Determining the Effect of Chronic Ethanol Ingestion on Pulmonary Macrophages

描述（由申请人提供）：过量饮酒（EtOH）是美国最常见的滥用物质，也是美国第三大可预防的死亡原因。在住院的人中，30%有与酒精有关的问题。已知有酒精滥用史的患者有43%的机会发展为急性呼吸窘迫综合征（ARDS）。ARDS的特点是肺部炎症，导致气体交换受损和促炎细胞因子[2]的释放。酒精中毒患者合并急性呼吸窘迫综合征的结果比非酒精中毒患者差，住院死亡率增加30%。酗酒者呼吸道感染风险增加的部分原因是肺泡巨噬细胞（AMs）[5]的免疫反应受损。先前的研究表明，慢性EtOH治疗会损害AM结合和灭活的金黄色葡萄球菌[6]的内化。此外，体内使用谷胱甘肽（GSH）前体治疗可改善慢性EtOH摄入过程中AM的吞噬。提示AMs功能下降是由于抗氧化能力下降所致；然而，酒精损害AM功能的确切机制尚不清楚。此外，EtOH对间质巨噬细胞（IM）功能的影响尚待研究。因此，我们假设慢性摄取乙胆碱引起的慢性氧化应激损害了单核细胞向肺巨噬细胞的成熟，导致微生物结合和吞噬所需受体的表达减少。在本研究中，我们将使用慢性EtOH摄取模型来研究EtOH在肺巨噬细胞中的作用。目的1：确定慢性EtOH治疗是否会损害肺泡和间质巨噬细胞的成熟。目的2：确定GSH前体治疗是否可以预防和/或挽救etoh诱导的巨噬细胞成熟和功能受损。这些研究将有助于深入了解etoh诱导巨噬细胞功能障碍的机制，并为降低感染风险提供潜在的治疗方法，从而改善酒精中毒患者的肺功能受损和死亡率。

DESCRIPTION (provided by applicant): Excessive consumption of alcohol (EtOH), the most commonly abused substance in the United States, is the third leading preventable cause of death in the USA. Among persons admitted to hospitals, 30% have alcohol-related problems. Patients with a known history of alcohol abuse have 43% chance of developing acute respiratory distress syndrome (ARDS)[1]. ARDS is characterized by lung inflammation that leads to impaired gas exchange and the release of pro-inflammatory cytokines[2]. The outcome of alcoholic patients with ARDS is worse than in non-alcoholics, as seen by a 30% increase in in-hospital mortality rates. The increased risk of respiratory infections in alcoholics is partially due to an impaired immune response of alveolar macrophages (AMs)[5]. Previous studies have shown chronic EtOH treatment impairs AM binding and internalization of inactivated Staphylococcus aureus[6]. Moreover, in vivo treatment with glutathione (GSH) precursors improved AM phagocytosis during chronic EtOH ingestion[6]. Suggesting the decreased function of AMs is due decreased antioxidant availability; however, the precise mechanism by which alcohol impairs AM function is poorly understood. Moreover, the effect of EtOH on interstitial macrophage (IM) function has yet to be examined. Therefore, we hypothesize that chronic oxidant stress induced by chronic EtOH ingestion impairs maturation of monocytes into pulmonary macrophages, leading to decreased expression of receptors required for the binding and phagocytosis of microbes. In this proposal, a chronic EtOH ingestion model will be used to examine the role of EtOH in pulmonary macrophage. Aim 1: Determine if chronic EtOH treatment impairs maturation of alveolar and interstitial macrophages. Aim 2: Determine if treatment with GSH precursors can prevent and/or rescue EtOH-induced impaired macrophage maturation and function. These studies will provide insight into the mechanism of EtOH-induced macrophage malfunction and provide potential treatments to decrease the risk of infection, thereby improve the compromised pulmonary function and mortality in alcoholics.