Augmentation of lung liquid clearance via adenovirus-mediated transfer of a Na,K-ATPase β1 subunit gene

Abstract

Previous studies have suggested that alveolar Na,K-ATPases play an important role in active Na+ transport and lung edema clearance. We reasoned that overexpression of Na,K-ATPase subunit genes could increase Na,K-ATPase function in lung epithelial cells and edema clearance in rat lungs. To test this hypothesis we produced replication deficient human type 5 adenoviruses containing cDNAs for the rat α1 β1 Na,K-ATPase subunits (adMRCMVα1 and adMRCMVβ1, respectively). As compared to controls, adMRCMVβ1 increased β1 subunit expression and Na,K-ATPase function by 2.5-fold in alveolar type 2 epithelial cells and rat airway epithelial cell monolayers. No change in Na,K-ATPase function was noted after infection with adMRCMVα1. Rat lungs infected with adMRCMVβ1, but not adMRCMVα1, had increased β1 protein levels and lung liquid clearance 7 d after tracheal instillation. Alveolar epithelial permeability to Na+ and mannitol was mildly increased in animals infected with adMRCMVβ1 and a similar Escherichia coli lacZ-expressing virus. Our data shows, for the first time, that transfer of the β1 Na,K- ATPase sub-unit gene augments Na,K-ATPase function in epithelial cells and liquid clearance in rat lungs. Conceivably, overexpression of Na,K-ATPases could be used as a strategy to augment lung liquid clearance in patients with pulmonary edema.