title: Zinc supplementation restores PU.1 and Nrf2 nuclear binding in alveolar macrophages and improves redox balance and bacterial clearance in the lungs of alcohol-fed rats.
abstract: BACKGROUND
  Chronic alcohol abuse causes oxidative stress, impairs alveolar macrophage immune function, and increases the risk of pneumonia and acute lung injury. Recently we determined that chronic alcohol ingestion in rats decreases zinc levels and macrophage function in the alveolar space; provocative findings in that zinc is essential for normal immune and antioxidant defenses. Alveolar macrophage immune function depends on stimulation by granulocyte/monocyte colony-stimulating factor, which signals via the transcription factor PU.1. In parallel, the antioxidant response element signals via the transcription factor Nrf2. However, the role of zinc bioavailability on these signaling pathways within the alveolar space is unknown.
  
  
  METHODS
  To determine the efficacy of dietary zinc supplementation on lung bacterial clearance and oxidative stress, we tested 3 different groups of rats: control-fed, alcohol-fed, and alcohol-fed with zinc supplementation. Rats were then inoculated with intratracheal Klebsiella pneumoniae, and lung bacterial clearance was determined 24 hours later. Isolated alveolar macrophages were isolated from uninfected animals and evaluated for oxidative stress and signaling through PU.1 and Nrf2.
  
  
  RESULTS
  Alcohol-fed rats had a 5-fold decrease in lung bacterial clearance compared to control-fed rats. Dietary zinc supplementation of alcohol-fed rats normalized bacterial clearance and mitigated oxidative stress in the alveolar space, as reflected by the relative balance of the thiol redox pair cysteine and cystine, and increased nuclear binding of both PU.1 and Nrf2 in alveolar macrophages from alcohol-fed rats.
  
  
  CONCLUSIONS
  Dietary zinc supplementation prevents alcohol-induced alveolar macrophage immune dysfunction and oxidative stress in a relevant experimental model, suggesting that such a strategy could decrease the risk of pneumonia and lung injury in individuals with alcohol use disorders.
authors: Atlanta VAMC, Emory University School of Medicine, Atlanta, GA 30033, USA. amehta4@emory.edu
authors: Ashish J
authors: AJ
authors: Mehta
authors: Pratibha C
authors: PC
authors: Joshi
authors: Xian
authors: X
authors: Fan
authors: Lou Ann S
authors: LA
authors: Brown
authors: Jeffrey D
authors: JD
authors: Ritzenthaler
authors: Jesse
authors: J
authors: Roman
authors: David M
authors: DM
authors: Guidot
mesh_terms: D000818:Animals; D008297:Male; D051381:Rats; D000437:Alcoholism / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D000431:Ethanol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000276:immunology; D007710:Klebsiella Infections / Q000378:metabolism / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development; D008168:Lung / Q000276:immunology / Q000503:physiopathology; D055370:Lung Injury / Q000188:drug therapy / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014131:Trace Elements / Q000494:pharmacology / Q000627:therapeutic use; D015534:Trans-Activators / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology / Q000627:therapeutic use; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000431:Ethanol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011518:Proto-Oncogene Proteins; D014131:Trace Elements; D015534:Trans-Activators; D015032:Zinc; D051267:NF-E2-Related Factor 2; D000099232:Proto-Oncogene Protein Spi-1