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Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7272-E7281. doi: 10.1073/pnas.1617383114. Epub 2017 Aug 14.

Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis.

Author information

1
Department of Biology, University of North Carolina at Pembroke, Pembroke, NC 28372; conner.sandefur@uncp.edu.
2
Marsico Lung Institute/University of North Carolina Cystic Fibrosis Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
3
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.

Abstract

Mucociliary clearance is composed of three components (i.e., mucin secretion, airway surface hydration, and ciliary-activity) which function coordinately to clear inhaled microbes and other foreign particles from airway surfaces. Airway surface hydration is maintained by water fluxes driven predominantly by active chloride and sodium ion transport. The ion channels that mediate electrogenic ion transport are regulated by extracellular purinergic signals that signal through G protein-coupled receptors. These purinoreceptors and the signaling pathways they activate have been identified as possible therapeutic targets for treating lung disease. A systems-level description of airway surface liquid (ASL) homeostasis could accelerate development of such therapies. Accordingly, we developed a mathematical model to describe the dynamic coupling of ion and water transport to extracellular purinergic signaling. We trained our model from steady-state and time-dependent experimental measurements made using normal and cystic fibrosis (CF) cultured human airway epithelium. To reproduce CF conditions, reduced chloride secretion, increased potassium secretion, and increased sodium absorption were required. The model accurately predicted ASL height under basal normal and CF conditions and the collapse of surface hydration due to the accelerated nucleotide metabolism associated with CF exacerbations. Finally, the model predicted a therapeutic strategy to deliver nucleotide receptor agonists to effectively rehydrate the ASL of CF airways.

KEYWORDS:

airway surface liquid; cystic fibrosis; mathematical modeling; purinergic signaling

PMID:
28808008
PMCID:
PMC5584404
DOI:
10.1073/pnas.1617383114
[Indexed for MEDLINE]
Free PMC Article

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