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Title: Fibrinolytic regulation of pulmonary epithelial sodium channels : a critical review
Author: Ji, Hong-Long
ISNI:       0000 0004 5989 4555
Awarding Body: University of Kent
Current Institution: University of Kent
Date of Award: 2015
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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, α, β, γ, and δ 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) δ ENaC is expressed in the apical membrane of human lung epithelial cells; 2) δ ENaC physically interacts with the other three ENaC counterparts; 3) the features of αβγ ENaC channels are conferred by δ ENaC; 4) urokinase activates ENaC activity; 5) urokinase deficiency is associated with a markedly distressed pulmonary ENaC function in vivo; 6) γ 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.
Supervisor: Michaelis, Martin ; von der Haar, Tobias Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science