Lidocaine ameliorates intestinal barrier dysfunction in irritable bowel syndrome by modulating corticotropin-releasing hormone receptor 2

作者全名："Wang, Yanrong; Qiao, Mingbiao; Yao, Xue; Feng, Zhonghui; Hu, Ruiqi; Chen, Jianguo; Liu, Lei; Liu, Jinbo; Sun, Yueshan; Guo, Yuanbiao"

作者地址："[Wang, Yanrong] Sichuan Tianfu New Area Peoples Hosp, Dept Lab Med, Chengdu, Peoples R China; [Qiao, Mingbiao] De Yang Peoples Hosp, Dept Pathol, Deyang, Peoples R China; [Yao, Xue; Liu, Lei; Sun, Yueshan; Guo, Yuanbiao] Chongqing Med Univ, Chengdu Hosp Affiliated 2, Southwest Jiaotong Univ, Med Res Ctr,Peoples Hosp Chengdu 3,Affiliated Hosp, Chengdu 610031, Peoples R China; [Feng, Zhonghui] Chongqing Med Univ, Peoples Hosp Chengdu 3, Chengdu Hosp 2, Ctr Gastrointestinal & Minimally Invas Surg,Dept G, Chengdu, Peoples R China; [Hu, Ruiqi; Chen, Jianguo; Liu, Jinbo] Southwest Med Univ, Dept Clin Lab, Affiliated Hosp, Luzhou, Peoples R China; [Sun, Yueshan; Guo, Yuanbiao] Chongqing Med Univ, Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Chengdu Hosp 2,Affiliated Hosp ,Med Res Ctr, Chengdu 610031, Sichuan, Peoples R China"

通信作者："Sun, YS; Guo, YB (通讯作者)，Chongqing Med Univ, Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Chengdu Hosp 2,Affiliated Hosp ,Med Res Ctr, Chengdu 610031, Sichuan, Peoples R China."

来源：NEUROGASTROENTEROLOGY AND MOTILITY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001067449500001

JCR分区：Q1

影响因子：3.5

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：corticotropin-releasing hormone receptor 2; intestinal barrier; lidocaine; stress; tight junctions

摘要："BackgroundIntestinal barrier dysfunction is a prevalent pathogenic factor underlying various disorders. Currently there is no effective resolution. Previous studies have reported the potential anti-inflammatory properties of lidocaine and its ability to alleviate visceral hypersensitivity in individuals with irritable bowel syndrome (IBS). Therefore, our study will further verify the effect of lidocaine on intestinal barrier dysfunction in IBS and investigate the underlying mechanisms.MethodsIn this study, we investigated the role of lidocaine by assessing visceral hypersensitivity, body weight, inflammatory factors, fluorescein isothiocyanate-dextran 4000 (FD4) flux, tight junctions (TJs) and spleen and thymus index in rats subjected to water avoidance stress (WAS) to mimic intestinal barrier dysfunction in IBS with and without lidocaine. In vitro, we investigated the role of corticotropin-releasing hormone receptor 2 (CRHR2) in lidocaine-treated Caco2 cells using small interfering RNA (siRNA) targeting CRHR2.Key ResultsIn WAS rats, lidocaine significantly restored weight loss, damaged TJs, spleen index and thymus index and inhibited abdominal hypersensitivity as well as blood levels of markers indicating intestinal permeability, such as diamine oxidase (DAO), D-lactic acid (D-Lac) and lipopolysaccharide (LPS). Consequently, the leakage of FD4 flux from intestine was significantly attenuated in lidocaine group, and levels of intestinal inflammatory factors (IL-1 & beta;, IFN-& gamma;, TNF-& alpha;) were reduced. Interestingly, lidocaine significantly suppressed corticotropin-releasing hormone (CRH) levels in lamina propria cells, while the CRH receptor CRHR2 was upregulated in intestinal epithelial cells. In vitro, lidocaine enhanced the expression of CRHR2 on Caco-2 intestinal epithelial cells and restored disrupted TJs and the epithelial barrier caused by LPS. Conversely, these effects were diminished by a CRHR2 antagonist and siRNA-CRHR2, suggesting that the protective effect of lidocaine depends on CRHR2.Conclusions and InferencesLidocaine ameliorates intestinal barrier dysfunction in IBS by potentially modulating the expression of CRHR2 on intestinal epithelial cells. Under water avoidance stress, the expression of CRHR2 was downregulated in rats, which resulted in decreased expression of tight junction proteins and increased intestinal permeability. lidocaine improved the severity of IBS rats by modulating intestinal epithelial TJs and protecting intestinal epithelial barrier function. The specific potential mechanism may be via activation of the CRHR2 signaling pathway.image"

基金机构：Chengdu Science and Technology Bureau [2021-YF05-00585-SN]; Foundation of Science and Technology Department of Sichuan Province [2022YFS0340]; Sichuan Science and Technology program [2023JDRC0088]

基金资助正文："Chengdu Science and Technology Bureau, Grant/Award Number: 2021-YF05-00585-SN; Foundation of Science and Technology Department of Sichuan Province, Grant/ Award Number: 2022YFS0340; the Sichuan Science and Technology program, Grant/Award Number: 2023JDRC0088"