A dynamic inflammatory model for bolus vs. continuous administration of endotoxin

Uncontrolled, persistent inflammation is a hallmark of individuals with medical conditions such as sepsis, a leading cause of death in U.S. hospitals. While a bolus administration of lipopolysaccharide (LPS) to healthy volunteers is a common short-term inflammation model, a continuous infusion of LPS over an extended time frame better represents the sustained inflammation present in conditions like sepsis. Numerous studies have used mathematical modeling to examine the inflammatory feedback in response to a bolus administration of endotoxin, and these models were validated against bolus murine and human data. Analysis of bolus versus continuous administration of endotoxin data reveals that a continuous administration of LPS results in delayed peaks of pro and anti-inflammatory cytokines and increases in peak magnitude of TNF-a and IL-10. To further the understanding behind these differences, we adapt a 2 ng/kg bolus-dose inflammatory response model formulated as a system of ordinary differential equations tracking selected cytokines and cells to study the inflammatory response to a continuous infusion of endotoxin over an extended period of time. Using sensitivity analysis and parameter estimation, we validate the model using experimental data from a study where 2 ng/kg of LPS is administered over a 4-hour period in nine healthy volunteers.