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Am J Physiol Lung Cell Mol Physiol 289: L104-L110, 2005. First published March 18, 2005; doi:10.1152/ajplung.00464.2004
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Decreased expression of both the {alpha}1- and {alpha}2-subunits of the Na-K-ATPase reduces maximal alveolar epithelial fluid clearance

Mark R. Looney,1,* Claudio Sartori,1,* Santanu Chakraborty,2 Paul F. James,2 Jerry B. Lingrel,3 and Michael A. Matthay1

1Cardiovascular Research Institute and the Departments of Medicine and Anesthesia, University of California, San Francisco, California; 2Department of Zoology, Miami University, Oxford, Ohio; and 3Department of Molecular Genetics, University of Cincinnati, Cincinnati, Ohio

Submitted 13 December 2004 ; accepted in final form 13 March 2005

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.

pulmonary edema; acute lung injury; cAMP; sodium transport; alveolar epithelium



Address for reprint requests and other correspondence: M. R. Looney, Cardiovascular Research Inst., 505 Parnassus Ave., Box 0130, San Francisco, CA 94143-0130 (E-mail: mlooney{at}itsa.ucsf.edu)




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