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.
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