CL- SECRETION AND NA+ ABSORPTION BY FETAL AND NEWBORN LUNG

直到妊娠结束，胎儿的呼吸道和肺泡发育 肺由氯离子转运驱动的液体分泌而膨胀。 穿过肺上皮细胞。在出生时，血液循环的增加 儿茶酚胺减缓液体分泌并刺激钠离子驱动的吸收 液体，从而清理空气空间。我们对这一现象的理解 控制肺产生和清除的离子转运机制 液体是有限的。因为CF胎肺的液体产生是正常的， 但成人CF肺的呼吸道以氯离子分泌缺陷为特征 和过度的Na+吸收，离子流经胎儿的路径 肺上皮可能与成人的不同。我们假设 1)胎肺可能存在唯一的氯离子分泌通道(S)，2) 嘌呤受体介导的氯离子分泌调节具有重要作用 在胎肺的基础液体生产中，3)环境气体(O2)和 激素(T3和皮质醇)通过调控调节Na+吸收 阿米洛利可抑制通道ENaC亚单位的表达。我们会 评估这些假说1)通过测量液体分泌物和生物电 与氯-转运相关的特性(跨上皮PD和 电导、根尖和基侧膜离子电导和驱动 外植体、单层和细胞的力、单通道氯离子特性) 来源于人肺的呼吸道和肺泡前区及CFTR(+/-) 和(-/-)转基因小鼠，2)来自嘌呤受体的区域个体发育 胎儿上皮细胞的表达及药物刺激功能 和新生儿肺，嘌呤受体引起的第二信使的变化 嘌呤能对跨上皮细胞离子流途径的影响 刺激和核苷酸及其分解产物的分析 3)定位ENaC亚单位的区域个体发生 胎儿和新生儿肺组织的表达及O2、T3和 皮质类固醇在这一分布上的作用，并通过测量Na+的吸收 ENaC“敲除”或过度表达的转基因小鼠的肺。这个 从这些研究中获得的知识有望为 肺液平衡障碍在早产儿肺部疾病中的作用 并提出了通过胎儿再激活来治疗CF的新方法 成人肺上皮细胞的突起。

Until the end of gestation, developing airways and alveoli of the fetal lung are inflated by liquid secretion that is driven by Cl- transport across pulmonary epithelia. At birth, the rise in circulating catecholamines slows liquid secretion and stimulates Na+-driven absorption of liquid, thereby clearing the airspaces. Our understanding of the mechanisms of ion transport that control production and clearance of lung liquid is limited. Because liquid production by CF fetal lung is normal, but airways of adult CF lung are characterized by defective Cl- secretion and overactive Na+ absorption, paths of ion flow across the fetal pulmonary epithelium may differ from those of the adult. We hypothesize that 1) a unique channel(s) for Cl- secretion may exist in fetal lung, 2) purinoceptor-mediated regulation of Cl- secretion plays an important role in basal liquid production by fetal lung, and 3) ambient gases (O2) and hormones (T3 and cortisol) regulation Na+ absorption by controlling expression of subunits of an amiloride-inhibitable channel, ENaC. We will evaluate these hypotheses 1) by measuring liquid secretion and bioelectric properties associated with Cl- transport (transepithelial PD and conductance, apical and basolateral membrane ion conductances and driving forces, single channel Cl- properties) of explants, monolayers, and cells derived from airways and prealveolar regions of human lung and CFTR (+/-) and (-/-) transgenic mice, 2) from regional ontogeny of purinoceptor expression and pharmacologically-stimulated function in epithelia of fetal and neonatal lung, the change in second messengers induced by purinoceptor occupancy, paths of transepithelial ion flow affected by purinergic stimulation, and assays of nucleotides and their breakdown products in fetal lung liquid, and 3) by mapping regional ontogenesis of ENaC subunit expression in fetal and neonatal lung and the effect of O2, T3, and corticosteroids on this distribution, and by measuring Na+ absorption by lungs of transgenic mice with ENaC "knockout" or oveerexpression. The knowledge gained from these studies is expected to shed new light on the role of dysfunctional lung liquid balance in lung diseases of prematurity and to suggest novel methods of treating CF by reactivation of fetal processes in adult pulmonary epithelia.