Alcohol-Induced Mitochondrial Derangements Cause Alveolar Macrophage Dysfunction

酒精引起的线粒体紊乱导致肺泡巨噬细胞功能障碍

• 批准号: 10155381
• 负责人: Samantha M. Yeligar
• 金额: $ 35.99万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155381
• 关键词: Adult Respiratory Distress Syndrome; Affect; Alcohol consumption; Alcohols; Alveolar; Alveolar Macrophages; Automobile Driving; Binding Sites; Bioenergetics; CCAAT-Enhancer-Binding Protein-alpha; Cell Line; Complex; Data; Disease; Down-Regulation; Electron Transport; Equilibrium; Ethanol; Foundations; Functional disorder; Future; Gene Expression; Genetic Transcription; Immune response; Impairment; In Vitro; Infection; Intervention; Invaded; Klebsiella pneumoniae; Lung; Lung Capacity; Lung diseases; Lung infections; Mediating; Mediator of activation protein; Membrane Potentials; Metabolic; Metabolic dysfunction; Metabolism; Methods; MicroRNAs; Microbe; Mitochondria; Mitochondrial DNA; Molecular; Morbidity - disease rate; Mus; Oranges; Oxidation-Reduction; Oxidative Stress; Pathogenicity; Patients; Phagocyte Bactericidal Dysfunction; Phagocytes; Phagocytosis; Predisposition; Production; Reactive Oxygen Species; Recording of previous events; Regulation; Respiratory Tract Infections; Risk; Role; SOD2 gene; Small Interfering RNA; Staphylococcus aureus; Time; Transcription Factor AP-1; Transcriptional Regulation; Up-Regulation; alcohol effect; alcohol exposure; alcohol use disorder; catalase; chronic alcohol ingestion; human subject; immune function; improved; in silico; in vivo; infection risk; inhibitor/antagonist; innovation; macrophage; mitochondrial dysfunction; mitochondrial membrane; mortality; mouse model; new therapeutic target; non-alcoholic; overexpression; pathogen; preclinical study; premature; problem drinker; promoter; targeted treatment; transcription factor; translational study; uptake

PROJECT SUMMARY/ABSTRACT: Patients with alcohol use disorders (AUD) are 2-4 times more susceptible to developing respiratory infections and acute respiratory distress syndrome, compared to non-alcoholic subjects. In the lung, alveolar macrophages (AM) are the first line of cellular defense in the alveolar space, and they function to phagocytize and clear invading pathogens. However, chronic alcohol ingestion increases mitochondria (MT)-derived oxidative stress and MT dysfunction, which impairs AM phagocytosis and increases risk for infections. In the proposed studies, the PI will examine the effects of alcohol-induced MT-derived oxidative stress on AM phagocytic dysfunction and susceptibility to infections (Aim 1). The PI will then elucidate the molecular mechanisms involved in alcohol-induced MT derangements, including fragmentation and dysfunction (Aim 2). Finally, since transcription factor B1, mitochondrial (TFB1M) is a critical mediator of MT DNA and MT gene transcription, the PI will determine the effect of alcohol on AM TFB1M expression and activity as modulated by microRNAs (Aim 3). These hypotheses will be investigated by using a mouse model of chronic alcohol consumption, an in vitro ethanol exposed mouse AM cell line, MH-S, and AM isolated from human subjects with AUD. The objectives of the studies outlined in this proposal are to elucidate the molecular mechanisms responsible for phagocytic dysfunction in alcoholic AM and identify novel and therapeutically targetable molecules responsible for EtOH-induced MT dysfunction. If successful, the proposed studies will identify novel therapeutic targets for future translational studies that could impact the management of patients with a history of AUD who are at risk for significant lung disorders, even during continued alcohol use, or potentially patients with disorders characterized by similar MT dysfunction.

项目摘要/摘要： 酒精使用障碍(AUD)患者患呼吸道疾病的易感性是后者的2-4倍 感染和急性呼吸窘迫综合征，与非酒精受试者相比。在肺、肺泡 巨噬细胞(AM)是肺泡腔的第一道细胞防线，其功能是吞噬细胞 清除入侵的病原体。然而，长期饮酒会增加线粒体(MT)来源 氧化应激和MT功能障碍，损害AM吞噬功能，增加感染风险。在 建议的研究，PI将检查酒精诱导的MT衍生的氧化应激对AM的影响 吞噬功能障碍和感染易感性(目标1)。然后，PI将澄清分子 涉及酒精诱导的MT紊乱的机制，包括碎裂和功能障碍(目标2)。 最后，由于转录因子B1，线粒体(TFB1M)是MT DNA和MT基因的关键介体 转录，PI将决定酒精对AM TFB1M表达和活性的影响 MicroRNAs(目标3)。这些假说将通过慢性酒精中毒的小鼠模型进行研究。 乙醇暴露的体外小鼠AM细胞株MH-S和人AM的体外研究 用澳元。本提案中概述的研究的目标是阐明分子机制。 负责酒精性AM的吞噬功能障碍，并确定新的治疗靶点 乙醇诱导的MT功能障碍的相关分子。 如果成功，拟议的研究将为未来的转译研究确定新的治疗靶点 这可能会影响有AUD病史的患者的管理，这些患者有明显肺部病变的风险 精神障碍，即使在持续饮酒期间，或者潜在的以类似MT为特征的疾病患者 功能障碍。