Fibrinolytic Regulation of Pulmonary Epithelial Sodium Channels: a Critical Review

Luminal fluid homeostasis in the respiratory system is crucial to maintain the gas-

blood exchange in normal lungs and mucociliary clearance in the airways. Epithelial

sodium channels (ENaC) govern ~70% of alveolar fluid clearance. Four ENaC subunits

have been cloned, namely, ?, ?, ?, and ? ENaC subunits in mammalian cells. This

critical review focuses on the expression and function of ENaC in human and murine

lungs, and the post-translational regulation by fibrinolysins. Nebulized urokinase was

intratracheally delivered for clinical models of lung injury with unknown mechanisms.

The central hypothesis is that proteolytically cleaved ENaC channels composed of four

subunits are essential pathways to maintain fluid homeostasis in the airspaces, and that

fibrinolysins are potential pharmaceutical ENaC activators to resolve edema fluid. This

hypothesis is strongly supported by our following observations: 1) ? ENaC is expressed

in the apical membrane of human lung epithelial cells; 2) ? ENaC physically interacts

with the other three ENaC counterparts; 3) the features of ??? ENaC channels are

conferred by ? ENaC; 4) urokinase activates ENaC activity; 5) urokinase deficiency is

associated with a markedly distressed pulmonary ENaC function in vivo; 6) ? ENaC is

proteolytically cleaved by urokinase; 7) urokinase augments the density of opening

channels at the cell surface; and 8) urokinase extends opening time of ENaC channels

to the most extent. Our integrated publications laid the groundwork for an innovative

concept of pulmonary transepithelial fluid clearance in both normal and diseased lungs.