A dynamical model of TGF-β activation in asthmatic airways

Pybus, Hannah J; O’dea, Reuben D; Brook, Bindi S

Abstract

Excessive activation of the regulatory cytokine transforming growth factor β (TGF-β) via contraction of airway smooth muscle (ASM) is associated with the development of asthma. In this study, we develop an ordinary differential equation model that describes the change in density of the key airway wall constituents, ASM and extracellular matrix (ECM), and their interplay with subcellular signalling pathways leading to the activation of TGF-β. We identify bistable parameter regimes where there are two positive steady states, corresponding to either reduced or elevated TGF-β concentration, with the latter leading additionally to increased ASM and ECM density. We associate the former with a healthy homeostatic state and the latter with a diseased (asthmatic) state. We demonstrate that external stimuli, inducing TGF-β activation via ASM contraction (mimicking an asthmatic exacerbation), can perturb the system irreversibly from the healthy state to the diseased one. We show that the properties of the stimuli, such as their frequency or strength, and the clearance of surplus active TGF-β, are important in determining the long-term dynamics and the development of disease. Finally we demonstrate the utility of this model in investigating temporal responses to bronchial thermoplasty, a therapeutic intervention in which ASM is ablated by applying thermal energy to the airway wall. The model predicts the parameter-dependent threshold damage required to obtain irreversible reduction in ASM content suggesting that certain asthma phenotypes are more likely to benefit from this intervention.

Citation

Pybus, H. J., O’dea, R. D., & Brook, B. S. (2023). A dynamical model of TGF-β activation in asthmatic airways. Mathematical Medicine and Biology, 40(3), 238-265. https://doi.org/10.1093/imammb/dqad004

• Journal Article Type: Article
• Acceptance Date: Jun 5, 2023
• Online Publication Date: Jun 7, 2023
• Publication Date: 2023-09
• Deposit Date: Jun 16, 2023
• Publicly Available Date: Jun 8, 2024
• Journal: Mathematical Medicine and Biology
• Print ISSN: 1477-8599
• Electronic ISSN: 1477-8602
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 40
• Issue: 3
• Pages: 238-265
• DOI: https://doi.org/10.1093/imammb/dqad004
• Keywords: Asthma, TGF-β activation, Dynamical system, Bifurcation analysis
• Public URL: https://nottingham-repository.worktribe.com/output/5433677
• Publisher URL: https://academic.oup.com/imammb/advance-article/doi/10.1093/imammb/dqad004/7191675
• Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Mathematical Medicine and Biology following peer review. The version of record [Hannah J Pybus and others, A dynamical model of TGF-β activation in asthmatic airways, Mathematical Medicine and Biology: A Journal of the IMA, 2023;, dqad004 is available online at: https://doi.org/10.1093/imammb/dqad004