title: Effect of chronic ethanol ingestion on alveolar type II cell: glutathione and inflammatory mediator-induced apoptosis.
abstract: BACKGROUND
  In septic patients, chronic alcohol abuse increases the incidence of the acute respiratory distress syndrome, a syndrome that requires alveolar type II cell proliferation and differentiation for repair of the damaged alveolar epithelium. We previously showed in a rat model that chronic ethanol ingestion decreased the antioxidant glutathione (GSH) in type II cells and exacerbated endotoxin-mediated acute lung injury. We hypothesized that this GSH depletion by ethanol, particularly mitochondrial GSH, predisposed type II cells to inflammatory mediator-induced apoptosis.
  
  
  METHODS
  Adult male rats were fed the Lieber-DeCarli diet for 2, 6, or 16 weeks. Alveolar type II cells were then isolated and treated with hydrogen peroxide or TNF-alpha. The effect on glutathione (cytosolic and mitochondrial), apoptotic events, and necrosis were determined. In other studies, rats were fed ethanol for 6 weeks and were treated with endotoxin and apoptosis of type II cells determined by the TUNEL method.
  
  
  RESULTS
  Chronic ethanol ingestion alone resulted in a progressive decrease in mitochondrial GSH and a progressive increase in the basal apoptosis and necrosis rate (p < or = 0.05). Furthermore, there was a progressive increase in the sensitivity of the cells to H2O2 or TNF-alpha induced cytochrome c release, caspase 3 activation, apoptosis, and necrosis (p < or = 0.05). Finally, there was a 2-fold increase in apoptotic type II cells in vivo when chronic ethanol ingestion was superimposed on endotoxemia.
  
  
  CONCLUSIONS
  These results suggested that chronic ethanol ingestion resulted in a progressive depletion of mitochondrial GSH and sensitization of type II cells to inflammatory mediator-induced apoptosis and necrosis. These effects may be particularly relevant during acute stress when proliferation and differentiation of these cells are critical to repair of the damaged alveolar epithelium and may have important ramifications for the treatment of acute respiratory distress syndrome in patients with a history of alcohol abuse.
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA. lbrow03@emory.edu
authors.forename: L A
authors.initials: LA
authors.lastname: Brown
authors.forename: F L
authors.initials: FL
authors.lastname: Harris
authors.forename: R
authors.initials: R
authors.lastname: Bechara
authors.forename: D M
authors.initials: DM
authors.lastname: Guidot
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000633:toxicity*; D003600:Cytosol / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D010084:Oxidation-Reduction; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D002492:Central Nervous System Depressants; D018836:Inflammation Mediators; D000431:Ethanol; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione