Epithelial sodium channels (ENaC) serve as the rate limiting step in net salt and water removal from the airspace by generating osmotic gradients for subsequent water transport. In the lung, the regulation of ENaC is fine-tuned so that a precise volume of water continually lines the airway epithelium, which keeps the lungs appropriately moist for effective gas exchange. In some patients with lung injury, it is not clear why lung ENaC fails to function. Normal ENaC activity is critically important in preterm infants, since they are born with immature lung, low levels of ENaC protein, and often require oxygen supplementation. In this study, we look at whether oxygen supplementation (hyperoxia) confounds lung injury by turning off ENaC. We use a term mouse model of hyperoxia induced oxidative stress in our studies. Our rationale is that under high oxygen, the antioxidant glutathione is oxidized to its disulfide form, termed GSSG. Our preliminary data indicates that GSSG can alter ENaC function through direct post translational modification of conserved Cys thiols on ENaC, albeit the modified Cys have not been mapped. Whether GSSG modifies ENaC under a biologically relevant model of hyperoxia induced lung injury has not been evaluated. Our goal is to delineate biologically relevant post-translational modification of lung ENaC by GSSG and determine whether lowering lung GSSG levels can improve health outcomes for preterm infants requiring oxygen supplementation.
(Public Health Interest) Epithelial sodium channels (ENaC) in the lung serves as the rate limiting step for moving salt and water out of the airspace, across layers of cells, and back into the body circulation. In some lung injury patients, ENaC activity turns off and the lung stays wet (in newborns) or floods (adult lung). This proposal evaluates the molecular mechanisms that regulate ENaC activity using a biologically relevant model of lung injury and explores potential new avenues of restoring ENaC activity under prolonged oxidative stress to improve lung function.
