Among the many organ systems affected by harmful alcohol use, the lungs are particularly susceptible to infections and injury. The mechanisms responsible for rendering people with alcohol use disorder (AUD) vulnerable to lung damage include alterations in host defenses of the upper and lower airways, disruption of alveolar epithelial barrier integrity, and alveolar macrophage immune dysfunction. Collectively, these derangements encompass what has been termed the "alcoholic lung" phenotype. Alcohol-related reductions in antioxidant levels also may contribute to lung disease in people with underlying AUD. In addition, researchers have identified several regulatory molecules that may play crucial roles in the alcohol-induced disease processes. Although there currently are no approved therapies to combat the detrimental effects of chronic alcohol consumption on the respiratory system, these molecules may be potential therapeutic targets to guide future investigation.
by
Julie A. Womack;
Terrence E. Murphy;
Harini Bathulapalli;
Kathleen M. Akgun;
Cynthia Gibert;
Ken M. Kunisaki;
David Rimland;
Maria Rodriguez-Barradas;
H. Klar Yaggi;
Amy C. Justice;
Nancy S. Redeker
by
Kirsha S. Gordon;
E. Jennifer Edelman;
Amy C. Justice;
David A. Fiellin;
KAthleen Akgun;
Stephen Crystal;
Mona Duggal;
Joseph L. Goulet;
David Rimland;
Kendall J. Bryant
Black and Hispanic (minority) MSM have a higher incidence of HIV than white MSM. Multiple sexual partners, being under the influence of drugs and/or alcohol during sex, having a detectable HIV-1 RNA, and non-condom use are factors associated with HIV transmission. Using data from the Veterans Aging Cohort Study, we consider minority status and sexual orientation jointly to characterize and compare these factors. White non-MSM had the lowest prevalence of these factors (p < 0.001) and were used as the comparator group in calculating odds ratios (OR). Both MSM groups were more likely to report multiple sex partners (white MSM OR 7.50; 95 % CI 5.26, 10.71; minority MSM OR 10.24; 95 % CI 7.44, 14.08), and more likely to be under the influence during sex (white MSM OR 2.15; 95 % CI 1.49, 3.11; minority MSM OR 2.94; 95 % CI 2.16, 4.01). Only minority MSM were more likely to have detectable HIV-1 RNA (OR 1.87; 95 % CI 1.12, 3.11). Both MSM groups were more likely to use condoms than white non-MSM. These analyses suggest that tailored interventions to prevent HIV transmission among minority MSM are needed, with awareness of the potential co-occurrence of risk factors.
Background: We previously demonstrated that chronic alcohol ingestion augments TGFβ1 expression in the lung fibroblast and increases the risk of fibroproliferative disrepair in a mouse model of acute lung injury. The effect of alcohol on TGFβ1 is mitigated by treatment with sulforaphane (SFP), which can activate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, the mechanisms by which alcohol amplifies, or SFP attenuates, TGFβ1 expression in the fibroblast are not known. MicroRNA (miR)-21 has been shown to inhibit Smad7, a TGFβ1 signaling inhibitor. In this study, we hypothesized that alcohol augments TGFβ1 expression through up-regulation of miR-21, which subsequently inhibits Smad7. Methods: Primary mouse lung fibroblasts were cultured ± alcohol ± SFP and assessed for gene expression of miR-21, and gene and/or protein expression of Nrf2, Nrf2-regulated antioxidant enzymes, Smad7, STAT3, and TGFβ1. NIH 3T3 fibroblasts were transfected with a miR-21 inhibitor and cultured ± alcohol. α-SMA, Smad7, and TGFβ1 protein expression were then assessed. In parallel, NIH 3T3 lung fibroblasts were transfected with Nrf2 silencing RNA (siRNA) and cultured ± alcohol ± SFP. Gene expression of miR-21, Nrf2, Smad7, and TGFβ1 was assessed. Results: MiR-21 gene expression was increased by 12-fold at 48 hours, and Smad7 gene expression and protein expression were reduced by ~30% in alcohol-treated fibroblasts. In parallel, inhibition of miR-21 attenuated alcohol-mediated decrease in Smad7 and increase in TGFβ1 and α-SMA protein expression. Treatment with SFP mitigated the effect of alcohol on miR-21, Smad7 and total and phosphorylated STAT3, and restored Nrf2-regulated antioxidant gene expression. Silencing of Nrf2 prevented the effect of SFP on miR-21, Smad7, and TGFβ1 gene expression in alcohol-treated NIH 3T3 fibroblasts. Conclusions: Alcohol treatment increases TGFβ1 in fibroblasts, at least in part, through augmentation of miR-21, which then inhibits Smad7 expression. These effects can be attenuated by activation of Nrf2 with SFP.