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 pro-contractile 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.
Highlights
Asthma is a chronic lung disease characterized by inflammation, airway hyper-responsiveness and airway remodelling
Due to the possible effect of combination of the large number of parameters in this model and the large differences in remodelling that occur between inflammation and contractile agonist challenges, we chose to perform a series of paired parameter explorations
These are used to investigate the effect of repeated inflammatory episodes, and mechanical forces that arise from repeated airway smooth muscle (ASM) contractions, on long-term airway remodelling and effective mechanical properties of the airway
Summary
Asthma is a chronic lung disease characterized by inflammation, airway hyper-responsiveness (excessive bronchoconstriction in response to relatively low doses of contractile agonist; AHR) and airway remodelling The last of these involves a series of structural changes, including thickening of the epithelial layer and subepithelial basement membrane (SBM; the collagen-dominated inner layer of the airway) and of airway smooth muscle (ASM) bundles (Holgate 2011; Brightling et al 2012; James et al 2012; Berair et al 2013). To investigate the combined effect of repeated, short timescale, inflammatory episodes and associated mechanical forces, arising from ASM cell (ASMC) contraction, on long-term airway remodelling To this end, we present a novel, quantitative mechanochemical modelling framework (informed by appropriate in vitro and in vivo studies) that integrates these processes for the first time. We use this model to elucidate emergent system dynamics and thereby identify key underlying pathogenic processes
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