title: Decreased expression of both the alpha1- and alpha2-subunits of the Na-K-ATPase reduces maximal alveolar epithelial fluid clearance.
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 alpha(1)- and/or alpha(2)-subunit of the Na-K-ATPase. There was no difference in basal and stimulated AFC in alpha(1)(+/-) or alpha(2)(+/-) mice compared with wild-type littermates. Also, the compound heterozygous mice (alpha(1)(+/-)/alpha(2)(+/-)) had normal basal AFC. However, the combined alpha(1)(+/-)/alpha(2)(+/-) 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 alpha(1)(+/-)/alpha(2)(+/-) 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 alpha(1)- or alpha(2)-subunits of the Na-K-ATPase does not impair basal or stimulated AFC. However, a 50% protein reduction in both the alpha(1)- and alpha(2)-subunits of the Na-K-ATPase produces a submaximal stimulated AFC, suggesting a synergistic role for alpha(1)- and alpha(2)-subunits in cAMP-dependent alveolar epithelial fluid clearance.
authors.affiliation: Cardiovascular Research Institute and the Department of Medicine and Anesthesia, University of California, San Francisco, 94143-0130, USA. mlooney@itsa.ucsf.edu
authors.forename: Mark R
authors.initials: MR
authors.lastname: Looney
authors.forename: Claudio
authors.initials: C
authors.lastname: Sartori
authors.forename: Santanu
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Paul F
authors.initials: PF
authors.lastname: James
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology*; D045604:Extracellular Fluid / Q000378:metabolism*; D005786:Gene Expression Regulation; D018496:Hyperoxia / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D011654:Pulmonary Edema / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000242:Cyclic AMP; C401838:Atp1a2 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase