An integrated mathematical epithelial cell model for airway surface liquid regulation by mechanical forces

Dan Wu; Richard C Boucher; Brian Button; Timothy Elston; Ching-Long Lin

doi:10.1016/j.jtbi.2017.11.010

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An integrated mathematical epithelial cell model for airway surface liquid regulation by mechanical forces

Journal article

Peer reviewed

An integrated mathematical epithelial cell model for airway surface liquid regulation by mechanical forces

Dan Wu, Richard C Boucher, Brian Button, Timothy Elston and Ching-Long Lin

Journal of theoretical biology, Vol.438, pp.34-45

02/07/2018

DOI: 10.1016/j.jtbi.2017.11.010

PMCID: PMC5764545

PMID: 29154907

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https://www.ncbi.nlm.nih.gov/pmc/articles/5764545View

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Abstract

•An epithelial cell model for airway surface liquid(ASL) regulation was developed.•The cell model reproduces various responses similar to in vitro epithelial cells.•The cell model was tested with various mechanical forces and evaporative flux.•ASL homeostasis in both normal and cystic fibrosis airway epithelia were studied. A robust method based on reverse engineering was utilized to construct the ion-channel conductance functions for airway epithelial sodium channels (ENaC), the cystic fibrosis transmembrane conductance regulator (CFTR), and calcium-activated chloride channels (CaCC). The ion-channel conductance models for both normal (NL) and cystic fibrosis (CF) airway epithelia were developed and then coupled to an adenosine triphosphate (ATP) metabolism model and a fluid transport model (collectively called the integrated cell model) to investigate airway surface liquid (ASL) volume regulation and hence mucus concentration, by mechanical forces in NL and CF human airways. The epithelial cell models for NL and CF required differences in Cl− secretion (decreased in CF) and Na+ absorption (raised in CF) to reproduce behaviors similar to in vitro epithelial cells exposed to mechanical forces (cyclic shear stress, cyclic compressive pressure and cilial strain) and selected modulators of ion channels and ATP release. The epithelial cell models were then used to investigate the effects of mechanical forces and evaporative flux on ASL and mucus homeostasis in both NL and CF airway epithelia. Because of reduced CF ASL volumes, CF mucus concentrations increased and produced a greater dependence of ASL volume regulation on cilia-mucus-ATP release interactions in CF than NL epithelial nodules. Similarly, the CF model was less tolerant to evaporation induced ASL volume reduction at all ATP release rates than the NL model. Consequently, this reverse engineered model appears to provide a robust tool for investigating CF pathophysiology and novel therapies.

Airway epithelial cell

Airway surface liquid regulation

Cystic fibrosis

Evaporative flux

Mechanosensitive ion channels

Details

Title: Subtitle: An integrated mathematical epithelial cell model for airway surface liquid regulation by mechanical forces
Creators: Dan Wu - University of North Carolina at Chapel Hill
Richard C Boucher - University of North Carolina at Chapel Hill
Brian Button - University of North Carolina at Chapel Hill
Timothy Elston - University of North Carolina at Chapel Hill
Ching-Long Lin - University of Iowa
Resource Type: Journal article
Publication Details: Journal of theoretical biology, Vol.438, pp.34-45
DOI: 10.1016/j.jtbi.2017.11.010
PMID: 29154907
PMCID: PMC5764545
NLM abbreviation: J Theor Biol
ISSN: 0022-5193
eISSN: 1095-8541
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: R01-HL094315, S10-RR22421, U01-HL114494
Language: English
Date published: 02/07/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Mechanical Engineering
Record Identifier: 9984195169302771

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