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）：该提案侧重于慢性酒精（ETOH）摄入对肺泡巨噬细胞功能的影响。 众所周知，慢性酒精摄入会增加肺炎的频率和严重程度。 发表的以及初步证据表明，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敏感性，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，表明慢性摄取摄入核激素受体，过氧化物酶体增殖物激活的受体伽马（PPARG），肺和肺泡巨噬细胞中的表达。此外，用PPARG配体治疗恢复了由慢性EtOH引起的巨噬细胞功能障碍。 该提案将研究以下假设：肺泡巨噬细胞PPARG表达的降低和活性导致巨噬细胞功能的危险。两个具体的目标将解决这一假设。 AIM 1将确定酒精引起的PPARG下调对肺泡巨噬细胞表型和功能的影响。 这些研究将采用一个良好的慢性EtoH摄入模型，其中Sprague-Dawley大鼠喂食含有ETOH的液体饮食2-12周。将检查从对照和ETOH喂养的大鼠中分离出的肺泡巨噬细胞的PPARG表达和活性，并通过研究巨噬细胞分化的标志物以及通过检查巨噬细胞生存能力，吞噬能力，​​呼吸爆发，呼吸爆发和细胞因子产生的研究进行了分析。 AIM 2将检查PPARG配体在慢性摄入后体内从体内从体内肺中的传染性颗粒清除的能力。将在体内施用噻唑烷二酮，罗格列酮，以对照和EtOH喂养的大鼠进行，并将定义恢复巨噬细胞功能中EtOH诱导的危险所需的剂量和治疗持续时间。这些研究将在独特的环境中进行，以检查ETOH对肺部细胞功能的影响。该提案的成功完成有可能进一步阐明增加的发病机理 酒精患者肺炎的频率和严重程度，并有助于鉴定新型 该临床上重要问题的预防或治疗靶标。