Alcohol, glutathione, and alveolar macrophage function

描述（由申请人提供）： 在美国，每年估计有400万例肺炎病例，占60万例住院治疗，每年花费230亿美元。酒精是社区获得性肺炎和医院获得性肺炎的常见危险因素。目前，慢性酒精滥用改变人类肺部免疫力并增加患肺炎可能性的机制基本上是未知的。我们假设，通过谷胱甘肽（GSH）耗竭增加氧化应激导致人肺泡巨噬细胞（AM）的功能和活力异常，随后损害肺泡清除感染性颗粒，导致肺部感染。在本提案中，将通过检查从两个患者队列中获得的AM的功能和活力来探索酒精滥用对肺炎发展的影响：具有慢性酒精滥用既往史的个体和急性肺损伤危重患者。此外，我们将确定口服抗氧化剂替代疗法对有慢性酒精滥用史的个体AM功能的疗效。这项研究的目标是有效的药物治疗，以减少社区获得性肺炎和医院获得性肺炎的风险，在数百万人谁长期滥用酒精。Ellen Burnham博士目前是埃默里大学肺部和重症监护医学研究员。在接下来的五年里，她将与埃默里酒精和重症监护临床研究计划的几名研究人员合作，以发展必要的临床和基础研究技能。在这项提案的支持下，Burnham博士不仅将接受这些已建立的临床和基础研究者的亲自监督，还将参加埃默里大学和罗林斯公共卫生学院的临床研究课程奖（CRCA）计划，并获得临床研究理学硕士学位，以进一步提高她进行高质量研究的能力。该奖项的最终目标是为Burnham博士发展一个独立的“转化”调查研究职业生涯，研究酒精滥用的全身影响，因为它与肺部和重症监护医学有关。

DESCRIPTION (provided by applicant): Each year in the United States, there are an estimated 4 million cases of pneumonia, accounting for 600,000 hospitalizations with an annual cost of $23 billion. Alcohol is a common risk factor for the development of both community-acquired and nosocomial pneumonia. Presently, the mechanisms by which chronic alcohol abuse alters human pulmonary immunity and increases the likelihood of developing pneumonia are essentially unknown. We hypothesize that increased oxidative stress via glutathione (GSH) depletion leads to abnormal function and viability of human alveolar macrophages (AM), and subsequently impairs alveolar clearance of infectious particles leading to pulmonary infections. In this proposal, the impact of alcohol abuse on the development of pneumonia will be explored by examining the function and viability of AM obtained from two patient cohorts: individuals with a prior history of chronic alcohol abuse and critically ill patients with acute lung injury. Additionally, we will determine the efficacy of oral antioxidant replacement therapy on AM function in individuals with a prior history of chronic alcohol abuse. The goal of this research endeavor is effective medical therapy to decrease the risk of community-acquired and nosocomial pneumonia in the millions of individuals who chronically abuse alcohol. Dr. Ellen Burnham is presently a fellow in Pulmonary and Critical Care Medicine at Emory University. During the next five years, she will work with several investigators in the Emory Alcohol and Critical Care Clinical Research Program in order to develop necessary clinical and basic research skills. With the support of this proposal, Dr. Burnham will not only receive personal supervision from these established clinical and basic investigators, but will also enroll in the Clinical Research Curriculum Award (CRCA) program at Emory University and the Rollins School of Public Health, and obtain a Masters of Science in Clinical Research to further enhance her ability to perform high-quality research. The ultimate goal of this award is to develop an independent research career in "translational" investigation for Dr. Burnham, examining the systemic effects of alcohol abuse as it relates to pulmonary and critical care medicine.