Proinflammatory Effects Of Acute Alcohol Ingestion in Humans

人类急性酒精摄入的促炎作用

• 批准号: 8594543
• 负责人: Majid Afshar
• 金额: $ 4.85万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594543
• 关键词: Acute; Acute Lung Injury; Address; Affect; Alcohol consumption; Alcoholic Intoxication; Alcohols; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Attenuated; Basic Science; Blood; Blood alcohol level measurement; Cells; Clinical; Clinical Research; Clinical Trials; Complement; Confidence Intervals; Control Groups; Critical Care; Data; Endotoxins; Environment; Epidemiologic Studies; Flow Cytometry; Future; Generations; Goals; Hospitalization; Hour; Human; Immune response; Immunoassay; Immunologics; In Vitro; Individual; Inflammatory; Infusion procedures; Injury; Interferons; Interleukin-2; Intravenous; Leukocyte Cell Biology; Leukocytes; Lipopolysaccharides; Lung; Lymphocyte; Lymphocyte Activation; Measures; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Neutrophil Activation; Odds Ratio; Organ; Outcome; Oxidants; Paper; Patients; Peer Review; Phase II Clinical Trials; Physicians; Phytohemagglutinins; Pilot Projects; Pneumonia; Predisposition; Production; Publications; Randomized; Research; Research Personnel; Research Technics; Risk; Risk Factors; Role; Scientist; Sepsis; Signal Transduction; Simulate; Study models; System; Techniques; Testing; Time; Tissues; Training; Translating; Translational Research; Trauma; Vaccination; Whole Blood; Work; Writing; alcohol effect; alcohol exposure; anti-endotoxin antibodies; binge drinking; career; chronic alcohol ingestion; cytokine; epidemiologic data; experience; follow-up; healthy volunteer; human subject; in vivo; leukocyte activation; meetings; monocyte; neutrophil; public health relevance; reactive oxygen intermediate; response; skills; tempol; trauma centers; two-arm study

DESCRIPTION (provided by applicant): Acute alcohol intoxication is clearly a risk for sustaining traumatic injury. Our recently completed epidemiologic study of trauma patients demonstrated that having a positive blood alcohol content is an independent risk factor for developing acute lung injury (ALI) in the first five days of hospitalization (Odds Ratio 1.40; 95% Confidence Interval 1.22-1.60; p< 0.0001). Our pilot study of ex vivo blood lymphocyte activation in human subjects that consumed alcohol to simulate binge drinking showed substantially increased PHA-induced interferon (IFN)-? and interleukin (IL)-2 secretion 20 minutes after alcohol ingestion and lasting for up to 5 hours. Our goal is to elucidate the mechanism by which acute alcohol intoxication increases the risk of organ injury in trauma patients. Our central hypothesis is that acute alcohol exposure potentiates leukocyte activation by increasing intracellular reactive oxygen intermediate (ROI) production, which amplifies expression of proinflammatory cytokines that can cause injury to tissues including lung. The following Specific Aims have been developed to address this hypothesis while providing me with valuable new research skills in basic and translational research techniques that will complement my previous training in clinical and epidemiologic investigation. We will test our hypothesis using a human alcohol binge-drinking model. Specifically we will (1) determine how acute alcohol ingestion modifies lymphocyte, monocyte, and neutrophil response to ex vivo activation and the potential role of intracellular ROI in mediating these effects; and (2) analyze how acute alcohol ingestion modifies cytokine expression, leukocyte activation, and ROI generation in response to intravenous endotoxin LPS infusion in normal human subjects. We anticipate that the proposed studies will increase our understanding of how alcohol intoxication can modify host response to increase risk of lung and other organ injury, determine if and how a follow-up Phase II Clinical Trial of antioxidants in intoxicated trauma patients should be conducted, provide me with an excellent framework on which to expand my translational research skills, and produce publications that will propel my career as a pulmonary and critical care physician scientist and translational investigator.

描述(由申请人提供)：急性酒精中毒显然是造成创伤性损伤的危险因素。我们最近完成的创伤患者流行病学研究表明，血液酒精含量阳性是在住院头五天发生急性肺损伤(ALI)的独立风险因素(优势比1.4；95%可信区间1.22-1.6；p&lt；0.0001)。我们对饮酒模拟酗酒的受试者的体外外周血淋巴细胞活化的初步研究显示，PHA诱导的干扰素(干扰素)显著增加。白介素2在酒精摄入后20分钟分泌，最长可持续5小时。我们的目标是阐明急性酒精中毒增加创伤患者器官损伤风险的机制。我们的中心假设是，急性酒精暴露通过增加细胞内活性氧中间产物(ROI)的产生，从而增强白细胞的激活，从而放大促炎症细胞因子的表达，从而对包括肺在内的组织造成损伤。为了解决这一假设，我们制定了以下具体目标，同时为我提供了宝贵的基础和翻译研究技术方面的新研究技能，这些技能将补充我之前在临床和流行病学调查方面的培训。我们将使用以下工具来验证我们的假设 一个酗酒的人类模型。具体地说，我们将(1)确定急性酒精摄入如何改变淋巴细胞、单核细胞和中性粒细胞对体外激活的反应，以及细胞内ROI在介导这些影响中的潜在作用；以及(2)分析急性酒精摄入如何改变细胞因子的表达、白细胞的激活和正常受试者静脉注射内毒素后ROI的产生。我们预计，拟议的研究将增加我们对酒精中毒如何改变宿主反应从而增加肺部和其他器官损伤风险的了解，确定是否应该以及如何对醉酒创伤患者进行抗氧化剂的第二阶段临床试验，为我提供一个极好的框架来扩展我的翻译研究技能，并出版将推动我作为肺和重症监护内科科学家和翻译研究员的职业生涯的出版物。