Aldehydes in Alcohol-Induced Organ Injury

酒精引起的器官损伤中的醛

• 批准号: 9883688
• 负责人: ZHANXIANG ZHOU
• 金额: $ 42.23万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883688
• 关键词: Acetaldehyde; Address; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcohols; Aldehydes; Bacteria; Bacterial Infections; Bacterial Translocation; Binding; Blood Circulation; Cells; Chronic; Cysteine; Data; Defensins; Dendritic Cells; Development; Dietary Zinc; Dose; Endotoxemia; Enteral; Equilibrium; Event; Functional disorder; Gatekeeping; Gene Expression; Genes; Genetic Transcription; Goals; Grant; Growth; Hepatic; Hepatitis; Immune; Immune System Diseases; Impairment; Inflammation; Innate Immune System; Interferons; Intestinal Mucosa; Intestinal permeability; Intestines; Liver; Lymphocyte; Measures; Mediating; Molecular Target; Muramidase; Mutation; Organ; Paneth Cells; Pathogenesis; Pathogenicity; Pathway interactions; Plasma; Play; Production; Proteomics; Recombinants; Regulation; Research; Role; STAT1 gene; Signal Pathway; Signal Transduction; Site; Structure; Th1 Cells; Therapeutic Intervention; Tight Junctions; Tissues; Transcriptional Regulation; Zinc; Zinc deficiency; alcohol effect; alcohol exposure; antimicrobial; antimicrobial peptide; bactericide; commensal bacteria; disulfide bond; dysbiosis; enteric dysbiosis; gut microbiota; gut-liver axis; high risk; host microbiota; ileum; immune function; innate immune function; intestinal crypt; liver development; macromolecule; organ injury; pathogenic bacteria; transcription factor

PROJECT SUMMARY Long-term heavy alcohol drinking causes organ injury, and multiple lines of evidence support a critical role of the intestine in alcohol-induced pathogenesis. Alcohol disassembles intestinal tight junctions and increases gut permeability to macromolecules. Alcohol also causes dysbiosis, an increase in pathogenic bacteria and a decrease in commensal bacteria. Consequently, alcohol increases translocation of the pathogenic bacteria and/or bacteria products and induces inflammation in multiple organs, particularly in the liver. Therefore, intestine is a major site to generate systemic factors mediating alcohol-induced organ injury. Recent studies demonstrated that reduced expression of intestinal antimicrobial peptides (AMPs) accounts for the alcohol- induced pathogenic bacteria translocation and the development of hepatitis. However, the mechanisms of how alcohol abuse induces host-microbiota dyshomeostasis remain largely unknown. The intestinal innate immune system plays a crucial role in maintaining the symbiotic balance between the host and gut microbiota by restricting the growth of pathogenic bacteria. In the past granting period, we have shown that alcohol exposure causes accumulation of acetaldehyde (AcH) not only in the liver and plasma but also in the intestinal tissues and lumen contents. The intestinal AcH levels correlated with alcohol-induced gut permeability increase and enteric dysbiosis as well as endotoxemia and hepatic inflammation. Most importantly, we demonstrated that a- defensins and lysozyme produced from the intestinal Paneth cells were reduced by alcohol exposure in association with the development of enteric and hepatic dysbiosis and hepatitis. Our findings suggest that AcH- induced Paneth cell dysfunction may represent an important mechanism underlying alcohol-induced disorders at the gut-liver axis. Paneth cells at the bottom of the intestinal crypts are professional AMP-producing innate immune cells, and the role of Paneth cell dysfunction in alcohol-induced pathogenesis at the gut-liver axis has not been defined. This project aims to determine if Paneth cell dysfunction is a crucial factor in alcohol-induced intestinal overgrowth of pathogenic bacteria, gut permeability increase, bacteria/bacteria products translocation and hepatic inflammation.

项目摘要 长期大量饮酒会导致器官损伤，多种证据支持 酒精引起的发病机理中的肠道。酒精拆卸肠紧密连接并增加肠道 对大分子的渗透性。酒精还会引起营养不良，致病细菌的增加和A 共生细菌减少。因此，酒精会增加致病细菌的易位 和/或细菌产物并诱导多个器官，特别是在肝脏中的炎症。所以， 肠道是产生介导酒精诱导器官损伤的系统因素的主要部位。最近的研究 证明肠道抗菌肽（AMP）的表达降低了酒精 - 诱导致病细菌易位和肝炎的发育。但是，如何 酗酒会诱导宿主 - 微生物群体dyshomeostasis，这在很大程度上还不清楚。肠道先天免疫 系统在维持宿主和肠道微生物群之间的共生平衡方面起着至关重要的作用 限制致病细菌的生长。在过去的授予期间，我们已经表明酒精暴露 导致乙醛（ACH）的积累，不仅在肝脏和血浆中，而且在肠道组织中也 和管腔内容。肠道ACH水平与酒精诱导的肠道渗透性的增加相关，并且 肠营养不良以及内毒素血症和肝发炎。最重要的是，我们证明了A- 通过酒精暴露在肠道细胞中产生的防御素和溶菌酶，通过酒精暴露在 与肠和肝营养不良和肝炎的发展相关。我们的发现表明ACH- 诱导的Paneth细胞功能障碍可能代表了酒精诱导的疾病的重要机制 在肠道轴上。肠道隐窝底部的Paneth细胞是专业的放大器的先天性 免疫细胞，以及泛细胞功能障碍在酒精诱导的发病机理中的作用 未定义。该项目旨在确定Paneth细胞功能障碍是否是酒精引起的关键因素 致病细菌的肠道过度生长，肠道渗透率增加，细菌/细菌产物易位 和肝发炎。