Alcohol modulates TLR2 signaling in airway epithelium

描述（由申请人提供）： 众所周知，酗酒对肺部有有害影响。例如，大量饮酒会增加患肺炎、急性呼吸窘迫综合征（ARDS）和支气管炎的风险。在这些酒精相关的肺部疾病中，酒精摄入被认为是为随后的损伤（如病毒感染、创伤或败血症）“准备”肺部。肺的先天免疫系统中的第一道防线是气道上皮，其表达Toll样受体（TLR）。当TLR 2被激活时，它启动细胞对革兰氏阳性微生物入侵的炎症反应。有趣的是，我们最近观察到酒精强烈上调气道上皮细胞TLR 2。我们的研究计划将帮助我们回答以下几个问题：1）确定酒精诱导气道上皮细胞TLR 2 mRNA和蛋白表达的时间过程和浓度依赖性; 2）确定一氧化氮产生的作用，ROS体外酒精触发的TLR 2上调中的（活性氧）产生和NF κ B活化，和3）在暴露于气管内肺炎链球菌的酒精喂养小鼠的体内模型中确定酒精触发的TLR 2上调对肺部炎症的影响。

DESCRIPTION (provided by applicant): Alcohol abuse is well known to have harmful effects on the lung. For example, heavy alcohol intake increases the risk for developing pneumonia, acute respiratory distress syndrome (ARDS), and bronchitis. In these alcohol-associated lung diseases, alcohol intake is thought to "prime" the lung for a subsequent injury, such as viral infection, trauma, or sepsis. The first line of defense in the innate immune system of the lung is the airway epithelium, which expresses Toll-like receptors (TLR). When TLR2 is activated, it initiates the cellular inflammatory response to gram-positive microbial invasion. Interestingly, we have recently observed that alcohol strongly upregulates airway epithelial cell TLR2. Our research plan will help us answer several questions: 1) Define the time course and concentration-dependence of TLR2 mRNA and protein expression triggered by alcohol in airway epithelial cells; 2) Identify the roles of nitric oxide production, ROS (Reactive oxygen species) production and NFkB activation in alcohol-triggered TLR2 upregulation in vitro, and 3) Determine the impact of alcohol-triggered TLR2 upregulation on lung inflammation in an in vivo model of alcohol-fed mice exposed to intratracheal Streptococcus pneumoniae.