Chronic alcohol drinking compromises lung immunity by altering immunometabolism in both human and mouse lungs

Heavy alcohol drinking dysregulates lung immunity and host defense, which makes individuals with AUD more susceptible to develop inflammatory condition in lungs with poor prognosis. Current study, we focused on exploring the effects of chronic alcohol consumption on lungs using NIAAA alcohol feeding model in mice with 10 days of a Lieber-DeCarli liquid diet containing 5% ethanol followed by a single ethanol binge (5 g/kg) and population based human lung transcriptome data from Genotype-Tissue Expression (GTEx) project consist of 328 alcohol drinkers and 110 non-drinkers. Flow cytometry and transcriptomics analysis in mice lungs revealed that alcohol consumption dysregulates cellularity of immune cell levels and lung immunity. Transcriptomics analysis both in lungs and liver at 9-, 24- hours and 14 days post ethanol binge in mice uncovered that the lungs were more sensitive to alcohol effect to down-regulate pathways of immune system regulations than liver. Comparative data analysis of lung transcriptomes between mice and human subjects not only confirmed similar dysregulation on lung immunity but also provided evidence that immunometabolic changes are the central driver of alterations in lung transcriptome with down regulating immune pathways and upregulating metabolic pathways. Since the NIAAA model recapitulates multiple changes in the lung transcriptome that had been observed in human subjects with chronic alcohol drinking, this makes the mouse model suitable for experimental studies exploring role of alcohol drinking in lung health. Chronic alcohol drinking reduced mTOR signaling and cellularity of immune cells, which can be further attenuated by selective inhibition of mTOR. BCAA-mTOR signaling axis can be an upstream regulator of alcohol induced dysregulation in lung immunity