LUNG EPITHELIAL ION TRANSPORT AFTER PREMATURE BIRTH

肺水肿是新生儿呼吸窘迫综合征一贯的病理特征，当液体进入肺部的速度大于液体清除的速度时，就会发生肺水肿。肺水肿会减少肺容量，损害氧合，增加对呼吸支持的需求。以前的研究已经阐明，早产后的呼吸衰竭与过多的液体和蛋白质进入肺内，从而导致肺泡泛滥有关。目前尚不清楚肺部液体清除延迟是否是新生儿呼吸窘迫综合征中导致肺水肿的另一个因素。由于跨上皮离子运动至少部分负责液体从远端空间的清除，我们假设异常的肺上皮离子传输通过延迟液体从远端空间的清除而导致肺泡水肿。我们的长期目标是提高我们对早产后导致呼吸衰竭的机制的理解。在这项建议中，我们的研究将包括评估远端肺上皮细胞的跨膜Na和Cl通量和Na-K-ATPase活性，以及离子转运变化的分子基础。我们计划(L)确定中性粒细胞损害肺上皮细胞离子转运的机制；(2)表征肺表面活性物质诱导的肺上皮离子转运的变化；(3)评估一氧化氮在早产前后调节肺上皮细胞氯分泌功能中的作用；(4)确定早产呼吸窘迫综合征时肺上皮细胞是否存在钠和氯转运以及Na-K-ATPase活性异常；以及(5)确定出生时更换表面活性物质是否有利于影响肺上皮细胞的钠和氯转运以及Na-K-ATPase活性。我们预测，在新生儿呼吸窘迫综合征发病机制中起重要作用的因素会损害钠转运，降低Na-K-ATPase活性，并促进出生后氯的分泌活性。我们的期望是，对早产后导致肺水肿和呼吸衰竭的因素有更全面的了解，将提高我们设计战略和干预措施的能力，以减轻新生儿呼吸窘迫的严重程度，并减少与此相关的不良后果。

Pulmonary edema is a consistent pathological feature of the neonatal respiratory distress syndrome and it occurs when fluid enters the, lung at a rate greater than the rate at which fluid is cleared. Pulmonary edema reduces lung volume, impairs oxygenation, and increases the need for respiratory support. Previous studies have clarified that respiratory failure after premature birth is associated with excess fluid and protein entry into the lung with resultant alveolar flooding. It is unclear whether delayed clearance of fluid from the lung is an additional factor contributing to lung edema in the neonatal respiratory distress syndrome. Because transepithelial ion movement is responsible, at least in part, for clearance of fluid from the distal airspace, we hypothesize that abnormal lung epithelial ion transport contributes to alveolar edema by delaying fluid clearance from the distal airspaces. Our long-term goal is to improve our understanding of the mechanisms that contribute to respiratory failure after premature birth. In this proposal, our studies will include assessment of transmembrane Na and Cl flux and Na-K-ATPase activity in distal lung epithelial cells as well as the molecular bases for alterations in ion transport. We plan to (l) define the mechanism by which neutrophils impair ion transport in lung epithelial cells; (2) characterize the changes in lung epithelial ion transport that are induced by pulmonary surfactant; (3) evaluate the role of nitric oxide in regulating Cl secretory function in lung epithelium around the time of premature birth; (4) determine if Na and Cl transport and Na-K-ATPase activity are abnormal in lung epithelial cells in the respiratory distress syndrome of prematurity; and (5) determine if surfactant replacement at birth favorably influences Na and Cl transport and Na-K-ATPase activity in lung epithelial cells. We predict that factors important in the pathogenesis of neonatal respiratory distress syndrome impair Na transport, decrease Na-K-ATPase activity, and promote postnatal Cl secretory activity. Our expectation is that a more complete understanding of the factors that contribute to pulmonary edema and respiratory failure after premature birth will improve our ability to design strategies and interventions that will reduce the severity of neonatal respiratory distress and diminish the adverse outcomes associated with this condition.