Chapter 7 Regulation of Na,K-ATPase by Reactive Oxygen Species

Pulmonary edema occurs in patients with acute respiratory distress syndrome (ARDS) and congestive heart failure. Effective edema clearance is critical for these patients to survive. The edema clearance is carried out mostly by the coordination of the apical Na⁺ channels and the basolateral Na,K-ATPase effecting active Na⁺ transport. Downregulation of Na⁺ transport occurs frequently in ARDS patients and results in impaired edema clearance. Hypoxia, hyperoxia, particulate matter and thrombin inhibit edema clearance. Reactive oxygen species (ROS) generated from the electron transport chain in the mitochondria and/or NADPH oxidase appears to be critical for the impaired edema clearance under these stress conditions. During hypoxia, ROS activate PKCζ, which in turn phosphorylates Na,K-ATPase α₁ subunit at Ser-18, leading to the endocytosis of Na,K-ATPase from the plasma membrane. The endocytosis of Na,K-ATPase results in decreased Na,K-ATPase activity and can be prevented by antioxidants. We propose that ROS act as signaling molecules regulating the activity of Na,K-ATPase, which is important for alveolar fluid reabsorption. Further studies into the mechanisms by which Na,K-ATPase is regulated will be of importance for development of novel strategies for the treatment of edema patients.