Ethanol (EtOH)-Induced TGF-β1 and Reactive Oxygen Species Production Are Necessary for EtOH-Induced Alveolar Macrophage Dysfunction and Induction of Alternative Activation
Version of Record online: 2 MAY 2012
Copyright © 2012 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 36, Issue 11, pages 1952–1962, November 2012
How to Cite
Brown, S. D. and Brown, L. A. S. (2012), Ethanol (EtOH)-Induced TGF-β1 and Reactive Oxygen Species Production Are Necessary for EtOH-Induced Alveolar Macrophage Dysfunction and Induction of Alternative Activation. Alcoholism: Clinical and Experimental Research, 36: 1952–1962. doi: 10.1111/j.1530-0277.2012.01825.x
- Issue online: 29 OCT 2012
- Version of Record online: 2 MAY 2012
- Manuscript Accepted: 26 FEB 2012
- Manuscript Received: 1 SEP 2011
- The National Institute of Alcohol Abuse and Alcoholism. Grant Numbers: R01 AA12197, R01 HL096924, P50 AA 135757, F31 AA017812
- Oxidative Stress;
- Alternative Activation
Previous studies have shown that chronic ethanol (EtOH) ingestion results in impaired alveolar macrophage function, increased TGF-β1 production, and decreased antioxidant availability. Similarly, alternative activation (M2 activation) of alveolar macrophages also induces TGF-β1 production and impairs macrophage function. However, the potential links between EtOH-induced alveolar macrophage derangements, M2 activation, TGF-β1 production signaling, and oxidant stress have yet to be examined. We hypothesized that EtOH-induced oxidant stress and induction of TGF-β1 signaling result in alternative activation which subsequently impairs the phagocytic capacity of alveolar macrophages.
Primary rat alveolar macrophages and the alveolar macrophages cell line NR8383 were treated with 0.08% EtOH ± the antioxidant glutathione (GSH) or a TGF-β1 neutralizing antibody for 5 days. Outcome measures included TGF-β1 production, reactive oxygen species (ROS) production, phagocytic capacity, and expression of markers of M2 activation.
Chronic EtOH treatment greatly decreased alveolar macrophage phagocytic function, increased ROS production, increased TGF-β1, and increased expression of markers of M2 activation. GSH supplementation and inhibition of TGF-β1 signaling during EtOH treatment prevented these alterations.
EtOH treatment increased oxidant stress, TGF-β1 production, and alternative activation in NR8383 cells. However, GSH supplementation and ablation of TGF-β1 signaling prevented these effects. This suggested that the EtOH-induced switch to an M2 phenotype was a result of decreased antioxidant availability and increased TGF-β1 signaling. Preventing EtOH-induced induction of alternative activation may improve alveolar macrophage function in alcoholic subjects and decrease the risk of respiratory infections.