Alcohol-Dependent Pulmonary Inflammation: A Role for HMGB-1.

Previous studies demonstrate that acute alcohol intoxication significantly impairs lung immune responses, which can lead to the tissue undefended from microbial infection and resulting disease. Data suggest that acute intoxication presents an axis where simultaneously suppressing early pro-inflammatory cytokines while inducing anti-inflammatory signals contribute to alcohol-dependent immune suppression in the lung, and thus undeterred microbial replication. Interestingly, alcoholics and those with alcohol use disorder present with increased pneumonia and Acute Respiratory Disease (ARDs), suggesting a more active priming of inflammatory responses in the lungs. There is current research evaluating the acute effects of binge ethanol consumption on adolescents and is of grave concern, though long-term effects of adolescent ethanol binge exposure is less studied. We hypothesize that adolescent binge drinking may prime the individual to severe pulmonary distress, when later challenged by a microbial pathogen. Herein, we evaluate a model of Adolescent Intermittent Ethanol (AIE) exposure to investigate pulmonary pathology after microbial challenge. Ethanol (EtOH) was administered to adolescent mice using a binge exposure schedule and then rested to early adulthood. These mice were then challenged with a sub-lethal intra-nasal inoculation of K. pneumoniae and evaluated for severity of disease. We find that AIE exposure initially activates inflammatory mediators within the lung, which resolves over time. However when challenged with a microbial pathogen after this resolution period, these animals present with more severity of inflammation, pulmonary tissue damage and mortality when challenged with a pulmonary microbial infection. Interestingly, our data suggests a role for alcohol-dependent release of the protein HMGB-1 from host cells, for both morbidity and mortality in our model of microbial-dependent pulmonary inflammation.