Oxidized glutathione regulation of epithelial sodium channels in newborn lung injury

项目总结/摘要 上皮钠通道（ENaC）是从空气中净盐和水去除的限速步骤 通过产生渗透梯度用于随后的水运输。在肺中，ENaC的调节是微调的， 因此，一定量的水不断地衬在气道上皮细胞上， 潮湿，以便进行有效的气体交换。在一些肺损伤患者中，尚不清楚为什么肺ENaC不能发挥功能。 正常的ENaC活性对早产儿至关重要，因为他们出生时肺部不成熟， ENaC蛋白，通常需要补充氧气。在这项研究中，我们观察氧气是否 补充（高氧）通过关闭ENaC来混淆肺损伤。我们使用一个长期的小鼠模型， 在我们的研究中，高氧诱导氧化应激。我们的理论是，在高氧下，抗氧化剂 谷胱甘肽被氧化成其二硫化物形式，称为GSSG。我们的初步数据表明，GSSG可以改变 ENaC通过直接翻译后修饰ENaC上保守的Cys巯基来发挥功能，尽管修饰的Cys巯基在ENaC上的表达是不稳定的。 Cys尚未映射。GSSG是否在生物相关的高氧模型下改变ENaC 尚未评价诱导的肺损伤。我们的目标是描绘生物相关的翻译后 通过GSSG修饰肺ENaC，并确定降低肺GSSG水平是否可以改善健康 需要补充氧气的早产儿的结局。

Project Summary/Abstract 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.