Gender differences in the innate immune response and vascular reactivity following the administration of endotoxin to human volunteers*

Eijk, Lucas T. van; Dorresteijn, Mirrin J.; Smits, Paul; Hoeven, Johannes G. van der; Netea, Mihai G.; Pickkers, Peter

doi:10.1097/01.ccm.0000266534.14262.e8

Cited by 160 publications

(102 citation statements)

References 46 publications

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“…The high prevalence of male gender in the nonsurvivor group is intriguing. This has been shown in adults, with females demonstrating better outcomes from sepsis despite having a more robust inflammatory response to LPS than males (26). The reasons for these gender-based differences are unclear, particularly in the pediatric population.…”

Section: Discussionmentioning

confidence: 94%

Monocyte mRNA Phenotype and Adverse Outcomes From Pediatric Multiple Organ Dysfunction Syndrome

et al. 2007

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Impairment of the ability to mount an inflammatory response is associated with death from adult critical illness. This phenomenon, characterized by reduced monocyte production of proinflammatory mediators such as tumor necrosis factor ␣ (TNF-␣), is poorly understood in children. We hypothesized that differential expression of inflammation-related genes would be seen in monocytes from children with adverse outcomes from multiple organ dysfunction syndrome (MODS). Ex vivo lipopolysaccharide (LPS)-induced TNF-␣ production and plasma cytokines were prospectively measured biweekly in children with dysfunction of two or more organs. Concomitantly, monocyte expression of 28 pro-and antiinflammatory genes [cytokines, Toll-like receptor (TLR)/nuclear factor B (NF-B) signaling pathway members, inflammasome elements] was measured. Thirty children (22 survivors, eight nonsurvivors) were evaluated. High mRNA levels for interleukin (IL)-10, IL-1 receptor-associated kinase (IRAK-M), and the putative inflammasome inhibitor pyrin were associated with death (p Յ 0.02). Plasma IL-10 levels were higher and ex vivo TNF-␣ production was lower in nonsurvivors (p Ͻ 0.05). Among survivors, high mRNA levels for IL-10, IRAK-M, pyrin, IRAK1, or TLR4 were associated with longer durations of pediatric intensive care unit (PICU) stay and mechanical ventilation (p Յ 0.02). These data suggest that adverse outcomes from pediatric MODS are associated with an antiinflammatory monocyte mRNA phenotype. Future studies are warranted to explore mechanisms of immunodepression in pediatric critical illness. (Pediatr Res 62: 597-603, 2007)

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Section: Discussionmentioning

confidence: 94%

Monocyte mRNA Phenotype and Adverse Outcomes From Pediatric Multiple Organ Dysfunction Syndrome

et al. 2007

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“…This is in contrast with IL-1β release following an ex vivo LPS challenge of whole blood cultures, which caused the release of substantial amounts of IL-1β. Reports from other human endotoxemia experiments also note IL-1β responses are very low or lacking, despite high circulating levels of IL-6 and TNFα [30][31][32][33][34][35]. Interestingly, even in cases of severe sepsis, IL-1β can be detected in only a small fraction of patients and corresponds weakly with disease severity [36].…”

Section: Discussionmentioning

confidence: 99%

Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers

et al. 2014

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Human in vivo models of systemic inflammation are used to study the physiological mechanisms of inflammation and the effect of drugs and nutrition on the immune response. Although in vivo lipopolysaccharide (LPS) challenges have been applied as methodological tool in clinical pharmacology studies, detailed information is desired on dose-response relationships, especially regarding LPS hyporesponsiveness observed after low-dose in vivo LPS administration. A study was performed to assess the in vivo inflammatory effects of low intravenous LPS doses, and to explore the duration of the induced LPS hyporesponsiveness assessed by subsequent ex vivo LPS challenges. This was a randomized, double-blind, placebo-controlled study with single ascending low doses of LPS (0.5, 1 and 2 ng/kg body weight) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS:placebo 6:2). The in vivo inflammatory response was assessed by measurement of cytokines and CRP. Ex vivo LPS challenges were performed (at −2, 6, 12, 24, 48 and 72 hours relative to in vivo LPS administration) to estimate the duration and magnitude of LPS hyporesponsiveness by assessment of cytokine release (TNF-α, IL-1β, IL-6, IL-8). LPS administration dose-dependently increased body temperature (+1.5°C for 2 ng/kg LPS), heart rate (+28 bpm for 2 ng/kg LPS), CRP and circulating cytokines which showed clearly distinctive increases from placebo already at the lowest LPS dose level tested (0.5 ng/kg, contrast for timeframe 0-6 hours: TNF-α +413%, IL-6 +288%, IL-8 +254%; all p ≤ 0.0001). In vivo LPS administration dose-dependently induced a period of hyporesponsiveness in the ex vivo LPS-induced cytokine release (IL-1β, IL-6 and TNF-α), with maximal hyporesponsiveness observed at 6 hours, lasting no longer than 12 hours. For IL-6 and IL-8, indications for immune cell priming were observed. We demonstrated that an in vivo LPS challenge, with LPS doses as low as 0.5 ng/kg, elicits a cytokine response that is clearly distinctive from baseline cytokine levels. This study expanded the knowledge about the dose-effect relationship of LPS-induced hyporesponsiveness. As such, the low-dose LPS challenge has been demonstrated to be a feasible methodological tool for future clinical studies exploring pharmacological or nutritional immune-modulating effects.

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“…Studies have additionally been undertaken on healthy women 23 , older volunteers 24,25 and patient subgroups 26 depending on the experimental question. Elderly participants (i.e., greater than 60 years of age) may have a greater and more sustained response (higher fever, greater decrease in blood pressure), and interactions of endotoxin-induced inflammation with any co-morbid conditions or medications must be considered in the design of these studies.…”

Section: Notementioning

confidence: 99%

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

Fullerton

Segre

Maeyer

et al. 2016

JoVE

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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.

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Gender differences in the innate immune response and vascular reactivity following the administration of endotoxin to human volunteers*

Cited by 160 publications

References 46 publications

Monocyte mRNA Phenotype and Adverse Outcomes From Pediatric Multiple Organ Dysfunction Syndrome

Monocyte mRNA Phenotype and Adverse Outcomes From Pediatric Multiple Organ Dysfunction Syndrome

Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers

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

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