title: Ethanol (EtOH)-induced TGF-β1 and reactive oxygen species production are necessary for EtOH-induced alveolar macrophage dysfunction and induction of alternative activation.
abstract: BACKGROUND
  Previous studies have shown that chronic ethanol (EtOH) ingestion results in impaired alveolar macrophage function, increased TGF-β(1)  production, and decreased antioxidant availability. Similarly, alternative activation (M2 activation) of alveolar macrophages also induces TGF-β(1)  production and impairs macrophage function. However, the potential links between EtOH-induced alveolar macrophage derangements, M2 activation, TGF-β(1)  production signaling, and oxidant stress have yet to be examined. We hypothesized that EtOH-induced oxidant stress and induction of TGF-β(1)  signaling result in alternative activation which subsequently impairs the phagocytic capacity of alveolar macrophages.
  
  
  METHODS
  Primary rat alveolar macrophages and the alveolar macrophages cell line NR8383 were treated with 0.08% EtOH ± the antioxidant glutathione (GSH) or a TGF-β(1)  neutralizing antibody for 5 days. Outcome measures included TGF-β(1)  production, reactive oxygen species (ROS) production, phagocytic capacity, and expression of markers of M2 activation.
  
  
  RESULTS
  Chronic EtOH treatment greatly decreased alveolar macrophage phagocytic function, increased ROS production, increased TGF-β(1) , and increased expression of markers of M2 activation. GSH supplementation and inhibition of TGF-β(1)  signaling during EtOH treatment prevented these alterations.
  
  
  CONCLUSIONS
  EtOH treatment increased oxidant stress, TGF-β(1)  production, and alternative activation in NR8383 cells. However, GSH supplementation and ablation of TGF-β(1)  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-β(1)  signaling. Preventing EtOH-induced induction of alternative activation may improve alveolar macrophage function in alcoholic subjects and decrease the risk of respiratory infections.
authors.affiliation: Department of Pediatrics, Emory University, and Center for Developmental Lung Biology, Children's Healthcare of Atlanta, Georgia 30322, USA.
authors.forename: Sheena D
authors.initials: SD
authors.lastname: Brown
authors.forename: Lou Ann S
authors.initials: LA
authors.lastname: Brown
mesh_terms: D000818:Animals; D002460:Cell Line; D000431:Ethanol / Q000633:toxicity*; D008262:Macrophage Activation / Q000187:drug effects* / Q000502:physiology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D000431:Ethanol