Na,K-ATPase Overexpression Improves Alveolar Fluid Clearance in a Rat Model of Elevated Left Atrial Pressure

Background — Acute elevation of left atrial pressure (LAP) increases extravascular water and impairs active Na + transport in rat lungs. We have reported that overexpression of Na,K-ATPase subunit genes in the alveolar epithelium increases alveolar fluid clearance (AFC) in normal and injured rat lungs with normal LAP. We reasoned that adenovirus-mediated transfer of an Na,K-ATPase β-subunit gene to the alveolar epithelium could improve AFC in rat lungs in the presence of acutely elevated LAP. Methods and Results — Normal rats were infected with 4×10 9 plaque-forming units of E1a − /E3 − recombinant adenoviruses that contained a cytomegalovirus promoter coupled to a rat Na,K-ATPase β 1 -subunit cDNA (adβ 1 ) or no cDNA (adNull) 7 days before study. Na,K-ATPase α 1 - and β 1 -subunit abundance in basolateral cell membranes isolated from the peripheral lung was significantly increased in adβ 1 -infected lungs compared with sham and adNull-infected controls. In all groups, elevation of LAP reduced membrane-bound Na,K-ATPase abundance; however, abundance in adβ 1 -infected lungs remained greater than in controls. AFC, measured with a fluid-filled isolated lung preparation in the presence of elevated LAP (15 cmH 2 O), in Na,K-ATPase β 1 -subunit-overexpressing lungs was up to 100% greater than in controls and was not different from rats studied at normal LAP (0 cmH 2 O). Conclusions — These data suggest that alveolar overexpression of an Na,K-ATPase β 1 -subunit can counteract downregulation of membrane-bound solute transporters owing to elevated pulmonary vascular pressures and can restore active Na + transport and AFC in this rat model of acute hydrostatic pulmonary edema.