Pulmonary epithelial wound healing and the immune system. Mathematical modeling and bifurcation analysis of a bistable system

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2024-10-23 DOI:10.1016/j.jtbi.2024.111968

Clara R. Lotter, Jonathan A. Sherratt

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引用次数: 0

Abstract

Respiratory diseases such as asthma, acute respiratory distress syndrome (ARDS), influenza or COVID-19 often directly target the epithelium. Elevated immune levels and a ‘cytokine storm’ are directly associated with defective healing dynamics of lung diseases such as COVID-19 or ARDS. The infected cells leave wounded regions in the epithelium which must be healed for the lung to return to a healthy state and carry out its main function of gas-exchange. Due to the complexity of the various interactions between cells of the lung epithelium and surrounding tissue, it is necessary to develop models that can complement experiments to fully understand the healing dynamics. In this mathematical study we model the mechanism of epithelial regeneration. We assume that healing is exclusively driven by progenitor cell proliferation, induced by a chemical activator such as epithelial growth factor (EGF) and cytokines such as interleukin-22 (IL22). Contrary to previous studies of wound healing, we consider the immune system, specifically the T effector cells TH1, TH17, TH22 and Treg to strongly contribute to the healing process, by producing IL22 or regulating the immune response. We therefore obtain a coupled system of two ordinary differential equations for the epithelial and immune cell densities and two functions for the levels of chemicals that either induce epithelial proliferation or recruit immune cells. These functions link the two cell equations. We find that to allow the epithelium to regenerate to a healthy state, the immune system must not exceed a threshold value at the onset of the healing phase. This immune threshold is supported experimentally but was not explicitly built into our equations. Our assumptions are therefore sufficient to reproduce experimental results concerning the ratio TH17/Treg cells as a threshold to predict higher mortality rates in patients. This immune threshold can be controlled by parameters of the model, specifically the base-level growth factor concentration. This conclusion is based on a mathematical bifurcation analysis and linearization of the model equations. Our results suggest treatment of severe cases of lung injury by reducing or suppressing the immune response, in an individual patient, assessed by their disease parameters such as course of lung injury and immune response levels.

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肺上皮伤口愈合与免疫系统。双稳态系统的数学建模和分岔分析。

哮喘、急性呼吸窘迫综合征（ARDS）、流感或 COVID-19 等呼吸系统疾病通常直接针对上皮细胞。免疫水平升高和 "细胞因子风暴 "与 COVID-19 或 ARDS 等肺部疾病的愈合动力学缺陷直接相关。受感染的细胞会在上皮细胞中留下损伤区域，这些区域必须愈合，肺部才能恢复健康状态，并发挥气体交换的主要功能。由于肺上皮细胞和周围组织之间的各种相互作用非常复杂，因此有必要建立模型来补充实验，以充分了解愈合动态。在这项数学研究中，我们建立了上皮再生机制模型。我们假设愈合完全由祖细胞增殖驱动，并由上皮细胞生长因子（EGF）等化学激活剂和白细胞介素-22（IL22）等细胞因子诱导。与以往的伤口愈合研究相反，我们认为免疫系统，特别是 T 效应细胞 TH1、TH17、TH22 和 Treg，通过产生 IL22 或调节免疫反应，对愈合过程做出了巨大贡献。因此，我们得到了上皮细胞和免疫细胞密度的两个常微分方程耦合系统，以及诱导上皮细胞增殖或招募免疫细胞的化学物质水平的两个函数。这些函数将两个细胞方程联系起来。我们发现，为了让上皮再生到健康状态，免疫系统在愈合阶段开始时不得超过一个阈值。这一免疫阈值得到了实验的支持，但并没有明确地建立在我们的方程中。因此，我们的假设足以重现有关 TH17/Treg 细胞比例的实验结果，作为预测患者较高死亡率的阈值。这一免疫阈值可由模型参数控制，特别是基础生长因子浓度。这一结论基于数学分岔分析和模型方程的线性化。我们的研究结果表明，在治疗严重肺损伤病例时，可以根据肺损伤病程和免疫反应水平等疾病参数，减少或抑制个体患者的免疫反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.