A Unified Computational Model for the Human Response to Lipopolysaccharide-Induced Inflammation

Windoloski, Kristen; Bangsgaard, Elisabeth O.; Dobreva, Atanaska; Ottesen, Johnny T.; Olufsen, Mette S.

doi:10.1007/16618_2022_39

Cited by 2 publications

(1 citation statement)

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“…To support the convergence of the gradient‐based optimizer used to estimate identifiable model parameters, we further improved the nominal model fit to the peak magnitudes of cytokine profiles by scaling the peak cytokine concentrations as described in detail in Windoloski et al. ( 2023 ) and Windoloski ( 2023 ). Scaling analysis was applied to all simulations to capture mean and individual variation in cytokine responses.…”

Section: Methodsmentioning

confidence: 99%

Characterization of differences in immune responses during bolus and continuous infusion endotoxin challenges using mathematical modelling

Windoloski,

Janum,

Berg

et al. 2024

Experimental Physiology

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Endotoxin administration is commonly used to study the inflammatory response, and though traditionally given as a bolus injection, it can be administered as a continuous infusion over multiple hours. Several studies hypothesize that the latter better represents the prolonged and pronounced inflammation observed in conditions like sepsis. Yet very few experimental studies have administered endotoxin using both strategies, leaving significant gaps in determining the underlying mechanisms responsible for their differing immune responses. We used mathematical modelling to analyse cytokine data from two studies administering a 2 ng kg−1 dose of endotoxin, one as a bolus and the other as a continuous infusion over 4 h. Using our model, we simulated the dynamics of mean and subject‐specific cytokine responses as well as the response to long‐term endotoxin administration. Cytokine measurements revealed that the bolus injection led to significantly higher peaks for interleukin (IL)‐8, while IL‐10 reaches higher peaks during continuous administration. Moreover, the peak timing of all measured cytokines occurred later with continuous infusion. We identified three model parameters that significantly differed between the two administration methods. Monocyte activation of IL‐10 was greater during the continuous infusion, while tumour necrosis factor and IL‐8 recovery rates were faster for the bolus injection. This suggests that a continuous infusion elicits a stronger, longer‐lasting systemic reaction through increased stimulation of monocyte anti‐inflammatory mediator production and decreased recovery of pro‐inflammatory catalysts. Furthermore, the continuous infusion model exhibited prolonged inflammation with recurrent peaks resolving within 2 days during long‐term (20–32 h) endotoxin administration.

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Section: Methodsmentioning

confidence: 99%