Alcohol, glutathione, and alveolar macrophage function

描述(由申请人提供)： 在美国，每年估计有400万肺炎病例，占60万次住院治疗，每年的成本为230亿美元。酒精是社区获得性肺炎和医院获得性肺炎发展的共同危险因素。目前，慢性酒精滥用改变人类肺部免疫并增加患肺炎的可能性的机制基本上是未知的。我们假设，谷胱甘肽(GSH)耗竭导致氧化应激增加，导致人肺泡巨噬细胞(AM)功能和活性异常，进而损害肺泡对感染颗粒的清除，从而导致肺部感染。在这项建议中，将通过检测从两个患者队列获得的AM的功能和生存能力来探讨酒精滥用对肺炎发展的影响。这两个患者队列是：有慢性酒精滥用史的个人和有急性肺损伤的危重患者。此外，我们将确定口服抗氧化剂替代疗法对既往有慢性酒精滥用史的人AM功能的疗效。这项研究的目标是进行有效的医疗治疗，以降低数百万长期酗酒者的社区获得性和医院获得性肺炎的风险。埃伦·伯纳姆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护理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。在这项提议的支持下，Burnham博士不仅将接受这些知名临床和基础研究人员的亲自监督，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)项目，并获得临床研究理学硕士学位，以进一步增强她进行高质量研究的能力。该奖项的最终目标是为伯纳姆博士发展一项独立的研究生涯，开展与肺部和重症监护医学相关的酒精滥用的系统性影响的“转化性”调查。

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.