Impact of Stress on Alcoholic Gut Injury

压力对酒精性肠道损伤的影响

基本信息

批准号：
9143185
负责人：
RADHAKRISHNA RAO
金额：
--
依托单位：
MEMPHIS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-10-01 至 2020-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9143185
关键词：
Acetaldehyde Affect Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcoholic beverage heavy drinker Alcoholic liver damage Alcoholism Alcohols Alpha Cell Attenuated C-Peptide Caco-2 Cells Calcium Cell Culture Techniques Cell Survival Cells Chemicals Chronic Chronic stress Cirrhosis Data Development Down-Regulation Elements Endotoxemia Endotoxins Epithelial Ethanol Fatty Liver Functional disorder Genes Genetic Glucocorticoids Health Hepatitis Homeostasis Injury Intestines Knockout Mice Lactobacillus casei Lipopolysaccharides Liver Liver diseases MAPK8 gene MAPK9 gene Mechanics Mediating Mitochondria Modeling Molecular Mus Outcome Outcome Study Oxidative Stress Pathogenesis Peptides Permeability Pharmacology Phosphotransferases Play Population Post-Traumatic Stress Disorders Prevalence Probiotics Psychological Stress Publications Risk Factors Role SRC gene Signal Pathway Signal Transduction Stress Testing Tight Junctions Tissues Veterans World Health Organization absorption binge drinker burden of illness feeding gastrointestinal in vivo intestinal epithelium intestinal homeostasis liver injury macromolecule monolayer mouse model novel novel therapeutics prevent problem drinker public health relevance release factor restraint stress

项目摘要

DESCRIPTION (provided by applicant): Alcohol-related health problems are the worldwide health concern. More than 50% of Veterans use alcohol and nearly 23% are binge or heavy drinkers. Pathogenesis of alcoholic liver disease (ALD) involves endotoxemia caused by gut barrier dysfunction. About 25% of alcoholics develop ALD, but the factors that make them susceptible to ALD remain to be determined. The relationship between stress and alcoholism is well known, so this project focuses on the effects of stress on alcoholic tissue injury. Our preliminary studies showed that different types of stress disrupt tight junctions (TJs) and increase permeability in the intestinal epithelium by a mechanism that involves intracellular signaling elements. Preliminary data also indicated that chronic restraint stress exacerbates alcohol-induced gut permeability and associated liver injury. Probiotics are well known to promote gastrointestinal cell survival and barrier function. Our preliminary data indicated that Lactobacillus casei (L. casei) ameliorates stress and ethanol-induced gut barrier dysfunction. On the basis of these results it is hypothesized that: a) stress-induced cell signaling promotes alcohol-induced TJ disruption and barrier dysfunction in the intestinal epithelium, b) chronic stress exacerbates ethanol-induced gut barrier dysfunction, endotoxemia and liver injury by a CaV1.3 channel and JNK2-dependent mechanism, and c) L. casei ameliorates stress and ethanol-induced gut barrier dysfunction, endotoxemia and liver injury. Using a cell culture model of the intestinal epithelium and gene knock out mice we will determine that: 1) Ca2+-induced mitochondrial oxidative stress mediates stress-induced activation of Ask1/MKK7/JNK2/c-Src signaling and TJ disruption in the intestinal epithelium, 2) Glucocorticoids mediate stress-induced cell signaling in the intestinal epithelium and exacerbation of alcoholic gut permeability, 3) Stress-activated signaling promotes acetaldehyde-induced TJ disruption, 4) CaV1.3 channel and [Ca2+]i mediate the synergistic effects of chronic stress and ethanol on gut and liver, 5) Down regulation of JNK2 blocks stress and alcohol-induced gut barrier dysfunction and liver injury, 6) L. casei prevents stress-induced cell signalin and attenuates acetaldehyde-induced TJ disruption in Caco-2 cells and mouse intestine ex vivo, 7) L. casei attenuates stress and ethanol- induced gut permeability and liver injury in vivo, and 8) Peptide-like factor released by L. casei blocks gut barrier dysfunction and prevents liver injur caused by stress and ethanol. The outcome of these studies will have direct impact on the fields of stress-induced alteration of intestinal mucosal homeostasis as well as pathogenesis of alcoholic liver disease. .

描述（由申请人提供）：与酒精相关的健康问题是世界范围内的健康问题，超过 50% 的退伍军人饮酒，近 23% 的人酗酒或酗酒，酒精性肝病 (ALD) 的发病机制涉及肠道屏障功能障碍引起的内毒素血症。压力与酒精中毒之间的关系是众所周知的，因此我们的初步研究表明压力对酒精性组织损伤的影响。压力类型初步数据还表明，长期束缚应激会恶化酒精引起的肠道通透性和相关的肝损伤，众所周知，益生菌可以促进胃肠道细胞的存活。根据这些结果，我们的初步数据表明，干酪乳杆菌（L. casei）可改善应激和乙醇引起的肠道屏障功能障碍。研究发现：a) 应激诱导的细胞信号传导促进酒精诱导的 TJ 破坏和肠上皮屏障功能障碍，b) 慢性应激通过 CaV1.3 通道和 JNK2 依赖性加剧乙醇诱导的肠道屏障功能障碍、内毒素血症和肝损伤c) 干酪乳杆菌改善应激和乙醇引起的肠道屏障功能障碍、内毒素血症和肝损伤，我们将使用肠上皮和基因敲除小鼠的细胞培养模型来确定。认为：1) Ca2+ 诱导的线粒体氧化应激介导应激诱导的 Ask1/MKK7/JNK2/c-Src 信号激活和肠上皮中的 TJ 破坏，2) 糖皮质激素介导应激诱导的肠上皮细胞信号传导和恶化酒精性肠道通透性，3) 应激激活的信号传导促进乙醛诱导的 TJ 破坏，4) CaV1.3 通道和 [Ca2+]i 介导慢性应激和乙醇对肠道和肝脏的协同作用，5) JNK2 的下调可阻断应激和酒精引起的肠道屏障功能障碍和肝损伤，6) 干酪乳杆菌可预防应激-细胞诱导的信号传导并减弱 Caco-2 细胞和离体小鼠肠道中乙醛诱导的 TJ 破坏，7) 干酪乳杆菌减弱应激和乙醇诱导的肠道8) 干酪乳杆菌释放的肽样因子可阻断肠道屏障功能障碍并预防应激和乙醇引起的肝损伤。这些研究的结果将对应激引起的改变领域产生直接影响。肠粘膜稳态以及酒精性肝病的发病机制。