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A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling

Hill, Michael; Philp, Christopher J.; Billington, Charlotte K.; Tatler, Amanda L.; Johnson, Simon R.; O'Dea, Reuben D.; Brook, Bindi S.

Authors

Michael Hill michael.hill1@nottingham.ac.uk

Christopher J. Philp christopher.philp@nottingham.ac.uk

Charlotte K. Billington

SIMON JOHNSON simon.johnson@nottingham.ac.uk
Professor of Respiratory Medicine



Abstract

Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. Our model predictions are consistent with previously described inflammation-induced remodelling within an axisymmetric airway geometry. Additionally, our simulations reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and procontractile cytokines. Simulation results also reveal emergence of a persistent contractile tone observed in asthmatics, via either a pathological mechanotransductive feedback loop, a failure to clear agonists from the tissue, or a combination of both. Furthermore, we identify various parameter combinations that may contribute to the existence of different asthma phenotypes, and we illustrate a combination of factors which may predispose severe asthmatics to fatal bronchospasms.

Citation

Hill, M., Philp, C. J., Billington, C. K., Tatler, A. L., Johnson, S. R., O'Dea, R. D., & Brook, B. S. (in press). A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling. Biomechanics and Modeling in Mechanobiology, https://doi.org/10.1007/s10237-018-1037-4

Journal Article Type Article
Acceptance Date May 22, 2018
Online Publication Date Jul 2, 2018
Deposit Date Jun 19, 2018
Publicly Available Date Jul 2, 2018
Journal Biomechanics and Modeling in Mechanobiology
Print ISSN 1617-7959
Electronic ISSN 1617-7940
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1007/s10237-018-1037-4
Public URL http://eprints.nottingham.ac.uk/id/eprint/52504
Publisher URL https://link.springer.com/article/10.1007%2Fs10237-018-1037-4
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

Files

Hill2018_Article_ATheoreticalModelOfInflammatio.pdf (3.7 Mb)
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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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