Alveolar Type 1 Cells Express the α2 Na,K-ATPase, Which Contributes to Lung Liquid Clearance

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Abstract
The alveolar epithelium is composed of alveolar type 1 (AT1) and alveolar type 2 (AT2) cells, which represent ≈95% and ≈5% of the alveolar surface area, respectively. Lung liquid clearance is driven by the osmotic gradient generated by the Na,K-ATPase. AT2 cells have been shown to express the α1 Na,K-ATPase. We postulated that AT1 cells, because of their larger surface area, should be important in the regulation of active Na+ transport. By immunofluorescence and electron microscopy, we determined that AT1 cells express both the α1 and α2 Na,K-ATPase isoforms. In isolated, ouabain-perfused rat lungs, the α2 Na,K-ATPase in AT1 cells mediated 60% of the basal lung liquid clearance. The β-adrenergic agonist isoproterenol increased lung liquid clearance by preferentially upregulating the α2 Na,K-ATPase protein abundance in the plasma membrane and activity in alveolar epithelial cells (AECs). Rat AECs and human A549 cells were infected with an adenovirus containing the rat Na,K-ATPase α2 gene (Adα2), which resulted in the overexpression of the α2 Na,K-ATPase protein and caused a 2-fold increase in Na,K-ATPase activity. Spontaneously breathing rats were also infected with Adα2, which increased α2 protein abundance and resulted in a ≈250% increase in lung liquid clearance. These studies provide the first evidence that α2 Na,K-ATPase in AT1 cells contributes to most of the active Na+ transport and lung liquid clearance, which can be further increased by stimulation of the β-adrenergic receptor or by adenovirus-mediated overexpression of the α2 Na,K-ATPase.