Submitted on February 27, 2007
Accepted on April 9, 2008
Overexpression of the Na,K-ATPase 
2 subunit improves lung liquid clearance during ventilation-induced lung injury
Yochai Adir1, Lynn C Welch2, Vidas Dumasius2, Phillip Factor3, Jacob Iasha Sznajder2, and Karen M. Ridge2*
1 Technion-Israel Institute of Technology, Israel
2 Pulmonary and Critical Care, Northwestern Unversity, Chicago, Illinois, United States
3 Medicine, Columbia University, New York, United States
* To whom correspondence should be addressed. E-mail: kridge{at}northwestern.edu.
Mechanical ventilation with high tidal volumes (HVT) impairs lung liquid clearance (LLC) and downregulates alveolar epithelial Na,K-ATPase. We have previously reported that the Na,K-ATPase 
2 subunit contributes to LLC in normal rat lungs. Here we tested whether overexpression of Na,K-ATPase 2 subunit in the alveolar epithelium would increase clearance in a HVT model of lung injury. We infected rat lungs with a replication incompetent adenovirus that expresses Na,K-ATPase 2 subunit gene (Ad2) 7 days prior to HVT mechanical ventilation. HVT ventilation decreased LLC by ~50% in untreated, sham and Adnull infected rats. Overexpression of Na,K-ATPase 2 subunit, prevented the decrease in clearance caused by HVT and was associated with significant increases in Na,K-ATPase 2 protein abundance and activity in peripheral lung Basolateral membrane fractions. Ouabain at 10-5 M, a concentration that inhibits the 2 but not the Na,K-ATPase 1, decreased LLC in Ad2 infected rats to the same level as sham and Adnull infected lungs suggesting that the increased clearance in Ad2 lungs was due to Na,K-ATPase 2 expression and activity. In summary, we provide evidence that augmentation of the Na,K-ATPase 2 subunit, via gene transfer, may accelerate LLC in the injured lung.
