A dynamical model of TGF-β activation in asthmatic airways.

IF 0.8 4区 数学 Q4 BIOLOGY Mathematical Medicine and Biology-A Journal of the Ima Pub Date : 2023-09-15 DOI:10.1093/imammb/dqad004
Hannah J Pybus, Reuben D O'Dea, Bindi S Brook
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Abstract

Excessive activation of the regulatory cytokine transforming growth factor $\beta $ (TGF-$\beta $) via contraction of airway smooth muscle (ASM) is associated with the development of asthma. In this study, we develop an ordinary differential equation model that describes the change in density of the key airway wall constituents, ASM and extracellular matrix (ECM), and their interplay with subcellular signalling pathways leading to the activation of TGF-$\beta $. We identify bistable parameter regimes where there are two positive steady states, corresponding to either reduced or elevated TGF-$\beta $ 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-$\beta $ 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-$\beta $, 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.

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哮喘气道中 TGF-β 激活的动态模型。
通过气道平滑肌(ASM)收缩过度激活调节细胞因子转化生长因子(TGF-$\beta $)与哮喘的发生有关。在这项研究中,我们建立了一个常微分方程模型,该模型描述了气道壁主要成分 ASM 和细胞外基质(ECM)密度的变化,以及它们与导致 TGF-$\beta $ 激活的亚细胞信号通路的相互作用。我们确定了双稳态参数区,其中有两种正稳态,分别对应于 TGF-$\beta $ 浓度降低或升高,后者还会导致 ASM 和 ECM 密度增加。我们将前者与健康的平衡状态联系起来,将后者与疾病(哮喘)状态联系起来。我们证明,通过 ASM 收缩(模拟哮喘加重)诱导 TGF-$\beta $ 激活的外部刺激,可以不可逆转地扰乱系统,使其从健康状态转变为疾病状态。我们表明,刺激的特性,如刺激的频率或强度,以及剩余活性 TGF-$\beta $ 的清除,对于决定长期动态和疾病的发展非常重要。最后,我们展示了该模型在研究支气管热成形术时间反应方面的实用性,支气管热成形术是一种通过对气道壁施加热能来消融 ASM 的治疗干预措施。该模型预测了ASM含量不可逆减少所需的参数依赖性阈值损伤,这表明某些哮喘表型更有可能从这种干预措施中获益。
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来源期刊
CiteScore
2.20
自引率
0.00%
发文量
15
审稿时长
>12 weeks
期刊介绍: Formerly the IMA Journal of Mathematics Applied in Medicine and Biology. Mathematical Medicine and Biology publishes original articles with a significant mathematical content addressing topics in medicine and biology. Papers exploiting modern developments in applied mathematics are particularly welcome. The biomedical relevance of mathematical models should be demonstrated clearly and validation by comparison against experiment is strongly encouraged. The journal welcomes contributions relevant to any area of the life sciences including: -biomechanics- biophysics- cell biology- developmental biology- ecology and the environment- epidemiology- immunology- infectious diseases- neuroscience- pharmacology- physiology- population biology
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