PPAR gamma and alveolar macrophage function during chronic alcohol ingestion

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DESCRIPTION (provided by applicant): This proposal focuses on the impact of chronic alcohol (ETOH) ingestion on alveolar macrophage function. It is well established that chronic alcohol ingestion increases the frequency and severity of pneumonia. Published as well as preliminary evidence demonstrates that chronic alcohol ingestion increases the susceptibility of the alveolar macrophage to inflammatory mediator-induced apoptosis and impairs macrophage phagocytic ability and cytokine production. The preliminary data in this proposal provide novel evidence that chronic ETOH ingestion reduces the expression of the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARg), in the lung and in the alveolar macrophage. Furthermore, macrophage dysfunction caused by chronic ETOH ingestion was restored by treatment with PPARg ligands. This proposal will examine the hypothesis that alcohol-mediated reductions in alveolar macrophage PPARg expression and activity cause derangements in macrophage function. Two specific aims will address this hypothesis. Aim 1 will determine the impact of alcohol-induced down-regulation of PPARg on alveolar macrophage phenotype and function. These studies will employ a well-characterized model of chronic ETOH ingestion wherein Sprague-Dawley rats are fed liquid diets containing ETOH for 2-12 weeks. Alveolar macrophages isolated from control and ETOH-fed rats will be examined for PPARg expression and activity and subjected to an analysis of markers of macrophage differentiation as well as functional assessment through studies examining macrophage viability, phagocytotic capacity, respiratory burst, and cytokine production. Aim 2 will examine the ability of PPARg ligands to improve the clearance of infectious particles from the lung in vivo following chronic ETOH ingestion. The thiazolidinedione, rosiglitazone, will be administered in vivo to control and ETOH-fed rats, and the dosage and duration of treatment required to restore ETOH-induced derangements in macrophage function will be defined. These studies will be performed within an environment uniquely suited to examine ETOH effects on lung cell function. The successful completion of this proposal has the potential to further clarify the pathogenesis of the increased frequency and severity of pneumonia in the alcoholic patient and to contribute to identification of novel prophylactic or therapeutic targets for this clinically important problem.