• Laura A Dada and Jacob I Sznajder.
• Division of Pulmonary and Critical Care Medicine, Feinberg School ofMedicine, Northwestern University, Chicago, Illinois, USA. lauradada@northwestern.edu
• Adv Exp Med Biol. 2007 Jan 1;618:159-68.

AbstractAlveolar hypoxia occurs during ascent to high altitude and is also observed in patients with ARDS and acute hypoxemic respiratory failure, in which alveolar flooding is associated with a decrease in edema fluid clearance and increased mortality. The mechanisms that lead to the impairment of alveolar fluid clearance are not completely understood. Alveolar fluid reabsorption is accomplished mostly by active Na+ transport across the alveolar epithelium which creates an osmotic gradient responsible for the clearance of lung edema from the alveolar spaces. In vivo and in vitro hypoxia inhibits both the epithelial sodium channels, responsible for the apical sodium entry, and the basolateral Na,K-ATPase, responsible for Na+ extrusion. We have shown that acute hypoxia inhibits Na,K-ATPase function by promoting its endocytosis from the plasma membrane to intracellular compartments. This process is mediated by the generation of mitochondrial reactive oxygen species (ROS) as shown by pharmacological and genetic approaches. Hypoxia and ROS promote the PKC-zeta dependent phosphorylation of the Na,K-ATPase alpha subunit triggering its endocytosis in a clathrin-AP2 dependent process. The phosphorylation occurs at the Ser-18 in the alpha subunit N-terminus, and mutation of this serine prevents both the decrease in function and the endocytosis. More prolonged hypoxia causes the ubiquitination and degradation of Na,K-ATPase. Thus, methods that counterbalance the inhibition of edema clearance during hypoxia and improve the lung's ability to clear pulmonary edema are needed. As such, a better understanding of the mechanisms that increase Na,K-ATPase function, (i.e., activation of dopaminergic or adrenergic receptors, gene transfer) may lead to the development of therapeutic approaches to upregulate the Na-K-ATPase function and increase edema clearance.

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