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Na,K-ATPase Gene Transfer Increases Liquid Clearance during Ventilation-induced Lung Injury

Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, and Evanston Northwestern Healthcare, Evanston, Illinois

Correspondence and requests for reprints should be addressed to Jacob I. Sznajder, M.D., Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, 303 East Chicago, Tarry 14-707, Chicago, IL 60611. E-mail: j-sznajder{at}northwestern.edu

Mechanical ventilation with high tidal volumes (HV_T) downregulates alveolar Na,K-ATPase function and impairs lung liquid clearance. We hypothesized that overexpression of Na,K-ATPase in the alveolar epithelium could counterbalance these changes and increase clearance in a rat model of mild ventilation-induced lung injury. We used a surfactant-based system to deliver 4 x 10⁹ plaque-forming units of E1a^-/E3^- recombinant adenovirus containing either a rat ß₁ Na,K-ATPase subunit cDNA (adß₁) or no cDNA (adnull) to rat lungs 7 days before ventilation with a V_T of approximately 40 ml/kg (peak airway pressure of less than 35 cm H₂O) for 40 minutes. Lung liquid clearance and Na, K-ATPase activity and protein abundance were increased in HV_T adß₁-infected lungs as compared with sham and adnull-infected HV_T lungs. These results suggest that Na,K-ATPase subunit gene overexpression in the alveolar epithelium increases Na,K-ATPase function and lung liquid clearance in a model of HV_T. We provide here the first evidence that using a genetic approach improves active Na⁺ transport and thus liquid clearance in the setting of mild ventilation-induced lung injury.

Key Words: gene therapy • ventilation-induced lung injury • Na,K-ATPase

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