Determining the Effect of Chronic Ethanol Ingestion on Pulmonary Macrophages

描述（由申请人提供）：过量饮酒（EtOH）是美国最常滥用的物质，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。已知有酗酒史的患者有43%的机会发生急性呼吸窘迫综合征（ARDS）[1]。ARDS的特征是肺部炎症，导致气体交换受损和促炎细胞因子的释放[2]。酒精中毒患者并发ARDS的预后比非酒精中毒者差，住院死亡率增加30%。酗酒者呼吸道感染的风险增加部分是由于肺泡巨噬细胞（AM）的免疫反应受损[5]。先前的研究表明，慢性EtOH处理会损害灭活金黄色葡萄球菌的AM结合和内化[6]。此外，在慢性EtOH摄入过程中，用谷胱甘肽（GSH）前体进行的体内治疗改善了AM的吞噬作用[6]。这表明AM功能的降低是由于抗氧化剂的可用性降低;然而，酒精损害AM功能的确切机制尚不清楚。此外，EtOH对间质性巨噬细胞（IM）功能的影响还有待研究。因此，我们假设慢性乙醇摄入诱导的慢性氧化应激损害单核细胞成熟为肺巨噬细胞，导致微生物结合和吞噬所需的受体表达减少。在这个提议中，慢性EtOH摄入模型将用于检查EtOH在肺巨噬细胞中的作用。目的1：确定慢性EtOH处理是否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。这些研究将深入了解EtOH诱导的巨噬细胞功能障碍的机制，并提供潜在的治疗方法来降低感染的风险，从而改善酗酒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.