ClinicalTrials.gov; No.: NCT02497729; URL: www.clinicaltrials.gov.

ClinicalTrials.gov; No.: NCT02497729; URL: www.clinicaltrials.gov.

Data availabilitySummary statistics generated by COVID-19 Host Genetics Initiative are available online (https://www.covid19hg.org/results/r6/). The analyses described here use the freeze 6 data. The COVID-19 Host Genetics Initiative continues to regularly release new data freezes. Summary statistics for samples from individuals of non-European ancestry are not currently available owing to the small individual sample sizes of these groups, but the results for 23 loci lead variants are reported in Supplementary Table 3. Individual-level data can be requested directly from the authors of the contributing studies, listed in Supplementary Table 1.

Background Alcohol abuse increases the risk for acute lung injury (ALI). In both experimental models and in clinical studies, chronic alcohol ingestion causes airway oxidative stress and glutathione depletion and increases the expression of transforming growth factor beta-1 (TGFβ1), a potent inducer of fibrosis, in the lung. Therefore, we hypothesized that alcohol ingestion could promote aberrant fibrosis following experimental ALI and that treatment with the glutathione precursor s-adenosylmethionine (SAMe) could mitigate these effects. Methods Three month old C57BL/6 mice were fed standard chow ± alcohol (20% v/v) in their drinking water for 8 wks and ± SAMe (4% w/v) during the last 4 wks. ALI was induced by intratracheal instillation of bleomycin (2.5 units/kg) and lungs were assessed histologically at 7 and 14 days for fibrosis, and at 14 days for the expression of extracellular matrix proteins and TGFβ1. Results Alcohol ingestion had no apparent effect on lung inflammation at 7 days, but at 14 days after bleomycin treatment it increased lung tissue collagen deposition, hydroxyproline content, and the release of activated TGFβ1 into the airway. In contrast, SAMe supplementation completely mitigated alcohol-induced priming of these aberrant fibrotic changes through decreased TGFβ1 expression in the lung. In parallel, SAMe decreased alcohol-induced TGFβ1 and Smad3 mRNA expressions by lung fibroblasts in vitro. Conclusion These new experimental findings demonstrate that chronic alcohol ingestion renders the experimental mouse lung susceptible to fibrosis following bleomycin-induced ALI, and that these effects are likely driven by alcohol-mediated oxidative stress and its induction and activation of TGFβ1.

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