Patients with alcohol use disorders (AUD) are 2-4 times more susceptible to developing respiratory infections and acute respiratory distress syndrome, compared to non-alcoholic subjects. In the lung, alveolar macrophages (AM) are the first line of cellular defense in the alveolar space, and they function to phagocytize and clear invading pathogens. However, chronic alcohol ingestion increases mitochondria (MT)-derived oxidative stress and MT dysfunction, which impairs AM phagocytosis and increases risk for infections. In the proposed studies, the PI will examine the effects of alcohol-induced MT-derived oxidative stress on AM phagocytic dysfunction and susceptibility to infections (Aim 1). The PI will then elucidate the molecular mechanisms involved in alcohol-induced MT derangements, including fragmentation and dysfunction (Aim 2). Finally, since transcription factor B1, mitochondrial (TFB1M) is a critical mediator of MT DNA and MT gene transcription, the PI will determine the effect of alcohol on AM TFB1M expression and activity as modulated by microRNAs (Aim 3). These hypotheses will be investigated by using a mouse model of chronic alcohol consumption, an in vitro ethanol exposed mouse AM cell line, MH-S, and AM isolated from human subjects with AUD. The objectives of the studies outlined in this proposal are to elucidate the molecular mechanisms responsible for phagocytic dysfunction in alcoholic AM and identify novel and therapeutically targetable molecules responsible for EtOH-induced MT dysfunction. If successful, the proposed studies will identify novel therapeutic targets for future translational studies that could impact the management of patients with a history of AUD who are at risk for significant lung disorders, even during continued alcohol use, or potentially patients with disorders characterized by similar MT dysfunction.
The risk of respiratory infections is increased in alcoholics because the capacity of lung macrophages to engulf and clear infectious microbes is impaired. This impaired immune function is primarily due to mitochondria derangements, which generate reactive oxygen species. In this proposal, the PI will determine if targeting therapeutics to mitochondria will decrease oxidative stress, restore proper mitochondria function, and improve the ability of lung macrophages to engulf and clear infectious pathogens.
