A new cell death program regulated by toll-like receptor 9 through p38 mitogen-activated protein kinase signaling pathway in a neonatal rat model with sepsis associated encephalopathy

作     者：Ruixi Zhou Junjie Ying Xia Qiu Luting Yu Yan Yue Qian Liu Jing Shi Xihong Li Yi Qu Dezhi Mu Ruixi Zhou;Junjie Ying;Xia Qiu;Luting Yu;Yan Yue;Qian Liu;Jing Shi;Xihong Li;Yi Qu;Dezhi Mu

作者机构：Department of PediatricsWest China Second University HospitalSichuan UniversityChengduSichuan 610041China Key Laboratory of Birth Defects and Related Diseases of Women and ChildrenSichuan UniversityMinistry of EducationChengduSichuan 610041China 

出 版 物：《Chinese Medical Journal》 (中华医学杂志（英文版）)

年 卷 期：2022年第135卷第12期

页      面：1474-1485页

核心收录：

学科分类：100218[医学-急诊医学] 1002[医学-临床医学] 1010[医学-医学技术（可授医学、理学学位）] 10[医学] 

基　　金：This work was supported by grants from the National Natural Science Foundation of China(Nos.81630038,81771634,81842011,81801629,81971433,81971428,and 82071353) the National Key Research and Development Program(Nos.2017YFA0104200 and 2017YFA0104201) the grants from the Science and Technology Bureau of Sichuan Province(Nos.2021YJ0017 and 2020YFS0041) the Fundamental Research Funds for the Central University(No.SCU2020D006) the National Key Project of Neonatal Children(No.1311200003303) 

主　　题：Sepsis associated encephalopathy TLR9 Apoptosis Pyroptosis Necroptosis p38 mitogen-activated protein kinase 

摘      要：Background:Sepsis,a serious condition with high mortality,usually causes sepsis associated encephalopathy(SAE)that involves neuronal cell ***,the cell death programs involved and their underlying mechanisms are not *** study aimed to explore the regulatory mechanisms of different cell death programs in ***:A neonatal rat model of SAE was established by cecal ligation and *** rate and vital signs(mean arterial pressure and heart rate)were monitored,nerve reflexes were evaluated,and cortical pathological changes were observed by hematoxylin and eosin *** expression of pyroptosis,apoptosis,and necroptosis(PANoptosis)-related proteins,mitogen-activated protein kinase(MAPK),and its upstream regulator toll-like receptor 9(TLR9)were *** expression of TLR9 in neurons was observed by immunofluorescence *** ultrastructure of neurons was observed by transmission electron ***:First,PANoptosis was found in cortical nerve cells of the SAE ***,the subunits of MAPKs,p38 MAPK,Jun N-terminal kinase,and extracellular signal-regulated kinase(ERK)were *** pharmacologically inhibiting each of the subunits,only p38 MAPK was found to be associated with ***,blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and *** necroptosis was pharmacologically inhibited,apoptosis and pyroptosis were ***,we found that the expression of TLR9,a regulator of MAPKs,was significantly increased in this *** down-regulation of TLR9,p38 MAPK,and ERK signaling pathways were inhibited,which led to the inhibition of *** analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE ***:Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE ***9 activated PANoptosis through the p38 MAPK signaling pathw