The mechanisms that regulate alveolar epithelial salt and water transport, play a major role in determining lung fluid balance in patients with pulmonary edema and acute respiratory failure. Clinical studies have demonstrated that patients with impaired lung epithelial fluid transport have worse clinical outcomes. Although considerable progress has been made in understanding the basic salt and water transport mechanisms that regulate epithelial fluid transport in the lung, more work is needed to understand the cell specific and ion specific transporting function of the distal lung epithelium. In this renewal application, three aims are designed to identify new mechanisms that regulate fluid transport across the distal epithelium of the lung.
Aim 1 will test the hypothesis that CFTR dependent chloride transport plays a major role in regulating cAMP mediated fluid clearance from the distal air spaces of lung. Using a novel in vitro epithelial fluid transport model, the experiments will test the role of CFTR in alveolar epithelial type I and type II cells as well as in an important distal airway epithelial cell, the Clara cell. Intact lung studies in CFTR deficient mice will also be done under pathologically relevant conditions (sepsis and hyperoxia).
Aim 2 will examine how moderate hypoxia decreases fluid transport from the distal air spaces of the lung, testing the hypothesis that impaired trafficking of ENaC to the apical membrane and Na,K-ATPase subunits to the basolateral membrane of alveolar type II cells impairs fluid transport.
This aim will also test the mechanism by which cAMP agonist therapy reverses the depressant effect of hypoxia on lung epithelial fluid clearance.
Aim 3 will determine if endogenous production of nitric oxide downregulates cAMP stimulated epithelial fluid clearance in clinically relevant models of acute lung injury, including vascular endothelial growth factor induced pulmonary edema as well as in ventilator associated lung injury. Overall, these studies will provide important new insights into the basic mechanisms that regulate epithelial fluid transport and lung fluid balance in the normal and the injured lung.
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