Proinflammatory Effects Of Acute Alcohol Ingestion in Humans

描述（由申请人提供）：急性酒精中毒显然是一种持续创伤性损伤的风险。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住院前5天发生急性肺损伤（ALI）的独立危险因素（比值比1.40; 95%置信区间1.22-1.60; p< 0.0001）。我们的试点研究离体血液淋巴细胞活化的人类受试者，消耗酒精，以模拟狂饮显着增加PHA诱导的干扰素（IFN）-？和白细胞介素（IL）-2分泌20分钟后摄入酒精，并持续长达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体（ROI）的产生来增强白细胞活化，这放大了可导致包括肺在内的组织损伤的促炎细胞因子的表达。以下具体目标是为了解决这一假设而制定的，同时为我提供了基础和转化研究技术方面的宝贵新研究技能，这将补充我以前在临床和流行病学调查方面的培训。我们将使用以下方法来检验我们的假设： 一个人类酗酒模型具体而言，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离体活化的反应，以及细胞内ROI在介导这些效应中的潜在作用;（2）分析急性酒精摄入如何改变正常人受试者静脉内毒素LPS输注后细胞因子表达，白细胞活化和ROI生成。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以增加肺和其他器官损伤风险的理解，确定是否以及如何在中毒性创伤患者中进行抗氧化剂的后续II期临床试验，为我提供一个很好的框架，以扩展我的转化研究技能，并制作出版物，这将推动我的职业生涯作为一个肺和重症监护医生科学家和翻译研究者。

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.