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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 asa continuous infusion over multiple hours. Several studies hypothesize that thelatter better represents the prolonged and pronounced inflammation observed inconditions like sepsis. Yet, very few experimental studies have administeredendotoxin using both strategies, leaving significant gaps in determining theunderlying mechanisms responsible for their differing immune responses. We usemathematical modeling to analyze cytokine data from two studies administering a2 ng/kg dose of endotoxin, one as a bolus and the other as a continuousinfusion over four hours. Using our model, we simulate the dynamics of mean andsubject-specific cytokine responses as well as the response to long-termendotoxin administration. Cytokine measurements reveal that the bolus injectionleads to significantly higher peaks for IL-8, while IL-10 reaches significantlyhigher peaks during continuous administration. Moreover, the peak timing of allmeasured cytokines occurs later in the continuous infusion. We identify threemodel parameters that significantly differ between the two administrationmethods. Monocyte activation of IL-10 is greater during the continuousinfusion, while recovery rates of IL-8 is faster for the bolus injection. Thissuggests that a continuous infusion elicits a stronger, longer-lasting systemicreaction through increased stimulation of monocyte anti-inflammatory mediatorproduction and decreased recovery of pro-inflammatory catalysts. Furthermore,our continuous infusion model exhibits prolonged inflammation with recurrentpeaks resolving within two days during long-term (20-32 hours) endotoxinadministration.

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