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Toxicokinetics of Endotoxin and its relation to Pro-Inflammatory Cytokines Tumor Necrosis Factor α (TNF-α) and Interleukin-6 (IL-6) in a Pig sepsis model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Section of Clinical Microbiology and Infectious Medicine, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background and purpose: Infection with Gram-negative bacteria and the immune system’s subsequent recognition of the potent membrane-bound activator endotoxin (ETX), can lead to persistent immune activation. The purpose of the current work was to develop a model-based description of the time-course of ETX concentrations and its effect on the release of the pro-inflammatory, cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6).

Methods: Non-linear mixed effects models were developed based on data from experimental studies in a porcine model of sepsis. Intravenous infusions of E. coli ETX were administered to the piglets at different doses and durations of infusion. ETX, TNF-α and IL-6 plasma levels were measured throughout the infusion time.

Results: The concentration-time profile of ETX was well described with a one-compartment model with non-linear elimination. Observation of contamination in early ETX measurements was handled by initializing the central compartment to an estimated parameter. The concentration of ETX over time was used as the driver of the inflammatory response. An indirect response model with ETX stimulated production (Emax model), delayed through a transit chain (three compartments) was used to describe the observed cytokine concentration-time profiles. To describe tolerance to ETX exposure, an exponential time-dependent increase was added to the parameter describing the potency of ETX to stimulate cytokine release (EC50).

Conclusions: A mathematical model was developed to depict the time-course of ETX in plasma and its induction of the two immune response markers TNF-α and IL-6. This model-based approach is unique in its description of the three time-courses, and may later be expanded to better understand immune cell release in bacterial infections and sepsis-type pathophysiological changes

Keyword [en]
endotoxin, TNF-α, inteleukin-6, PKPD model, semi-mechanistic, sepsis, population model, Gram-negative infections
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-280004OAI: oai:DiVA.org:uu-280004DiVA: diva2:909422
Available from: 2016-03-07 Created: 2016-03-07 Last updated: 2016-03-07

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