Determining the Effect of Chronic Ethanol Ingestion on Pulmonary Macrophages

确定慢性乙醇摄入对肺巨噬细胞的影响

• 批准号: 7541572
• 负责人: Sheena Denise Brown
• 金额: $ 2.9万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541572
• 关键词: Acute; Adult Respiratory Distress Syndrome; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Alveolar; Alveolar Macrophages; American; Antioxidants; Binding; Breathing; Cause of Death; Chronic; Communities; Consumption; Diagnostic; Ethanol; Gases; Glutathione; Glycine; Heavy Drinking; Hospital Mortality; Hospitals; Immune response; Impairment; Infection; Inflammatory; Ingestion; Invaded; Lung Inflammation; Mediator of activation protein; Methionine; Microbe; Modeling; Newborn Respiratory Distress Syndrome; Outcome; Oxidants; Patients; Persons; Phagocytosis; Play; Rate; Rattus; Recording of previous events; Respiratory Tract Infections; Risk; Role; Staphylococcus aureus; Stress; Surface; Systemic infection; United States; acquired immunity; alcohol abuse therapy; alcohol related problem; chronic alcohol ingestion; cytokine; improved; in vivo; insight; interstitial; macrophage; monocyte; mortality; non-alcoholic; pathogen; peripheral blood; prevent; problem drinker; pulmonary function; receptor expression

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.

描述（由申请人提供）：美国最常见的滥用物质的酒精（ETOH）是美国的第三个主要可预防原因。在接受医院的人中，有30％的人有与酒精有关的问题。酗酒史的患者患有43％的急性呼吸窘迫综合征（ARDS）的机会[1]。 ARDS的特征是肺部炎症，导致气体交换受损和促炎性细胞因子的释放[2]。酗酒患者的ARDS的结果比非酒精饮料的情况差，院内死亡率增加了30％。酒精中毒中呼吸道感染的风险增加部分是由于肺泡巨噬细胞的免疫反应受损（AMS）[5]。先前的研究表明，慢性ETOH治疗会损害灭活金黄色葡萄球菌的AM结合和内在化[6]。此外，用谷胱甘肽（GSH）前体进行体内治疗改善了慢性EtOH摄入期间的AM吞噬作用[6]。表明AM的功能降低是由于抗氧化剂可用性降低。但是，酒精损害AM功能的确切机制知之甚少。此外，EtOH对间质巨噬细胞（IM）功能的影响尚未研究。因此，我们假设由慢性摄取摄入引起的慢性氧化应激会损害单核细胞成熟到肺巨噬细胞中，从而导致菌群结合和吞噬作用所需的受体表达降低。在此提案中，将使用慢性EtoH摄入模型来检查EtOH在肺巨噬细胞中的作用。目标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。 AIM 2：确定用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。这些研究将洞悉ETOH诱导的巨噬细胞故障的机制，并提供潜在的治疗方法以降低感染的风险，从而改善酗酒者的肺功能和死亡率受损。