PPAR gamma/alveolar macrophage function and alcohol

PPAR γ/肺泡巨噬细胞功能和酒精

• 批准号: 7073524
• 负责人: C MICHAEL HART
• 金额: $ 20.72万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7073524
• 关键词: SDS polyacrylamide gel electrophoresis; alcoholic beverage consumption; alcoholism /alcohol abuse; alveolar macrophages; cell differentiation; comorbidity; confocal scanning microscopy; cytotoxicity; disease /disorder proneness /risk; drug screening /evaluation; ethanol; laboratory rat; oxidative stress; peroxisome proliferator activated receptor; phagocytosis; phenotype; pneumonia; polymerase chain reaction; receptor expression; respiratory function; respiratory pharmacology; rosiglitazone; troglitazone

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.

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。 已发表的证据和初步证据表明，长期饮酒会增加肺泡巨噬细胞对炎症介质诱导的细胞凋亡的敏感性，并损害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，证明长期摄入 ETOH 会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，长期摄入 ETOH 引起的巨噬细胞功能障碍可以通过 PPARg 配体治疗得到恢复。 该提案将检验酒精介导的肺泡巨噬细胞 PPARg 表达和活性减少导致巨噬细胞功能紊乱的假设。有两个具体目标将解决这一假设。目标 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。 这些研究将采用一种特征明确的慢性 ETOH 摄入模型，其中 Sprague-Dawley 大鼠被喂食含有 ETOH 的液体饮食 2-12 周。将检查从对照和 ETOH 喂养的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来分析巨噬细胞分化标记物以及功能评估。目标 2 将检查 PPARg 配体在慢性摄入 ETOH 后改善体内肺部感染性颗粒清除的能力。将噻唑烷二酮罗格列酮体内给予对照大鼠和喂食 ETOH 的大鼠，并确定恢复 ETOH 诱导的巨噬细胞功能紊乱所需的治疗剂量和持续时间。这些研究将在特别适合检查 ETOH 对肺细胞功能影响的环境中进行。该提案的成功完成有可能进一步阐明增加的发病机制 酒精患者肺炎的频率和严重程度，并有助于识别新的肺炎 这一临床重要问题的预防或治疗目标。