title: Chronic alcohol ingestion primes the lung for bleomycin-induced fibrosis in mice.
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.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine , Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Viranuj
authors.initials: V
authors.lastname: Sueblinvong
authors.forename: Vern E
authors.initials: VE
authors.lastname: Kerchberger
authors.forename: Ramin
authors.initials: R
authors.lastname: Saghafi
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Mills
authors.forename: Xian
authors.initials: X
authors.lastname: Fan
authors.forename: David M
authors.initials: DM
authors.lastname: Guidot
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001761:Bleomycin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004032:Diet; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011014:Pneumonia / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012436:S-Adenosylmethionine / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D000199:Actins; D000903:Antibiotics, Antineoplastic; D002492:Central Nervous System Depressants; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D000431:Ethanol; D012436:S-Adenosylmethionine; D006909:Hydroxyproline
keywords: Acute Respiratory Distress Syndrome; Fibrosis; Glutathione; TGFβ1; s-Adenosylmethionine
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