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

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...

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Main Authors:	Hill, Michael, Philp, Christopher J., Billington, Charlotte K., Tatler, Amanda L., Johnson, Simon R., O'Dea, Reuben D., Brook, Bindi S.
Format:	Article
Language:	English
Published:	Springer Verlag 2018
Online Access:	http://eprints.nottingham.ac.uk/52504/ http://eprints.nottingham.ac.uk/52504/ http://eprints.nottingham.ac.uk/52504/ http://eprints.nottingham.ac.uk/52504/9/Hill2018_Article_ATheoreticalModelOfInflammatio.pdf

id	nottingham-52504
recordtype	eprints
spelling	nottingham-525042018-07-13T10:00:11Z http://eprints.nottingham.ac.uk/52504/ 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. 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. Springer Verlag 2018-07-02 Article PeerReviewed application/pdf en cc_by http://eprints.nottingham.ac.uk/52504/9/Hill2018_Article_ATheoreticalModelOfInflammatio.pdf 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 https://link.springer.com/article/10.1007%2Fs10237-018-1037-4 doi:10.1007/s10237-018-1037-4 doi:10.1007/s10237-018-1037-4
repository_type	Digital Repository
institution_category	Local University
institution	University of Nottingham Malaysia Campus
building	Nottingham Research Data Repository
collection	Online Access
language	English
description	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.
format	Article
author	Hill, Michael Philp, Christopher J. Billington, Charlotte K. Tatler, Amanda L. Johnson, Simon R. O'Dea, Reuben D. Brook, Bindi S.
spellingShingle	Hill, Michael Philp, Christopher J. Billington, Charlotte K. Tatler, Amanda L. Johnson, Simon R. O'Dea, Reuben D. Brook, Bindi S. A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling
author_facet	Hill, Michael Philp, Christopher J. Billington, Charlotte K. Tatler, Amanda L. Johnson, Simon R. O'Dea, Reuben D. Brook, Bindi S.
author_sort	Hill, Michael
title	A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling
title_short	A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling
title_full	A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling
title_fullStr	A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling
title_full_unstemmed	A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling
title_sort	theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling
publisher	Springer Verlag
publishDate	2018
url	http://eprints.nottingham.ac.uk/52504/ http://eprints.nottingham.ac.uk/52504/ http://eprints.nottingham.ac.uk/52504/ http://eprints.nottingham.ac.uk/52504/9/Hill2018_Article_ATheoreticalModelOfInflammatio.pdf
first_indexed	2018-09-06T14:27:35Z
last_indexed	2018-09-06T14:27:35Z
_version_	1610868647221264384

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

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