Overexpression of the Na-K-ATPase alpha2-subunit improves lung liquid clearance during ventilation-induced lung injury.
Mechanical ventilation with high tidal volumes (HV(T)) impairs lung liquid clearance (LLC) and downregulates alveolar epithelial Na-K-ATPase. We have previously reported that the Na-K-ATPase alpha(2)-subunit contributes to LLC in normal rat lungs. Here we tested whether overexpression of Na-K-ATPase alpha(2)-subunit in the alveolar epithelium would increase clearance in a HV(T) model of lung injury. We infected rat lungs with a replication-incompetent adenovirus that expresses Na-K-ATPase alpha(2)-subunit gene (Adalpha(2)) 7 days before HV(T) mechanical ventilation. HV(T) ventilation decreased LLC by approximately 50% in untreated, sham, and Adnull-infected rats. Overexpression of Na-K-ATPase alpha(2)-subunit prevented the decrease in clearance caused by HV(T) and was associated with significant increases in Na-K-ATPase alpha(2) protein abundance and activity in peripheral lung basolateral membrane fractions. Ouabain at 10(-5) M, a concentration that inhibits the alpha(2) but not the Na-K-ATPase alpha(1), decreased LLC in Adalpha(2)-infected rats to the same level as sham and Adnull-infected lungs, suggesting that the increased clearance in Adalpha(2) lungs was due to Na-K-ATPase alpha(2) expression and activity. In summary, we provide evidence that augmentation of the Na-K-ATPase alpha(2)-subunit, via gene transfer, may accelerate LLC in the injured lung.
Adir
Yochai
Y
Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 240 E. Huron, McGaw M300, Chicago, IL 60611, USA.
Welch
Lynn C
LC
Dumasius
Vidas
V
Factor
Phillip
P
Sznajder
Jacob I
JI
Ridge
Karen M
KM
D000818:Animals; D015633:Extravascular Lung Water / Q000378:metabolism*; D018014:Gene Transfer Techniques; D008171:Lung Diseases / Q000188:drug therapy / Q000503:physiopathology*; D011650:Pulmonary Alveoli / Q000502:physiology; D051381:Rats; D012121:Respiration, Artificial / Q000009:adverse effects*; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis*
C498532:Atp1a2 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase