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，是美国第三大可预防的死亡原因。在住院的人中，30%的人有与酒精有关的问题。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)[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]。酒精性ARDS患者的预后比非酒精性ARDS患者更差，住院死亡率增加了30%。酗酒者呼吸道感染风险的增加部分是由于肺泡巨噬细胞(AM)免疫反应受损[5]。以前的研究表明，慢性乙醇治疗损害了AM结合和灭活金黄色葡萄球菌的内化[6]。此外，在体内使用谷胱甘肽(GSH)前体可以改善慢性乙醇摄入过程中AM的吞噬功能[6]。提示AM的功能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，乙醇对间质巨噬细胞(IM)功能的影响还有待研究。因此，我们推测，长期摄入乙醇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的受体表达减少。在这项提案中，将使用慢性乙醇摄入模型来研究乙醇在肺巨噬细胞中的作用。目的1：确定慢性乙醇治疗是否损害肺泡和间质巨噬细胞的成熟。目的2：确定GSH前体治疗是否能预防和/或挽救乙醇诱导的巨噬细胞成熟和功能受损。这些研究将深入了解乙醇诱导的巨噬细胞功能障碍的机制，并提供潜在的治疗方法，以降低感染的风险，从而改善酒精中毒患者的肺功能损害和死亡率。

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.