Risk factor-dependent dynamics of atopic dermatitis: modelling multi-scale regulation of epithelium homeostasis.
Risk factor-dependent dynamics of atopic dermatitis: modelling multi-scale regulation of epithelium homeostasis.
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DOI：
10.1098/rsfs.2012.0090
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发表时间：
2013-04-06
期刊：
影响因子：
4.4
通讯作者：
Tanaka RJ
中科院分区：
文献类型：
--
作者：
Domínguez-Hüttinger E;Ono M;Barahona M;Tanaka RJ
上皮组织通过在防止外部刺激流入的物理屏障和对渗透刺激的炎症反应之间发挥调节作用，为机体提供了抵御有害环境刺激的第一层保护。重要的是，这种相互依赖的调节发生在不同的时间尺度上：组织水平的屏障渗透性是在几个小时的过程中调节的，而导致炎症的细胞水平的酶促反应在几分钟内发生。这种多尺度调控是上皮功能的关键，其功能障碍导致多种疾病。本文提出了表皮上皮调节机制的数学模型，包括细胞和组织水平上两个不同时间尺度上的过程。我们使用这个模型来研究表皮屏障完整性和皮肤炎症之间的基本调节相互作用，以及它们的功能障碍如何导致特应性皮炎（AD）。我们的模型在细胞和组织水平上表现出双重（阳性和阴性）控制结构。我们还确定了众所周知的AD危险因素诱导的变异如何打破双重控制的平衡。我们基于时间尺度分离的模型分析表明，每个危险因素导致AD不同严重程度的定性不同动态行为，多个危险因素的重合显著增加了上皮功能的脆弱性。所提出的数学框架也应适用于具有类似时间尺度分离和控制结构的其他炎症性疾病。
Epithelial tissue provides the body with its first layer of protection against harmful environmental stimuli by enacting the regulatory interplay between a physical barrier preventing the influx of external stimuli and an inflammatory response to the infiltrating stimuli. Importantly, this interdependent regulation occurs on different time scales: the tissue-level barrier permeability is regulated over the course of hours, whereas the cellular-level enzymatic reactions leading to inflammation take place within minutes. This multi-scale regulation is key to the epithelium's function and its dysfunction leads to various diseases. This paper presents a mathematical model of regulatory mechanisms in the epidermal epithelium that includes processes on two different time scales at the cellular and tissue levels. We use this model to investigate the essential regulatory interactions between epidermal barrier integrity and skin inflammation and how their dysfunction leads to atopic dermatitis (AD). Our model exhibits a structure of dual (positive and negative) control at both cellular and tissue levels. We also determined how the variation induced by well-known risk factors for AD can break the balance of the dual control. Our model analysis based on time-scale separation suggests that each risk factor leads to qualitatively different dynamic behaviours of different severity for AD, and that the coincidence of multiple risk factors dramatically increases the fragility of the epithelium's function. The proposed mathematical framework should also be applicable to other inflammatory diseases that have similar time-scale separation and control architectures.
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