Alcohol-Induced Mitochondrial Derangements Cause Alveolar Macrophage Dysfunction

项目总结/摘要： 酒精使用障碍（AUD）患者发生呼吸道疾病的可能性是其他患者的2-4倍。 感染和急性呼吸窘迫综合征，与非酒精受试者相比。在肺中，肺泡 巨噬细胞（AM）是肺泡空间中的第一道细胞防御线，并且它们的功能是吞噬 清除入侵的病原体然而，慢性酒精摄入增加线粒体（MT）源性 氧化应激和MT功能障碍，损害AM吞噬作用并增加感染风险。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（目的1）。然后PI将阐明分子 参与酒精诱导的MT紊乱的机制，包括断裂和功能障碍（目的2）。 最后，由于转录因子B1，线粒体（TFB 1 M）是MT DNA和MT基因的关键介质 PI将确定酒精对AM TFB 1 M表达和活性的影响，如由 microRNA（Aim 3）。这些假设将通过使用慢性酒精的小鼠模型进行研究 消耗，体外乙醇暴露的小鼠AM细胞系，MH-S，和从人类受试者分离的AM 关于AUD本建议中概述的研究目标是阐明分子机制 负责酒精性AM中吞噬功能障碍并鉴定新的和治疗靶向的 负责EtOH诱导的MT功能障碍的分子。 如果成功，拟议的研究将为未来的转化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，这些患者有显著的肺部疾病风险， 疾病，即使在持续饮酒期间，或可能患有类似MT特征的疾病的患者 功能障碍

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.