Decreased expression of both the α1- and α2-subunits of the Na-K-ATPase reduces maximal alveolar epithelial fluid clearance

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Abstract
Impaired epithelial sodium channel function predisposes to delayed resorption of pulmonary edema and more severe experimental lung injury, whereas even a small fraction of the normal Na-K-ATPase activity is thought to be sufficient to maintain normal ion transport. However, direct proof is lacking. Therefore, we studied baseline and cAMP stimulated alveolar fluid clearance (AFC) in mice with a 50% decrease in lung protein expression of the α1- and/or α2-subunit of the Na-K-ATPase. There was no difference in basal and stimulated AFC in α1+/−or α2+/−mice compared with wild-type littermates. Also, the compound heterozygous mice (α1+/−/α2+/−) had normal basal AFC. However, the combined α1+/−/α2+/−mice showed a significant decrease in cAMP-stimulated AFC compared with wild-type littermates (11.1 ± 1.0 vs. 14.9 ± 1.8%/30 min, P < 0.001). When exposed to 96 h of >95% hyperoxia, the decrease in stimulated AFC in the α1+/−/α2+/−mice was not associated with more lung edema compared with wild-type littermates (lung wet-to-dry weight ratio 6.6 ± 0.9 vs. 5.9 ± 1.1, respectively; P = not significant). Thus a 50% decrease in protein expression of the α1- or α2-subunits of the Na-K-ATPase does not impair basal or stimulated AFC. However, a 50% protein reduction in both the α1- and α2-subunits of the Na-K-ATPase produces a submaximal stimulated AFC, suggesting a synergistic role for α1- and α2-subunits in cAMP-dependent alveolar epithelial fluid clearance.