Determining the Effect of Chronic Ethanol Ingestion on Pulmonary Macrophages

Emory University, Atlanta GA

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Abstract

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.