ENaC-mediated alveolar fluid clearance and lung fluid balance depend on the channel-activating protease 1

EMBO Mol Med. 2010 Jan;2(1):26-37. doi: 10.1002/emmm.200900050.


Sodium transport via epithelial sodium channels (ENaC) expressed in alveolar epithelial cells (AEC) provides the driving force for removal of fluid from the alveolar space. The membrane-bound channel-activating protease 1 (CAP1/Prss8) activates ENaC in vitro in various expression systems. To study the role of CAP1/Prss8 in alveolar sodium transport and lung fluid balance in vivo, we generated mice lacking CAP1/Prss8 in the alveolar epithelium using conditional Cre-loxP-mediated recombination. Deficiency of CAP1/Prss8 in AEC induced in vitro a 40% decrease in ENaC-mediated sodium currents. Sodium-driven alveolar fluid clearance (AFC) was reduced in CAP1/Prss8-deficient mice, due to a 48% decrease in amiloride-sensitive clearance, and was less sensitive to beta(2)-agonist treatment. Intra-alveolar treatment with neutrophil elastase, a soluble serine protease activating ENaC at the cell surface, fully restored basal AFC and the stimulation by beta(2)-agonists. Finally, acute volume-overload increased alveolar lining fluid volume in CAP1/Prss8-deficient mice. This study reveals that CAP1 plays a crucial role in the regulation of ENaC-mediated alveolar sodium and water transport and in mouse lung fluid balance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • Epithelial Sodium Channels / genetics
  • Epithelial Sodium Channels / metabolism*
  • Extravascular Lung Water / metabolism*
  • Gene Deletion
  • Gene Expression
  • Lung / metabolism*
  • Mice
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / metabolism*
  • Pulmonary Edema / metabolism
  • Respiratory Mucosa / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Water-Electrolyte Balance* / drug effects


  • Adrenergic beta-Agonists
  • Epithelial Sodium Channels
  • Serine Endopeptidases
  • prostasin