Adenovirus-mediated transfer of an Na+/K+-ATPase beta(1) subunit gene improves alveolar fluid clearance and survival in hyperoxic rats

Pulmonary edema is cleared via active Na+ transport by alveolar epithelial Na+/K+-ATPases and Na+ channels. Rats exposed to acute hyperoxia have a hig h mortality rate, decreased Na+/K+-ATPase function, and decreased alveolar fluid clearance (AFC), We hypothesized that Na+/K+-ATPase subunit gene over expression could improve AFC in rats exposed to hyperoxia, We delivered 4 X 10(9) PFU of recombinant adenoviruses containing rat alpha (1) and beta (1 ) Na+/K+-ATPase subunit cDNAs (ad alpha (1) and ad beta (1), respectively) to rat lungs 7 days prior to exposure to 100% O-2 for 64 hr, As compared wi th controls and ad alpha (1), AFC in the ad beta (1) rats was increased by >300%. Permeability for large solutes was less in the ad beta (1) than in t he other hyperoxia groups. Glutathione oxidation, but not superoxide dismut ase activity, was increased only in the ad beta (1) group. Survival through 14 days of hyperoxia was 100% in the ad beta (1) group but was not differe nt from hyperoxic controls in animals given ad alpha (1). Our data show tha t overexpression of a beta (1) Na+/K+-ATPase subunit augments AFC and impro ves survival in this model of acute lung injury via antioxidant-independent mechanisms. Conceivably, restoration of AFC via gene transfer of Na+/K+-AT Pase subunit genes may prove useful for the treatment of acute lung injury and pulmonary edema.