Alcohol modulates TLR2 signaling in airway epithelium

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.