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Hypoxia 2009 Speakers
Laura Dada
Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University. Chicago, IL
Email: lauradada@northwestern.edu
Talk Title: Hypoxia inhibition of alveolar fluid reabsorption
Session: Lung fluid movement in hypoxia
Abstract: Alveolar hypoxia occurs during ascent to high altitude and is also observed in patients with ARDS and acute hypoxemic respiratory failure, as a result of alveolar flooding and 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 from 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 it was shown by pharmacological and genetics approaches. Hypoxia and ROS promotes the PKC-zeta dependent phosphorylation of the Na,K-ATPase alpha subunit which triggers 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 lungs ability to clear pulmonary edema are needed. As such, better understanding of 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 regulate the Na-K-ATPase function and increase edema clearance.

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