Neutrophil-Microvascular Endothelial Cell Interactions in a Chronic Ethanol Model

慢性乙醇模型中中性粒细胞-微血管内皮细胞的相互作用

基本信息

批准号：
7276203
负责人：
Sonja M Tang
金额：
$ 3.98万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-13 至 2008-04-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7276203
关键词：
Acetylcysteine Acute Acute Lung Injury Adherence Adhesions Adult Respiratory Distress Syndrome Alcohol abuse Alcohol consumption Alcohol dependence Alcoholic Beverages Alcohols Alveolar Animal Feed Animals Antioxidants Apoptosis Apoptotic Attenuated Bacteria Bacterial Pneumonia Biology Cell Adhesion Molecules Cell Communication Cessation of life Chronic Clinical Clinical Treatment Communities Consumption Data Diet Dietary Supplementation Disruption Economics Endothelial Cells Endothelium Epidemiologic Studies Epithelial Ethanol Glutathione Goals Half-Life Health Healthcare Systems Hospitals Hypoxemia Individual Infection Inflammation Injury Klebsiella pneumonia bacterium Lead Life Lung Mediating Medical Modeling Necrosis Neutrophil Infiltration Newborn Respiratory Distress Syndrome Outcome Oxidants Oxidative Stress Pathology Patients Phagocytosis Pneumonia Predisposition Production Proteins Pulmonary Edema Rattus Recording of previous events Recruitment Activity Research Respiratory Burst Respiratory Failure Respiratory physiology Risk Risk Factors Role Sepsis Stress Supplementation Testing Therapeutic Time Up-Regulation alcohol effect chronic alcohol ingestion clinically significant cost day drinking drug of abuse feeding insight interstitial killings lung injury macrophage migration mortality neutrophil particle problem drinker protein expression research study response time use

项目摘要

DESCRIPTION (provided by applicant): In recent years our group has shown increasing evidence that chronic alcohol abuse has detrimental effects on lung function; in particular, exacerbation of acute respiratory distress syndrome (ARDS) and increased oxidative stress. In addition, alcohol abusers have an increased mortality when admitted to the hospital with community acquired pneumonia. We question what the underlying pathology of impaired bacterial clearance is that can ultimately lead to death in chronic alcoholics. During bacterial pneumonia, neutrophils are recruited to the alveolar space to phagocytize the infectious particles. Upon phagocytosis, neutrophils undergo apoptosis in order to kill the bacteria. In healthy individuals, macrophage phagocytize the apoptotic neutrophils. In previous studies, we have observed a reduction in macrophage phagocytosis in chronic ethanol-fed animals. We believe this resulting increase in apoptotic neutrophils in the alveolar compartment could be a contributing factor to ARDS and the increased mortality in chronic alcoholics with bacterial pneumonia. In this proposal we will attempt to elucidate the mechanisms of pulmonary neutrophil recruitment and transendothelial migration by examining rolling, adhesion, and migration of neutrophils in real-time using a well-established chronic ethanol model. In addition, we will investigate the effects of Klebsiella pneumoniae infection on neutrophil-endothelial cell interactions. Finally, we will test antioxidant rescue therapies via dietary supplementation with glutathione, N-acetylcysteine, and S-adenosylmethionine. These groups of experiments will provide insight into neutrophil-microvascular endothelial cell interactions and possible therapeutic treatments for chronic alcoholics with community acquired pneumonia.

描述（由申请人提供）：近年来，我们小组越来越多的证据表明，长期酗酒对肺功能有不利影响；特别是急性呼吸窘迫综合征（ARDS）的恶化和氧化应激的增加。此外，酗酒者因社区获得性肺炎入院时的死亡率也会增加。我们质疑细菌清除受损的根本病理是什么，最终会导致慢性酗酒者死亡。在细菌性肺炎期间，中性粒细胞被募集到肺泡腔以吞噬感染性颗粒。吞噬作用后，中性粒细胞发生细胞凋亡以杀死细菌。在健康个体中，巨噬细胞吞噬凋亡的中性粒细胞。在之前的研究中，我们观察到长期乙醇喂养的动物巨噬细胞吞噬作用减少。我们认为，肺泡室中凋亡性中性粒细胞的增加可能是导致 ARDS 和慢性酗酒者合并细菌性肺炎死亡率增加的一个因素。在本提案中，我们将尝试通过使用完善的慢性乙醇模型实时检查中性粒细胞的滚动、粘附和迁移来阐明肺中性粒细胞募集和跨内皮迁移的机制。此外，我们将研究肺炎克雷伯菌感染对中性粒细胞-内皮细胞相互作用的影响。最后，我们将通过膳食补充谷胱甘肽、N-乙酰半胱氨酸和 S-腺苷甲硫氨酸来测试抗氧化救援疗法。这些实验组将深入了解中性粒细胞-微血管内皮细胞的相互作用以及慢性酗酒者社区获得性肺炎的可能治疗方法。