Pybus, Hannah J.
(2020)
Mathematical Models of Pro-remodelling Growth Factor Activation in Asthmatic Airways.
PhD thesis, University of Nottingham.
Abstract
Asthma is a highly prevalent chronic disease of the lungs, characterised by inflammation, airway hyperresponsiveness and remodelling. Activation of the latent regulatory cytokine transforming growth factor β (TGF-β), during bronchoconstriction, triggers a cascade of inflammatory injury repair responses that may initiate airway remodelling, leading to asthma exacerbations and impaired lung function. The underlying mechanisms linking the characteristics of asthma and the mechanical activation of TGF-β, however, are not yet clear.
In this thesis we first develop a model comprising a system of coupled ODEs to investigate the change in density of the key airway wall constituents in response to TGF-β-induced subcellular signalling. We demonstrate that external stimuli, mimicking an asthmatic exacerbation, perturb the healthy homeostatic state to a diseased state and show that the properties of the time-dependent stimuli are critical determinants of long-term airway remodelling.
Thereafter, we develop a biomechanical model informed by precision-cut lung-slice (PCLS) experiments. PCLS, in which viable airways embedded within lung parenchyma are stretched or induced to contract, are a widely used ex vivo assay to investigate bronchoconstriction and, more recently, mechanical activation of TGF-β in asthmatic airways. In this thesis we develop a nonlinear fibre-reinforced biomechanical model of TGF-β activation accounting for airway smooth muscle (ASM) contraction and extracellular matrix (ECM) strain-stiffening. Through numerical simulation, we predict the stresses and deformation of an axisymmetric airway within a PCLS of finite thickness, exposing the importance of PCLS geometry, imposed stretch and ASM contractility. Motivated by the typically thin geometry of the PCLS, we then consider two simplifying limits of the model, a one-dimensional membrane representation and an asymptotic reduction in the thin-PCLS-limit, that permit analytical progress. Comparison against numerical solution of the full problem shows that the asymptotic reduction successfully captures the key elements of the full model behaviour that the membrane model does not.
Finally, we couple subcellular mechanotransductive signalling pathways to the nonlinear biomechanical models and simulate TGF-β mediated contraction and the subsequent change in effective mechanical properties as TGF-β activation continues. Crucially, the computational tractability of the asymptotically reduced biomechanical model permits efficient parameter sweeps and increases coupling feasibility. In agreement with experimental observations, we find that ASM contraction and ECM strain-stiffening increases TGF-β activation as the PCLS deforms with prescribed axisymmetric cyclic stretch. Our findings highlight, and potentially elucidate, the underlying mechanotransductive feedback mechanisms linking airway mechanics and TGF-β activation in asthma.
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