Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis

doi:10.1186/s10020-022-00562-w

科研成果详情

题名	Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis
作者	Cheng, Bo 1; Du, Mengyu 1; He, Shuxuan 1; Yang, Lan 1; Wang, Xi2; Gao, Hui 1; Chang, Haiqing 1; Gao, Wei 1; Li, Yan 1; Wang, Qiang 1; Li, Yansong 1
发表日期	2022-12
发表期刊	MOLECULAR MEDICINE 影响因子和分区
语种	英语
原始文献类型	Article
关键词	Sepsis Intestinal barrier dysfunction CD40L-CD40 Enteric glia cells S-nitrosoglutathione CD40L–CD40
其他关键词	NERVOUS-SYSTEM ; CD40 LIGAND ; CELLS ; INJURY ; CONTRIBUTES ; CILOSTAZOL ; RELEASE ; DISEASE ; PROTEIN
摘要	Background Intestinal barrier dysfunction, which is associated with reactive enteric glia cells (EGCs), is not only a result of early sepsis but also a cause of multiple organ dysfunction syndrome. Inhibition of platelet activation has been proposed as a potential treatment for septic patients because of its efficacy in ameliorating the organ damage and barrier dysfunction. During platelet activation, CD40L is translocated from alpha granules to the platelet surface, serving as a biomarker of platelet activation a reliable predictor of sepsis prognosis. Given that more than 95% of the circulating CD40L originate from activated platelets, the present study aimed to investigate if inhibiting platelet activation mitigates intestinal barrier dysfunction is associated with suppressing reactive EGCs and its underlying mechanism. Methods Cecal ligation and puncture (CLP) was performed to establish the sepsis model. 24 h after CLP, the proportion of activated platelets, the level of sCD40L, the expression of tight-junction proteins, the intestinal barrier function and histological damage of septic mice were analyzed. In vitro, primary cultured EGCs were stimulated by CD40L and LPS for 24 h and EGCs-conditioned medium were collected for Caco-2 cells treatment. The expression of tight-junction proteins and transepithelial electrical resistance of Caco-2 cell were evaluated. Results In vivo, inhibiting platelet activation with cilostazol mitigated the intestinal barrier dysfunction, increased the expression of ZO-1 and occludin and improved the survival rate of septic mice. The efficacy was associated with reduced CD40L(+) platelets proportion, decreased sCD40L concentration, and suppressed the activation of EGCs. Comparable results were observed upon treatment with compound 6,877,002, a blocker of CD40L-CD40-TRAF6 signaling pathway. Also, S-nitrosoglutathione supplement reduced intestinal damage both in vivo and in vitro. In addition, CD40L increased release of TNF-alpha and IL-1 beta while suppressed the release of S-nitrosoglutathione from EGCs. These EGCs-conditioned medium reduced the expression of ZO-1 and occludin on Caco-2 cells and their transepithelial electrical resistance, which could be reversed by CD40-siRNA and TRAF6-siRNA transfection on EGCs. Conclusions The inhibition of platelet activation is related to the suppression of CD40L-CD40-TRAF6 signaling pathway and the reduction of EGCs activation, which promotes intestinal barrier function and survival in sepsis mice. These results might provide a potential therapeutic strategy and a promising target for sepsis.
资助项目	National Natural Science Foundation of China [81801899, 81974540, 81971290]
出版者	SPRINGER
出版地	NEW YORK
ISSN	1076-1551
EISSN	1528-3658
卷号	28 期号:1 页码:127
DOI	10.1186/s10020-022-00562-w
页数	18
WOS类目	Biochemistry & Molecular Biology ; Cell Biology ; Medicine, Research & Experimental
WOS研究方向	Biochemistry & Molecular Biology ; Cell Biology ; Research & Experimental Medicine
WOS记录号	WOS:000885316600003
收录类别	SCIE ; SCOPUS ; PUBMED
URL	查看原文
Pubmed记录号	36401163
Scopus记录号	2-s2.0-85142402406
通讯作者地址	[Li, Yansong]Xi An Jiao Tong Univ, Dept Anesthesiol, Affiliated Hosp 1, Xian 710061, Shaanxi, Peoples R China. ; [Li, Yansong]Xi An Jiao Tong Univ, Ctr Brain Sci, Affiliated Hosp 1, Xian 710061, Shaanxi, Peoples R China.
scopus学科分类	Molecular Medicine;Molecular Biology;Genetics;Genetics (clinical)
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/184001
专题	附属第一医院_麻醉科
通讯作者	Li, Yansong
作者单位	1.Department of Anesthesiology & Center for Brain Science,First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China; 2.Department of Anesthesiology,First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325000,China
推荐引用方式 GB/T 7714	Cheng, Bo,Du, Mengyu,He, Shuxuan,et al. Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis[J]. MOLECULAR MEDICINE,2022,28(1):127.
APA	Cheng, Bo., Du, Mengyu., He, Shuxuan., Yang, Lan., Wang, Xi., ... & Li, Yansong. (2022). Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis. MOLECULAR MEDICINE, 28(1), 127.
MLA	Cheng, Bo,et al."Inhibition of platelet activation suppresses reactive enteric glia and mitigates intestinal barrier dysfunction during sepsis".MOLECULAR MEDICINE 28.1(2022):127.