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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL034322-11A1
Application #
5213547
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
1996
Total Cost
Indirect Cost
Schultz, André; Puvvadi, Ramaa; Borisov, Sergey M et al. (2017) Airway surface liquid pH is not acidic in children with cystic fibrosis. Nat Commun 8:1409
Blackmon, R L; Kreda, S M; Sears, P R et al. (2017) Direct monitoring of pulmonary disease treatment biomarkers using plasmonic gold nanorods with diffusion-sensitive OCT. Nanoscale 9:4907-4917
Esther Jr, Charles R; Turkovic, Lidija; Rosenow, Tim et al. (2016) Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis. Eur Respir J 48:1612-1621
Blackmon, Richard L; Kreda, Silvia M; Sears, Patrick R et al. (2016) Diffusion-sensitive optical coherence tomography for real-time monitoring of mucus thinning treatments. Proc SPIE Int Soc Opt Eng 9697:
Tyrrell, Jean; Qian, Xiaozhong; Freire, Jose et al. (2015) Roflumilast combined with adenosine increases mucosal hydration in human airway epithelial cultures after cigarette smoke exposure. Am J Physiol Lung Cell Mol Physiol 308:L1068-77
Esther Jr, Charles R; Coakley, Raymond D; Henderson, Ashley G et al. (2015) Metabolomic Evaluation of Neutrophilic Airway Inflammation in Cystic Fibrosis. Chest 148:507-515
Åstrand, Annika B M; Hemmerling, Martin; Root, James et al. (2015) Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition. Am J Physiol Lung Cell Mol Physiol 308:L22-32
Bove, Peter F; Dang, Hong; Cheluvaraju, Chaitra et al. (2014) Breaking the in vitro alveolar type II cell proliferation barrier while retaining ion transport properties. Am J Respir Cell Mol Biol 50:767-76
Esther Jr, Charles R; Boucher, Richard C; Johnson, M Ross et al. (2014) Airway drug pharmacokinetics via analysis of exhaled breath condensate. Pulm Pharmacol Ther 27:76-82
Mellnik, John; Vasquez, Paula A; McKinley, Scott A et al. (2014) Micro-heterogeneity metrics for diffusion in soft matter. Soft Matter 10:7781-96

Showing the most recent 10 out of 229 publications