水迷宫和新物体识别实验评估小鼠认知功能;检测海马组织中小胶质细胞活化标志物(Iba1)、焦亡相关蛋白[消皮素DN端片段(GSDMD-N)、半胱天冬酶-1(Caspase-1)、白细胞介素-1β(IL-1β)、白细胞介素-18(IL-18)]及 STAT 5A/TREM1/NLRP3轴各分子表达水平.结果:与假手术组比较,七氟烷组小鼠逃避潜伏期显著延长,穿越平台次数、目标象限停留时间及识别指数显著降低(均P＜0.05);海马区Iba1阳性细胞数、焦亡相关蛋白表达水平、STAT5A、TREM1及NLRP3表达水平显著升高(均P＜0.05).与七氟烷组比较,抑制STAT5A后,TREM1、NLRP3及焦亡指标均显著下降(均P＜0.05),认知功能改善(P＜0.05);抑制TREM1后,NLRP3及焦亡指标下降(均P＜0.05),STAT5A表达仍维持高水平(P＞0.05);抑制NLRP3后,焦亡及认知功能改善(均P＜0.05),对STAT5A和TREM1表达无统计学差异(均P＞0.05).三个抑制剂组在认知功能、焦亡指标及NLRP3表达水平上差异无统计学意义(均P＞0.05).结论:七氟烷激活STAT5A上调TREM1表达,活化NLRP3炎症小体,诱导海马小胶质细胞焦亡,导致衰老小鼠术后认知功能障碍.
Objective:To investigate the mechanism by which sevoflurane activates the NLRP3 inflammasome via the STAT5A/TREM1 axis to mediate hippocampal microglial pyroptosis,thereby contributing to postoperative cognitive dysfunction(POCD)in aged mice.Methods:Aged C57BL/6 mice(18～20 months old)were randomly divid-ed into five groups:sham operation group,sevoflurane group,sevoflurane+STAT 5A inhibitor group,sevoflurane+TREM1 inhibitor group,and sevoflurane+NLRP3 inhibitor group.After sevoflurane anesthesia,cognitive function was as-sessed using the Morris water maze and novel object recognition tests.Western blot and immunohistochemistry were employed to detect microglial activation marker(Iba1),pyroptosis-related proteins(GSDMD-N,Caspase-1,IL-1β,IL-18),and the expression levels of molecules in the STAT5A/TREM1/NLRP3 axis in the hippocampus.Results:Compared with the sham operation group,the sevoflurane group showed significantly prolonged escape latency,a re-duced number of platform crossings,as well as reduced time spent in the target quadrant and recognition index(all P＜0.05)The number of Iba1-positive cells in the hippocampus,the expression levels of pyroptosis-related proteins and the expression levels of STAT5 A,TREM1,and NLRP3 were significantly increased(all P＜0.05).Compared with the sevoflurane group,inhibition of STAT5A led to significant decreases in TREM1,NLRP3,and pyroptosis in-dicators,along with improved cognitive function(all P＜0.05).Inhibition of TREM1 resulted in decreased NLRP3 and pyroptosis indicators(P＜0.05),but STAT5A expression remained high(P＞0.05).Inhibition of NLRP3 amel-iorated pyroptosis and cognitive function(all P＜0.05),but had no significant effect on STAT5A or TREM1 expres-sion(P＞0.05).No significant differences in cognitive function,pyroptosis indicators,or NLRP3 expression were ob-served among the three inhibitor groups(all P＞0.05).Conclusion:Sevoflurane activates STAT5A to upregulate TREM1 expression,which in turn activates the NLRP3 inflammasome,thereby inducing hippocampal microglial py-roptosis and leading to postoperative cognitive dysfunction in aged mice.
樊晓龙;高勇;王力;韩旭;田全发;孙玉琴
山西医科大学附属汾阳医院山西省汾阳医院,山西汾阳 032200山西医科大学附属汾阳医院山西省汾阳医院,山西汾阳 032200山西医科大学附属汾阳医院山西省汾阳医院,山西汾阳 032200山西医科大学附属汾阳医院山西省汾阳医院,山西汾阳 032200山西医科大学附属汾阳医院山西省汾阳医院,山西汾阳 032200山西医科大学附属汾阳医院山西省汾阳医院,山西汾阳 032200
医药卫生
七氟烷信号转导和转录激活因子5A髓系细胞触发受体1NOD样受体热蛋白结构域相关蛋白3炎症小体小胶质细胞焦亡术后认知功能障碍衰老小鼠
SevofluraneSTAT5ATREM1NLRP3 inflammasomeMicroglial pyroptosisPostoperative cog-nitive dysfunctionAged mice
《陕西医学杂志》 2026 (9)
1185-1189,5
国家卫生健康委"十五五"规划全国重点课题(WSJK241122)
评论