Augmentation of Lung Liquid Clearance via Adenovirus-mediated Transfer of a Na,K-ATPase [small beta, Greek]1 Subunit Gene

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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 [small alpha, Greek] (1) and [small beta, Greek]1 Na,K-ATPase subunits (adMRCMV[small alpha, Greek] (1) and adMRCMV[small beta, Greek]1, respectively). As compared to controls, adMRCMV[small beta, Greek]1 increased [small beta, Greek]1 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 adMRCMV[small alpha, Greek]1. Rat lungs infected with adMRCMV[small beta, Greek]1, but not adMRCMV[small alpha, Greek]1, had increased [small beta, Greek]1 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 adMRCMV[small beta, Greek]1 and a similar Escherichia coli lacZ-expressing virus. Our data shows, for the first time, that transfer of the [small beta, Greek]1 Na,K-ATPase subunit 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. (J. Clin. Invest. 1998. 102:1421-1430.)

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