Lipoxin A(4) activates alveolar epithelial sodium channel, Na,K-ATPase, and increases alveolar fluid clearance

Am J Respir Cell Mol Biol. 2013 May;48(5):610-8. doi: 10.1165/rcmb.2012-0274OC.


Edema fluid resorption is critical for gas exchange, and both alveolar epithelial sodium channel (ENaC) and Na,K-ATPase are accredited with key roles in the resolution of pulmonary edema. Alveolar fluid clearance (AFC) was measured in in situ ventilated lungs by instilling isosmolar 5% BSA solution with Evans Blue-labeled albumin tracer (5 ml/kg) and measuring the change in Evans Blue-labeled albumin concentration over time. Treatment with lipoxin A4 and lipoxin receptor agonist (5(S), 6(R)-7-trihydroxymethyl 17 heptanoate) significantly stimulated AFC in oleic acid (OA)-induced lung injury, with the outcome of decreased pulmonary edema. Lipoxin A4 and 5(S), 6(R)-7-trihydroxymethyl 17 heptanoate not only up-regulated the ENaC α and ENaC γ subunits protein expression, but also increased Na,K-ATPase α1 subunit protein expression and Na,K-ATPase activity in lung tissues. There was no significant difference of intracellular cAMP level between the lipoxin A4 treatment and OA group. However, the intracellular cGMP level was significantly decreased after lipoxin A4 treatment. The beneficial effects of lipoxin A4 were abrogated by butoxycarbonyl-Phe-Leu-Phe-Leu-Ph (lipoxin A4 receptor antagonist) in OA-induced lung injury. In primary rat alveolar type II epithelial cells stimulated with LPS, lipoxin A4 increased ENaC α and ENaC γ subunits protein expression and Na,K-ATPase activity. Lipoxin A4 stimulated AFC through activation of alveolar epithelial ENaC and Na,K-ATPase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / drug therapy
  • Acute Lung Injury / immunology
  • Acute Lung Injury / metabolism
  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / immunology
  • Animals
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic GMP / metabolism
  • Epithelial Sodium Channel Agonists / administration & dosage*
  • Epithelial Sodium Channel Agonists / pharmacology
  • Epithelial Sodium Channel Blockers / pharmacology
  • Epithelial Sodium Channels / genetics
  • Epithelial Sodium Channels / metabolism*
  • Gene Expression / drug effects
  • Heptanoic Acids / pharmacology
  • Lipopolysaccharides / pharmacology
  • Lipoxins / administration & dosage*
  • Lipoxins / pharmacology
  • Male
  • Mucociliary Clearance
  • Oligopeptides / pharmacology
  • Peroxidase / metabolism
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism
  • Pulmonary Alveoli / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism


  • 5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester
  • Epithelial Sodium Channel Agonists
  • Epithelial Sodium Channel Blockers
  • Epithelial Sodium Channels
  • Heptanoic Acids
  • Lipopolysaccharides
  • Lipoxins
  • Oligopeptides
  • Tumor Necrosis Factor-alpha
  • lipoxin A4
  • butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine
  • Cyclic AMP
  • Peroxidase
  • Sodium-Potassium-Exchanging ATPase
  • Cyclic GMP