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

Authors

  • Viranuj Sueblinvong,

    Corresponding author
    1. Division of Pulmonary, Allergy and Critical Care Medicine , Emory University School of Medicine, Atlanta, Georgia
    • Reprint requests: Viranuj Sueblinvong, MD, 615 Michael Street, Suite 205, Atlanta, GA 30322; Tel.: 404-727-9560; Fax: 404-712-2974; E-mail: vsuebli@emory.edu

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  • Vern E. Kerchberger,

    1. Division of Pulmonary, Allergy and Critical Care Medicine , Emory University School of Medicine, Atlanta, Georgia
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  • Ramin Saghafi,

    1. Division of Pulmonary, Allergy and Critical Care Medicine , Emory University School of Medicine, Atlanta, Georgia
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  • Stephen T. Mills,

    1. Division of Pulmonary, Allergy and Critical Care Medicine , Emory University School of Medicine, Atlanta, Georgia
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  • Xian Fan,

    1. Division of Pulmonary, Allergy and Critical Care Medicine , Emory University School of Medicine, Atlanta, Georgia
    2. Atlanta VAMC , Decatur, Georgia
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  • David M. Guidot

    1. Division of Pulmonary, Allergy and Critical Care Medicine , Emory University School of Medicine, Atlanta, Georgia
    2. Atlanta VAMC , Decatur, Georgia
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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.

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