title: A spatial model of fluid recycling in the airways of the lung.
abstract: The genetic disease cystic fibrosis (CF) is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and results in viscous mucus and impaired mucociliary clearance leading to chronic recurring pulmonary infections. Although extensive experimental research has been conducted over the last few decades, CF lung pathophysiology remains controversial. There are two competing explanations for the observed depletion of periciliary liquid (PCL) in CF lungs. The low volume hypothesis assumes fluid hyperabsorption through surface epithelia due to an over-active epithelial Na(+) channel (ENaC), and the low secretion hypothesis assumes inspissated mucins secreted from glands due to lack of serous fluid secreted from gland acini. We present a spatial mathematical model that reflects in vivo fluid recycling via submucosal gland (SMG) secretion, and absorption through surface epithelia. We then test the model in CF conditions by increasing ENaC open probability and decreasing SMG flux while simultaneously reducing CFTR open probability. Increasing ENaC activity only results in increased fluid absorption across surface epithelia, as seen in in vitro experiments. However, combining potential CF mechanisms results in markedly less fluid absorbed while providing the largest reduction in PCL volume, suggesting that a compromise in gland fluid secretion dominates over increased ENaC activity to decrease the amount of fluid transported transcellularly in CF lungs in vivo. Model results also indicate that a spatial model is necessary for an accurate calculation of total fluid transport, as the effects of spatial gradients can be severe, particularly in close proximity to the SMGs.
authors.affiliation: Department of Mathematics, University of Auckland, 23 Princes St, Auckland CBD, Auckland 1010, New Zealand. Electronic address: ktsharp@xtra.co.nz.
authors.forename: Katie
authors.initials: K
authors.lastname: Sharp
authors.affiliation: Department of Biomedical Engineering, Level 4, University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: Edmund
authors.initials: E
authors.lastname: Crampin
authors.affiliation: Department of Mathematics, University of Auckland, 23 Princes St, Auckland CBD, Auckland 1010, New Zealand.
authors.forename: James
authors.initials: J
authors.lastname: Sneyd
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D001692:Biological Transport; D001826:Body Fluids / Q000378:metabolism*; D003198:Computer Simulation; D003550:Cystic Fibrosis / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000378:metabolism; D007477:Ions / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008564:Membrane Potentials; D008954:Models, Biological; D015203:Reproducibility of Results; D019108:Tight Junctions / Q000378:metabolism; D013997:Time Factors; D014867:Water / Q000378:metabolism
chemical_list: D007473:Ion Channels; D007477:Ions; D014867:Water; D000584:Amiloride
keywords: Cystic fibrosis; Fluid and ion transport; Ion channels; Submucosal glands