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

Hill, Michael and Philp, Christopher J. and Billington, Charlotte K. and Tatler, Amanda L. and Johnson, Simon R. and O'Dea, Reuben D. and Brook, Bindi S. (2018) A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling. Biomechanics and Modeling in Mechanobiology . ISSN 1617-7940

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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.

Item Type: Article
RIS ID: https://nottingham-repository.worktribe.com/output/944824
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Respiratory Medicine
University of Nottingham, UK > Faculty of Science > School of Mathematical Sciences
Identification Number: https://doi.org/10.1007/s10237-018-1037-4
Depositing User: Hill, Michael
Date Deposited: 19 Jun 2018 13:35
Last Modified: 04 May 2020 19:44
URI: http://eprints.nottingham.ac.uk/id/eprint/52504

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