PPAR gamma and alveolar macrophage function during chronic alcohol ingestion

描述（由申请人提供）：该提案重点关注慢性酒精（ETOH）摄入对肺泡巨噬细胞功能的影响。 众所周知，长期饮酒会增加肺炎的发生频率和严重程度。 已发表的和初步的证据表明，慢性酒精摄入增加了肺泡巨噬细胞对炎症介质诱导的细胞凋亡的易感性，并损害了巨噬细胞的吞噬能力和细胞因子的产生。该提案中的初步数据提供了新的证据，表明长期摄入ETOH可降低肺和肺泡巨噬细胞中核激素受体、过氧化物酶体增殖物激活受体γ（PPARg）的表达。此外，通过用PPARg配体治疗，由慢性ETOH摄入引起的巨噬细胞功能障碍得以恢复。 这项建议将检验酒精介导的肺泡巨噬细胞PPARg表达和活性降低导致巨噬细胞功能紊乱的假设。两个具体目标将解决这一假设。目的1将确定酒精诱导的PPARg下调对肺泡巨噬细胞表型和功能的影响。 这些研究将采用长期ETOH摄入的良好表征模型，其中Sprague-Dawley大鼠喂食含ETOH的流质饮食2-12周。将检查从对照和ETOH喂养大鼠中分离的肺泡巨噬细胞的PPARg表达和活性，并通过检查巨噬细胞活力、吞噬能力、呼吸爆发和细胞因子产生的研究进行巨噬细胞分化标志物分析和功能评估。目的2将检查PPARg配体在体内改善慢性ETOH摄入后从肺中清除感染性颗粒的能力。将对对照组和ETOH喂养大鼠体内给予噻唑烷二酮（罗格列酮），并确定恢复ETOH诱导的巨噬细胞功能紊乱所需的给药剂量和持续时间。这些研究将在专门适合检查ETOH对肺细胞功能影响的环境中进行。这一提案的成功完成有可能进一步阐明增加的 酒精中毒患者肺炎的频率和严重程度，并有助于识别新的 预防或治疗这一临床重要问题的目标。

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.