Global sensitivity analysis of a mathematical model of acute inflammation identifies nonlinear dependence of cumulative tissue damage on host interleukin-6 responses

JOURNAL OF THEORETICAL BIOLOGY

卷:358

Article

Mathew, Shibin¹  Bartels, John³  Banerjee, Ipsita^1,2  Vodovotz, Yoram^3,4,5,6 

[1] Univ Pittsburgh, Dept Chem & Petr Engn, Pittsburgh, PA 15261 USA

[2] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15219 USA

[3] Immunetr Inc, Pittsburgh, PA 15203 USA

[4] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA

[5] Univ Pittsburgh, Ctr Inflammat & Regenerat Modeling, McGowan Inst Regenerat Med, Pittsburgh, PA 15213 USA

[6] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15213 USA

关键词: Inflammation dynamics;    Meta-modeling;    Endotoxin;    Cytokines;    Nitric oxide;   

DOI  :  10.1016/j.jtbi.2014.05.036

来源: Elsevier

【 摘 要 】

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)-alpha, IL-6, IL-10, and nitric oxide (NO). The model was partially calibrated using data from endotoxemic C57BI/6 mice. Herein, we investigated the sensitivity of the area under the damage curve (AUC(D)) 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 AUC(IL6) showed a bimodal distribution, with the lower peak representing healthy response and the higher peak representing sustained inflammation. Damage was minimal at low AUC(IL6), 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 AUC(IL6), 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. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

Free