Abstract
Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111:B4) being infused intravenously for 1–30 h in rates of 0.063–16.0 μg/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-α to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-α concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-α production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-α, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-α and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.
Highlights
Bacterial infection will invoke the host immune system and elicit a response of varying magnitude and duration depending on factors relating to the host and/or the invading pathogen
We developed a mathematical model that simultaneously account for and connect the in vivo time-courses and interrelation of ETX, TNF-α and IL-6, and associated tolerance development, based on data from a large cohort of endotoxemic piglets
The dataset consisted of 116 individuals and 2391 observations (278 ETX, 1068 TNFα, and 1045 IL-6) and led to the final model structure presented in Fig 1, with maximum likelihood estimates and variances as presented in Table 2
Summary
Bacterial infection will invoke the host immune system and elicit a response of varying magnitude and duration depending on factors relating to the host and/or the invading pathogen. Though ETX exhibits no toxicity per se, recognition by the immune system lead to a response aimed at clearing the pathogen to protect the host. An aggravated response can lead to tissue and organ injury, a clinical condition known as sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [3]. The recognition of ETX through toll-like receptor 4 (TLR-4) on immune cells (e.g. tissue resident macrophages) will lead to a predominantly pro-inflammatory innate immune response involving the release of a plethora of cytokines in addition to activation and tissue infiltration of white blood cells [6,7,8]. Two key cytokines of innate immunity are tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL6) whose plasma concentration quickly increase over baseline values upon exposure to ETX, making them interesting biomarkers for the extent of early immune activation in a research setting [10]
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