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

Abstract

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 β₂‐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 β₂‐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.