Mathew Shibin, Bartels John, Banerjee Ipsita, Vodovotz Yoram
Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Immunetrics, Inc., Pittsburgh, PA 15203, USA.
J Theor Biol. 2014 Oct 7;358:132-48. doi: 10.1016/j.jtbi.2014.05.036. Epub 2014 Jun 5.
The precise inflammatory role of the cytokine interleukin (IL)-6 and its utility as a biomarker or therapeutic target have been the source of much debate, presumably due to the complex pro- and anti-inflammatory effects of this cytokine. We previously developed a nonlinear ordinary differential equation (ODE) model to explain the dynamics of endotoxin (lipopolysaccharide; LPS)-induced acute inflammation and associated whole-animal damage/dysfunction (a proxy for the health of the organism), along with the inflammatory mediators tumor necrosis factor (TNF)-α, IL-6, IL-10, and nitric oxide (NO). The model was partially calibrated using data from endotoxemic C57Bl/6 mice. Herein, we investigated the sensitivity of the area under the damage curve (AUCD) to the 51 rate parameters of the ODE model for different levels of simulated LPS challenges using a global sensitivity approach called Random Sampling High Dimensional Model Representation (RS-HDMR). We explored sufficient parametric Monte Carlo samples to generate the variance-based Sobol' global sensitivity indices, and found that inflammatory damage was highly sensitive to the parameters affecting the activity of IL-6 during the different stages of acute inflammation. The AUCIL6 showed a bimodal distribution, with the lower peak representing healthy response and the higher peak representing sustained inflammation. Damage was minimal at low AUCIL6, giving rise to a healthy response. In contrast, intermediate levels of AUCIL6 resulted in high damage, and this was due to the insufficiency of damage recovery driven by anti-inflammatory responses from IL-10 and the activation of positive feedback sustained by IL-6. At high AUCIL6, damage recovery was interestingly restored in some population of simulated animals due to the NO-mediated anti-inflammatory responses. These observations suggest that the host's health status during acute inflammation depends in a nonlinear fashion on the magnitude of the inflammatory stimulus, on the host's propensity to produce IL-6, and on NO-mediated downstream responses.
细胞因子白细胞介素（IL）-6的确切炎症作用及其作为生物标志物或治疗靶点的效用一直是诸多争论的根源，推测这是由于该细胞因子具有复杂的促炎和抗炎作用。我们之前开发了一个非线性常微分方程（ODE）模型，以解释内毒素（脂多糖；LPS）诱导的急性炎症动态以及相关的全动物损伤/功能障碍（生物体健康的一个指标），同时还能解释炎症介质肿瘤坏死因子（TNF）-α、IL-6、IL-10和一氧化氮（NO）的情况。该模型使用内毒素血症C57Bl/6小鼠的数据进行了部分校准。在此，我们使用一种名为随机抽样高维模型表示（RS-HDMR）的全局敏感性方法，研究了损伤曲线下面积（AUCD）对ODE模型的51个速率参数的敏感性，这些参数对应不同水平的模拟LPS刺激。我们探索了足够数量的参数蒙特卡罗样本，以生成基于方差的索伯尔全局敏感性指数，发现炎症损伤对影响急性炎症不同阶段IL-6活性的参数高度敏感。AUCIL6呈现双峰分布，较低的峰值代表健康反应，较高的峰值代表持续炎症。在低AUCIL6时损伤最小，产生健康反应。相反，中等水平的AUCIL6会导致高损伤，这是由于IL-10的抗炎反应驱动的损伤恢复不足以及IL-6维持的正反馈激活所致。在高AUCIL6时，有趣的是，由于NO介导的抗炎反应，在一些模拟动物群体中损伤恢复得以恢复。这些观察结果表明，急性炎症期间宿主的健康状况以非线性方式取决于炎症刺激的强度、宿主产生IL-6的倾向以及NO介导的下游反应。
