Proinflammatory Effects Of Acute Alcohol Ingestion in Humans

描述（由申请人提供）：急性酒精中毒显然有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（优势比1.40；95%可信区间1.22-1.60;p< 0.0001）。我们对人类受试者体内血液淋巴细胞激活的初步研究表明，通过饮酒模拟狂饮，pha诱导的干扰素(IFN)-？和白细胞介素(IL)-2分泌在饮酒后20分钟，并持续长达5小时。我们的目的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的激活，这增加了促炎细胞因子的表达，从而导致包括肺在内的组织损伤。以下具体目标是为了解决这一假设而制定的，同时为我提供了宝贵的基础研究和转化研究技术的新研究技能，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

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.