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Author Notes:

E-mail: vsuebli@emory.edu

VS and DMG designed the research project; VS, VT, TS, RS, DCN, and STM performed experiments and analyzed data; VS and DMG interpreted the results of the experiments; VS and DMG drafted, edited, and revised the manuscript.

The authors wish to thank Michael Koval, Dean P. Jones, and Xian Fan for their scientific discussions and helpful suggestions with this manuscript.

Subject:

Research Funding:

NIH K08 AA021404-01 for VS, NIH P50 AA013757 for VA and DMG, and NIH R01 AA 017627 and a VA Merit Review for DMG.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Substance Abuse
  • Nrf2
  • Antioxidant Response Element
  • TGF beta 1
  • Glutathione
  • Lung Fibroblasts
  • Alcohol
  • RESPIRATORY-DISTRESS-SYNDROME
  • ERYTHROID 2-RELATED FACTOR-2
  • EPITHELIAL BARRIER FUNCTION
  • MULTIPLE ORGAN DYSFUNCTION
  • CHRONIC ETHANOL INGESTION
  • SMOOTH-MUSCLE-CELLS
  • OXIDATIVE STRESS
  • GLUTATHIONE HOMEOSTASIS
  • ANTIOXIDANT RESPONSES
  • ALVEOLAR MACROPHAGE

TGF beta 1 Mediates Alcohol-Induced Nrf2 Suppression in Lung Fibroblasts

Tools:

Journal Title:

Alcoholism: Clinical and Experimental Research

Volume:

Volume 38, Number 11

Publisher:

, Pages 2731-2742

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: Chronic alcohol ingestion induces the expression of transforming growth factor beta-1(TGFβ1), inhibits nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated activation of the antioxidant response element (ARE), depletes alveolar glutathione pools, and potentiates acute lung injury. In this study, we examined the mechanistic relationship between TGFβ1 and Nrf2-ARE signaling in the experimental alcoholic lung. Methods: Wild-type mice were treated ± alcohol in drinking water for 8 weeks and their lungs were assessed for Nrf2 expression. In parallel, mouse lung fibroblasts were cultured ± alcohol and treated ± sulforaphane (SFP; an activator of Nrf2), ±TGFβ1, ±TGFβ1 neutralizing antibody, and/or ±activin receptor-like kinase 5 inhibitors (to block TGβ1 receptor signaling) and then analyzed for the expression of Nrf2, Kelch-like ECH-associated protein 1 (Keap1) and TGFβ1, Nrf2-ARE activity, and the expression of the Nrf2-ARE-dependent antioxidants glutathione s-transferase theta 2 (GSTT2) and glutamate-cysteine ligase catalytic subunit (GCLC). Finally, silencing RNA (siRNA) of Nrf2 was then performed prior to alcohol exposure and subsequent analysis of TGFβ1 expression. Results: Alcohol treatment in vivo or in vitro decreased Nrf2 expression in murine whole lung and lung fibroblasts, respectively. In parallel, alcohol exposure in vitro decreased Keap1 gene and protein expression in lung fibroblasts. Furthermore, alcohol exposure increased TGFβ1 expression but decreased Nrf2-ARE activity and expression of the ARE-dependent genes for GSTT2 and GCLC. These effects of alcohol were prevented by treatment with SFP; in contrast, Nrf2 SiRNA expression exacerbated alcohol-induced TGFβ1 expression. Finally, TGFβ1 treatment directly suppressed Nrf2-ARE activity whereas blocking TGFβ1 signaling attenuated alcohol-induced suppression of Nrf2-ARE activity. Conclusions: Alcohol-induced oxidative stress is mediated by TGFβ1, which suppresses Nrf2-ARE-dependent expression of antioxidant defenses and creates a vicious cycle that feeds back to further increase TGFβ1 expression. These effects of alcohol can be mitigated by activation of Nrf2, suggesting a potential therapy in individuals at risk for lung injury due to alcohol abuse.

Copyright information:

© 2014 by the Research Society on Alcoholism.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution, public display, and publicly performance, making multiple copies, provided the original work is properly cited. This license requires credit be given to copyright holder and/or author, copyright and license notices be kept intact. This license prohibits exercising rights for commercial purposes.

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