Chronic Alcohol Ingestion Primes the Lung for Bleomycin-Induced Fibrosis in Mice

• Type of Material: Article
• Authors: Viranuj Sueblinvong, Emory University; V. Eric Kerchberger, Emory University; Ramin Saghafi, Emory University; Stephen T Mills, Emory University; Xian Fan, Emory University; David M Guidot, Emory University
• Language: English
• Date: 2014-02-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2013 by the Research Society on Alcoholism
• Final Published Version (URL): http://dx.doi.org/10.1111/acer.12232
• Title of Journal or Parent Work: Alcoholism: Clinical and Experimental Research
• ISSN: 0145-6008
• Volume: 38
• Issue: 2
• Start Page: 336
• End Page: 343
• Grant/Funding Information: Cystic Fibrosis Foundation Program for Adult Care Excellence for VS; Emory Center for Respiratory Health for VS; NIH Career Development Award (NIAAA 1K08AA021404–01) for VS; Emory Alcohol and Lung Biology Center (NIAAA P50 AA013757) for VS and DMG; and a VA Merit Review for DMG.
• Keywords: Glutathione; TGF1; Substance Abuse; EXPRESSION; ACTIVATION; Life Sciences & Biomedicine; DYSFUNCTION; ETHANOL-FED RATS; Acute Respiratory Distress Syndrome; Fibrosis; GLUTATHIONE HOMEOSTASIS; FIBRONECTIN; ABUSE; Science & Technology; RESPIRATORY-DISTRESS-SYNDROME; IDIOPATHIC PULMONARY-FIBROSIS; s-Adenosylmethionine; N-ACETYLCYSTEINE
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

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 weeks and ±SAMe (4% w/v) during the last 4 weeks. 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. Conclusions: 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. © 2013 by the Research Society on lcoholism.