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

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.Electronic supplementary materialThe online version of this article (10.1007/s10237-018-1037-4) contains supplementary material, which is available to authorized users.

Growth and remodelling of living tissues: perspectives, challenges and opportunities

“…In addition, there are many other mixture-based models of biological growth and remodelling, some of which include methods of finite kinematic growth coupled with the concept of a constrained mixture. The interested reader is referred to the many other examples of mixture-based theories, including a study of cartilage growth [18], a model of tumour growth [19], a general framework for growth [73], growth in tissue engineering [74], a study of residual stress [21], a new multi-generational theory of growth [75], a focus on mass transfer within growth mechanics [76], hypertensive remodelling of arteries [77], development of the aorta [78], a study of diverse applications including cervical remodelling in pregnancy [79], a coupling of haemodynamics and arterial wall growth and remodelling [80], additional studies of tissue engineering [81,82], anisotropic volumetric remodelling [83] and asthmatic airway remodelling [84], to name a few.…”

Reduced biomechanical models for precision-cut lung-slice stretching experiments

“…Others consider finite deformations of incompressible rubber membranes with a central solid inclusion and under uniform pressure (Jianbing et al, 2015). Finally, models of agonist driven feedback that are focused on growth and remodelling are presented by Chernyavsky et al (2014), Aparício et al (2016), and Hill et al (2018). However, none of these previous models are suitable descriptions for finite deformation of a thin slice in which the tissue stresses may be determined.…”

S36 Hypoxia induced bronchodilation and hyperoxia induced bronchoconstriction in human airways

“…Whole human lungs or lobes were perfused and ventilated as previously described. 1 Hypoxia was induced by modifying the perfusion/ventilation circuit. Results Exposure to hypoxia caused a robust relaxation of bronchi from resting tension in 95% oxygen of 2.09±0.44 gf to 1.10±0.44 gf (À46±22%) (n=68) and active tension from 3.23±2.00 gf to 1.47±0.45 gf (À116±33% reversal of active tension) (n=94) which was fully reversed on reoxygenation with 95% oxygen.…”

“…A mathematical model developed by our group suggests that rate of inflammation resolution post-exacerbation is a critical determinant of long term airway remodelling. 1 We therefore sought to assess remodelling in unprecedented detail and its resolution across a large number of airways in a well-characterised model of chronic ovalbumin (OVA)-induced airway remodelling. 2 Methods 43 BALB/C mice underwent OVA sensitisation and 10 OVA or PBS control airway challenges over 34 days.…”