Impact of Stress on Alcoholic Gut Injury

压力对酒精性肠道损伤的影响

• 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
• 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

 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）： 与酒精有关的健康问题是全球健康问题。超过50％的退伍军人使用酒精，近23％是暴饮暴食者或繁重的饮酒者。酒精性肝病（ALD）的发病机理涉及肠道障碍功能障碍引起的内毒素血症。大约25％的酗酒者发展了ALD，但使它们容易受到ALD的因素仍有待确定。压力与酒精中毒之间的关系是众所周知的，因此该项目着重于压力对酒精组织损伤的影响。我们的初步研究表明，不同类型的压力 通过涉及细胞内信号传导元件的机制，破坏紧密连接（TJ）并增加肠上皮的渗透性。初步数据还表明，慢性约束应力加剧了酒精引起的肠道渗透性和相关的肝损伤。众所周知，益生菌是促进胃肠道细胞存活和屏障功能的众所周知。我们的初步数据表明，乳杆菌（L. casei）可以缓解压力和乙醇诱导的肠道屏障功能障碍。 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乙醇引起的肠道障碍功能障碍，内毒素血症和肝损伤。使用乳房上皮细胞和基因敲除小鼠的细胞培养模型，我们将确定：1）Ca2+诱导的线粒体氧化应激介绍了应激诱导的ask1/MKK7/MKK7/JNK2/C-SRC信号传导的激活，并介绍了饮食中表上皮的核心表现，2）核心上皮的固定型固定型和固定的固定素质。 exocerbation 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 injury caused by stress and ethanol.这些研究的结果将直接影响压力诱导的肠粘膜稳态改变以及酒精性肝病发病机理的领域。