AUGMENTATION OF LUNG LIQUID CLEARANCE VIA ADENOVIRUS-MEDIATED TRANSFER OF A NA,K-ATPASE BETA(1) SUBUNIT GENE

Previous studies have suggested that alveolar Na,K-ATPases play an imp ortant role in active Na+ transport and lung edema clearance. We reaso ned 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 huma n type 5 adenoviruses containing cDNAs for the rat alpha(1) and beta(1 ) Na,K-ATPase subunits (adMRCMV alpha(1) and adMRCMV beta(1), respecti vely). As compared to controls, adMRCMV beta(1) increased beta(1) subu nit 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 adMRCMV alpha( 1). Rat lungs infected with adMRCMV beta(1), but not adMRCMV alpha(1), had increased beta(1) protein levels and lung liquid clearance 7 d af ter tracheal instillation. Alveolar epithelial permeability to Na+ and mannitol was mildly increased in animals infected with adMRCMV beta(1 ) and a similar Escherichia coli lacZ-expressing virus. Our data shows , for the first time, that transfer of the beta(1) Na,K-ATPase subunit gene augments Na,K-ATPase function in epithelial cells and liquid cle arance in rat lungs. Conceivably, overexpression of Na,K-ATPases could be used as a strategy to augment lung liquid clearance in patients wi th pulmonary edema.