Characterization of a model of systemic inflammation in humans in vivo elicited by continuous infusion of endotoxin

D Kiers,L Van Ede,N P Riksen,M Kox,E J M Thijs,P Pickkers,R M Koch,J Gerretsen,L Hamers

doi:10.1038/srep40149

Abstract

Investigating the systemic inflammatory response in patients with critical illness such as sepsis, trauma and burns is complicated due to uncertainties about the onset, duration and severity of the insult. Therefore, in vivo models of inflammation are essential to study the pathophysiology and to evaluate immunomodulatory therapies. Intravenous bolus administration of endotoxin to healthy volunteers is a well-established model of a short-lived systemic inflammatory response, characterized by increased plasma cytokine levels, flu-like symptoms and fever. In contrast, patients suffering from systemic inflammation are often exposed to inflammatory stimuli for an extended period of time. Therefore, continuous infusion of endotoxin may better reflect the kinetics of the inflammatory response encountered in these patients. Herein, we characterize a novel model of systemic inflammation elicited by a bolus infusion of 1 ng/kg, followed by a 3hr continuous infusion of 1 ng/kg/h of endotoxin in healthy volunteers, and compared it with models of bolus administrations of 1 and 2 ng/kg of endotoxin. The novel model was well-tolerated and resulted in a more pronounced increase in plasma cytokine levels with different kinetics and more prolonged symptoms and fever compared with the bolus-only models. Therefore, the continuous endotoxin infusion model provides novel insights into kinetics of the inflammatory response during continuous inflammatory stimuli and accommodates a larger time window to evaluate immunomodulating therapies.

Highlights

Investigating the systemic inflammatory response in patients with critical illness such as sepsis, trauma and burns is complicated due to uncertainties about the onset, duration and severity of the insult
A controlled, transient and reproducible systemic inflammatory response in humans can be achieved with an intravenous (i.v.) bolus administration of endotoxin (lipopolysaccharide (LPS)), a compound derived from the cell membrane of Gram-negative bacteria
We characterize a novel human in vivo model of systemic inflammation elicited by continuous endotoxin infusion

Summary

Introduction

Investigating the systemic inflammatory response in patients with critical illness such as sepsis, trauma and burns is complicated due to uncertainties about the onset, duration and severity of the insult. Systemic inflammation is a common hallmark of patients with sepsis[1], trauma[2], burns[3], as well as those undergoing major surgery[4] This inflammatory response follows the activation of specific receptors by pathogen-, or danger associated molecular patterns (PAMPs and DAMPs), and is characterized by the production of cytokines and chemokines. Repeated endotoxin administration studies have demonstrated the development of endotoxin tolerance, representing an immune suppressed state that resembles sepsis-induced immunoparalysis[13] This experimental human endotoxemia model has been frequently used to investigate the pathophysiology of systemic inflammation, to assess a broad range of immunosuppressive and immunostimulatory drugs and non-pharmacological interventions[14,15,16,17], and to evaluate the effects of inflammation on other biologic processes, such as iron homeostasis[18]

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