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

直到妊娠结束，胎儿的气道和肺泡发育 肺由Cl-运输驱动液体分泌而膨胀 穿过肺上皮 出生时，血液循环的增加 儿茶酚胺减缓液体分泌并刺激Na+驱动的吸收 液体，从而清除空气空间。 我们理解 离子转运机制控制肺的产生和清除 液体有限。 因为CF胎儿肺的液体产生是正常的， 但成人CF肺的气道以Cl-分泌缺陷为特征 和过度活跃的Na+吸收，离子流穿过胎儿的路径 肺上皮可能与成人不同。 我们假设 1）胎儿肺中可能存在独特的Cl-分泌通道，2） 嘌呤受体介导的Cl-分泌调节起着重要作用 在胎儿肺的基础液体产生中，和3）环境气体（O2）， 激素（T3和皮质醇）通过控制Na+吸收来调节Na+吸收 阿米洛利可降解通道ENaC亚基的表达。 我们将 评估这些假设1）通过测量液体分泌和生物电 与Cl-转运相关的性质（经上皮PD和 电导、顶膜和基底膜离子电导和驱动 力，单通道Cl-特性） 来源于人肺的气道和肺泡前区和CFTR（+/-） 和（-/-）转基因小鼠; 2）嘌呤受体的局部个体发育 表达和药理学刺激功能 和新生儿肺中嘌呤受体诱导的第二信使的变化 嘌呤能影响的跨上皮离子流的占有率、路径 刺激，并测定核苷酸及其分解产物， 胎肺液; 3）定位ENaC亚基的区域个体发生 胎儿和新生儿肺中的表达以及O2、T3和 皮质类固醇对这种分布的影响，并通过测量Na+吸收， 用ENaC“敲除”或ENaC再表达的转基因小鼠的肺。 的 从这些研究中获得的知识有望揭示 肺液体平衡失调在早产儿肺部疾病中的作用 并提出了通过重新激活胎儿细胞来治疗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.