title: Alcohol worsens acute lung injury by inhibiting alveolar sodium transport through the adenosine A1 receptor.
abstract: OBJECTIVE
  Alcohol intake increases the risk of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) and is associated with poor outcomes in patients who develop these syndromes. No specific therapies are currently available to treat or decrease the risk of ARDS in patients with alcoholism. We have recently shown increased levels of lung adenosine inhibit alveolar fluid clearance, an important predictor of outcome in patients with ARDS. We hypothesized that alcohol might worsen lung injury by increasing lung adenosine levels, resulting in impaired active Na(+) transport in the lung.
  
  
  METHODS
  We treated wild-type mice with alcohol administered i.p. to achieve blood alcohol levels associated with moderate to severe intoxication and measured the rate of alveolar fluid clearance and Na,K-ATPase expression in peripheral lung tissue and assessed the effect of alcohol on survival during exposure to hyperoxia. We used primary rat alveolar type II cells to investigate the mechanisms by which alcohol regulates alveolar Na(+) transport.
  
  
  RESULTS
  Exposure to alcohol reduced alveolar fluid clearance, downregulated Na,K-ATPase in the lung tissue and worsened hyperoxia-induced lung injury. Alcohol caused an increase in BAL fluid adenosine levels. A similar increase in lung adenosine levels was observed after exposure to hyperoxia. In primary rat alveolar type II cells alcohol and adenosine decreased the abundance of the Na,K-ATPase at the basolateral membrane via a mechanism that required activation of the AMPK.
  
  
  CONCLUSIONS
  Alcohol decreases alveolar fluid clearance and impairs survival from acute lung injury. Alcohol induced increases in lung adenosine levels may be responsible for reduction in alveolar fluid clearance and associated worsening of lung injury.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Dada
authors.forename: Angel R
authors.initials: AR
authors.lastname: Gonzalez
authors.forename: Daniela
authors.initials: D
authors.lastname: Urich
authors.forename: Saul
authors.initials: S
authors.lastname: Soberanes
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Manghi
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Chiarella
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D018496:Hyperoxia; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D016019:Survival Analysis; D015996:Survival Rate
chemical_list: D002492:Central Nervous System Depressants; D043682:Receptor, Adenosine A1; D000431:Ethanol; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D000241:Adenosine