Foteinou P T, Calvano S E, Lowry S F, Androulakis I P
Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
Math Biosci. 2009 Jan;217(1):27-42. doi: 10.1016/j.mbs.2008.09.003. Epub 2008 Sep 20.
A receptor mediated model of endotoxin-induced human inflammation is proposed. The activation of the innate immune system in response to the endotoxin stimulus involves the interaction between the extracellular signal and critical receptors driving downstream signal transduction cascades leading to transcriptional changes. We explore the development of an in silico model that aims at coupling extracellular signals with essential transcriptional responses through a receptor mediated indirect response model. The model consists of eight (8) variables and is evaluated in a series of biologically relevant scenarios indicative of the non-linear behavior of inflammation. Such scenarios involve a self-limited response where the inflammatory stimulus is cleared successfully; a persistent infectious response where the inflammatory instigator is not eliminated, leading to an aberrant inflammatory response, and finally, a persistent non-infectious inflammatory response that can be elicited under an overload of the pathogen-derived product; as such high dose of the inflammatory insult can disturb the dynamics of the host response leading to an unconstrained inflammatory response. Finally, the potential of the model is demonstrated by analyzing scenarios associated with endotoxin tolerance and potentiation effects.
提出了一种内毒素诱导的人类炎症的受体介导模型。先天免疫系统对内毒素刺激的激活涉及细胞外信号与驱动下游信号转导级联反应并导致转录变化的关键受体之间的相互作用。我们探索了一种计算机模拟模型的开发，该模型旨在通过受体介导的间接反应模型将细胞外信号与基本转录反应耦合起来。该模型由八个变量组成，并在一系列表明炎症非线性行为的生物学相关场景中进行评估。这些场景包括成功清除炎症刺激的自限性反应；炎症引发物未被消除从而导致异常炎症反应的持续性感染反应；以及在病原体衍生产物过载情况下可能引发的持续性非感染性炎症反应；因为如此高剂量的炎症刺激会扰乱宿主反应的动态，导致不受控制的炎症反应。最后，通过分析与内毒素耐受和增强效应相关的场景来证明该模型的潜力。
