TY - JOUR

T1 - Characterization of differences in immune responses during bolus and continuous infusion endotoxin challenges using mathematical modelling

AU - Windoloski, Kristen A.

AU - Janum, Susanne

AU - Berg, Ronan M.G.

AU - Olufsen, Mette S.

N1 - Publisher Copyright: © 2024 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

PY - 2024

Y1 - 2024

N2 - 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 (Formula presented.) 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.

AB - 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 (Formula presented.) 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.

KW - administration method

KW - continuous infusion

KW - cytokines

KW - data analysis

KW - endotoxin challenge

KW - inflammation

KW - mathematical modelling

UR - http://www.scopus.com/inward/record.url?scp=85187460803&partnerID=8YFLogxK

U2 - 10.1113/EP091552

DO - 10.1113/EP091552

M3 - Journal article

C2 - 38466166

AN - SCOPUS:85187460803

JO - Experimental Physiology

JF - Experimental Physiology

SN - 0958-0670

ER -