并行传输
紧密连接
势垒函数
结肠炎
肌球蛋白轻链激酶
肠道通透性
炎症性肠病
MAPK/ERK通路
跨细胞
内科学
粘合连接
医学
胃肠病学
生物
化学
激酶
细胞生物学
磁导率
疾病
生物化学
细胞
磷酸化
钙粘蛋白
膜
作者
Meghali P. Nighot,Pei-Luan Liao,Nathan Morris,Dennis Mccarthy,Viszwapriya dharmaprakash,Inam Ullah Khan,Shannon Dalessio,Kushal Saha,Ashwinkumar Subramenium Ganapathy,A. Wang,Wei Ding,Gregory Yochum,Walter Koltun,Prashant K. Nighot,Thomas Y. Ma
出处
期刊:Journal of Crohn's and Colitis
[Oxford University Press]
日期:2022-11-02
标识
DOI:10.1093/ecco-jcc/jjac168
摘要
Abstract Background Proton pump inhibitors [PPIs] are widely used to treat a number of gastro-oesophageal disorders. PPI-induced elevation in intragastric pH may alter gastrointestinal physiology. The tight junctions [TJs] residing at the apical intercellular contacts act as a paracellular barrier. TJ barrier dysfunction is an important pathogenic factor in inflammatory bowel disease [IBD]. Recent studies suggest that PPIs may promote disease flares in IBD patients. The role of PPIs in intestinal permeability is not clear. Aim The aim of the present study was to study the effect of PPIs on the intestinal TJ barrier function. Methods Human intestinal epithelial cell culture and organoid models and mouse IBD models of dextran sodium sulphate [DSS] and spontaneous enterocolitis in IL-10−/− mice were used to study the role of PPIs in intestinal permeability. Results PPIs increased TJ barrier permeability via an increase in a principal TJ regulator, myosin light chain kinase [MLCK] activity and expression, in a p38 MAPK-dependent manner. The PPI-induced increase in extracellular pH caused MLCK activation via p38 MAPK. Long-term PPI administration in mice exaggerated the increase in intestinal TJ permeability and disease severity in two independent models of DSS colitis and IL-10−/− enterocolitis. The TJ barrier disruption by PPIs was prevented in MLCK−/− mice. Human database studies revealed increased hospitalizations associated with PPI use in IBD patients. Conclusions Our results suggest that long-term use of PPIs increases intestinal TJ permeability and exaggerates experimental colitis via an increase in MLCK expression and activity.
科研通智能强力驱动
Strongly Powered by AbleSci AI