Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation.

Alexander A.N Maini,Roel P.H De Maeyer,James N Fullerton,Derek W Gilroy,Elisabetta Segre

doi:10.3791/53913

Alexander A.N Maini, Roel P.H De Maeyer + Show 3 more

Open Access

https://doi.org/10.3791/53913

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Abstract

Activation of inflammatory pathways represents a central mechanism in multiple disease states both acute and chronic. Triggered via either pathogen or tissue damage-associated molecular motifs, common biochemical pathways lead to conserved yet variable physiological and immunological alterations. Dissection and delineation of the determinants and mechanisms underlying phenotypic variance in response is expected to yield novel therapeutic advances.Intravenous (IV) administration of endotoxin (gram-negative bacterial lipopolysaccharide), a specific Toll-like receptor 4 agonist, represents an in vivo model of systemic inflammation in man. National Institutes for Health Clinical Center Reference Endotoxin (CCRE, Escherichia coli O:113:H10:K negative) is employed to reliably and reproducibly generate vascular, hematological, endocrine, immunological and organ-specific functional effects that parallel, to varying degrees, those seen in the early stages of pathological states. Alteration of dose (0.06 - 4 ng/kg) and time-scale of exposure (bolus vs. infusion) allows replication of either acute or chronic inflammation and a range of severity to be elicited, with higher doses (2 - 4 ng/kg) frequently being used to create a 'sepsis-like' state. Established and novel medicinal compounds may additionally be administered prior to or post endotoxin exposure to appreciate their effect on the inflammatory cascade. Despite limitations in scope and generalizability, human IV endotoxin challenge offers a unique platform to gain mechanistic insights into inducible physiological responses and inflammatory pathways. Rationally employed it may aid translation of this knowledge into therapeutic innovations.

Highlights

Inflammation of differing etiology, severity and duration forms a central component in the pathology of multiple diseases
Inflammation is initiated by the presence of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) — commonly intracellular components released via tissue damage[3,4,5]
A bolus of 2 - 4 ng/kg reliably elicits the features of the systemic inflammatory response syndrome with raised core temperature, heart rate and white blood cell (WBC) count[16]

Summary

Introduction

Inflammation of differing etiology, severity and duration forms a central component in the pathology of multiple diseases. Inflammation is initiated by the presence of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) — commonly intracellular components released via tissue damage[3,4,5] These conserved molecular motifs bind pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) found on epithelial cells, endothelial cells and those of the innate immune system, to trigger common downstream intracellular signaling pathways[6]. Activation of the nuclear transcription factor nuclear factor κB, amongst others, leads to transcription of genes encoding pro-inflammatory cytokines that establish the inflammatory cascade[7] Inflammation induces both local and systemic effects designed to isolate and remove the primary insult. These potent mechanisms, often coordinated by lipid mediators may themselves be pathogenic[9,10]

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