Aldehydes in Alcohol-Induced Organ Injury

酒精引起的器官损伤中的醛

• 批准号: 10117159
• 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/10117159
• 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; systemic inflammatory response; 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.

项目概要 长期大量饮酒会导致器官损伤，多种证据支持 肠道在酒精诱发的发病机制中。酒精会破坏肠道紧密连接并增加肠道 对大分子的渗透性。酒精还会导致生态失调、致病菌增加和 共生细菌减少。因此，酒精会增加病原菌的易位 和/或细菌产物并诱发多个器官炎症，特别是肝脏。所以， 肠道是产生介导酒精性器官损伤的全身因子的主要场所。最近的研究 证明肠道抗菌肽（AMP）表达减少是酒精中毒的原因 诱导致病菌移位和肝炎的发展。然而，其机制如何 酒精滥用会导致宿主微生物群失调，目前仍不清楚。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发挥着至关重要的作用 限制病原菌的生长。在过去的授权期内，我们已经证明酒精暴露 不仅会导致乙醛（AcH）在肝脏和血浆中积聚，还会在肠道组织中积聚 和管腔内容物。肠道 AcH 水平与酒精引起的肠道通透性增加相关 肠道菌群失调以及内毒素血症和肝脏炎症。最重要的是，我们证明了—— 肠道潘氏细胞产生的防御素和溶菌酶因酒精暴露而减少 与肠道和肝脏生态失调以及肝炎的发生有关。我们的研究结果表明 AcH- 诱导的潘氏细胞功能障碍可能是酒精诱发疾病的重要机制 在肠肝轴上。肠隐窝底部的潘氏细胞是天生专业产生 AMP 的细胞 免疫细胞，以及潘氏细胞功能障碍在酒精诱导的肠肝轴发病机制中的作用 没有被定义。该项目旨在确定潘氏细胞功能障碍是否是酒精诱发的关键因素 肠道病原菌过度生长、肠道通透性增加、细菌/细菌产物易位 和肝脏炎症。