Iso-osmolar prehydration shifts the cytokine response towards a more anti-inflammatory balance in human endotoxemia

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

doi:10.1179/096805105x58715

Cited by 26 publications

(14 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Experimental endotoxemia resulted in flu-like symptoms (shivering, headache, backache, muscle ache and nausea) that gradually declined to base-line values at the end of the experiment (T=8 h). There were no differences between the treatment groups, measured by a cumulative subjective symptom scoring list that has been described previously 15 (data not shown). Body temperature in the three treatment groups increased by 2.2±0.1°C; no differences were observed between groups.…”

Section: Symptoms and Hemodynamic Sequelaementioning

confidence: 56%

The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial

et al. 2013

View full text Add to dashboard Cite

© F e r r a t a S t o r t i F o u n d a t i o nimmune response, and subclinical organ injury during systemic inflammation induced by experimental endotoxemia in humans in vivo. Methods DesignThis double-blind, randomized, placebo-controlled trial (Clinicaltrials.gov identifier:01349699) was approved by the local ethics committee, and carried out according to standards of Good Clinical Practice and the Declaration of Helsinki. After written informed consent, 30 healthy non-smoking male subjects were randomly treated with either iron loading (iron sucrose), or iron chelation (deferasirox) or placebo, prior to the intravenous administration of 2 ng/kg purified E.Coli endotoxin, as described in detail in the Online Supplementary Methods. Iron loading and iron chelation therapyAt T = -2 h (i.e. 2 h before endotoxin administration), iron chelation therapy (deferasirox (Exjade ® ), Novartis, The Netherlands) or placebo (starch powder) was administered orally. A commonly applied dose of 30 mg/kg of deferasirox 13 was dissolved in water and was stirred until the moment of intake. Subjects drank the suspension within 1 min. The time point of deferasirox administration was chosen so that maximal plasma levels were achieved between 0 and 2 h after endotoxin administration, just before and during the expected peak of the pro-inflammatory cytokine response. At T = -1 h, a generally applied therapeutic dose 14 of 1.25 mg/kg iron sucrose (Venofer ® , Vifor Nederland BV, The Netherlands), or placebo (NaCl 0.9%), was intravenously administered through blinded syringes and lines. Because the two therapies had different administration routes, a double dummy was used to ensure adequate blinding. Iron homeostasis analysisSerum iron, ferritin, transferrin and soluble transferrin receptor (sTfR), hepcidin, GDF-15 and LPI were determined as described in the Online Supplementary Design and Methods. Oxidative stress and cytokine measurementsOxidative stress (malondialdehyde) and plasma levels of proinflammatory cytokines TNF-α and IL-6, the anti-inflammatory cytokines IL-10 and IL-1ra, and markers of endothelial activation Vascular Cell Adhesion Molecule (VCAM) and Intercellular Adhesion Molecule (ICAM) were determined as described in the Online Supplementary Design and Methods. Subclinical organ injurySubclinical endothelial injury was assessed by measuring the changes in response of the forearm vasculature to the infusion of vasoactive medication into the brachial artery, using venous occlusion plethysmography. For the determination of subclinical renal tubular damage, urinary Glutathione S-Transferase Alpha-1-1 (GSTA1-1) and Glutathione S-Transferase-Pi-1-1 (GSTP1-1) were determined. A detailed description is provided in the Online Supplementary Design and Methods. Stastistical analysisData are expressed as mean±SEM, or median (25th-75th percentile), depending on their distribution. P=0.05 was considered statistically significant. For all outcome variables, the intervention groups were compared to the placebo group in two ...

show abstract

Section: Symptoms and Hemodynamic Sequelaementioning

confidence: 56%

The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial

et al. 2013

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…15 Following written informed consent and screening, 24 healthy male subjects were prehydrated with 1.5 L NaCl 0.45%/glucose 2.5%. 16 At T 5 0 hours, 2 ng/kg purified standard reference Escherichia coli O:113 lipopolysaccharide (LPS) (Clinical Center Reference Endotoxin, National Institutes of Health, Bethesda, MD) was administered IV. Lexaptepid (NOXXON Pharma AG, Berlin, Germany) was diluted in glucose 5%, according to the manufacturer's instructions.…”

Section: Experimental Human Endotoxemiamentioning

confidence: 99%

Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans

Eijk¹,

John²,

Schwoebel

et al. 2014

Blood

Self Cite

View full text Add to dashboard Cite

Key Points• Lexaptepid modulates the inflammation-induced decrease in serum iron during experimental human endotoxemia.• Hepcidin targeting with the novel compound lexaptepid may be a viable approach to the treatment of anemia of inflammation in humans.Increased hepcidin production is key to the development of anemia of inflammation. We investigated whether lexaptepid, an antihepcidin L-oligoribonucleotide, prevents the decrease in serum iron during experimental human endotoxemia. This randomized, doubleblind, placebo-controlled trial was carried out in 24 healthy males. At T 5 0 hours, 2 ng/kg Escherichia coli lipopolysaccharide was intravenously administered, followed by an intravenous injection of 1.2 mg/kg lexaptepid or placebo at T 5 0.5 hours. The lipopolysaccharide-induced inflammatory response was similar in subjects treated with lexaptepid or placebo regarding clinical and biochemical parameters. At T 5 9 hours, serum iron had increased by 15.9 6 9.8 mmol/L from baseline in lexaptepidtreated subjects compared with a decrease of 8.3 6 9.0 mmol/L in controls (P < .0001). This study delivers proof of concept that lexaptepid achieves clinically relevant hepcidin inhibition enabling investigations in the treatment of anemia of inflammation. This trial was registered at www.clinicaltrial.gov as #NCT01522794. (Blood. 2014;124(17):2643-2646

show abstract

Iso-osmolar prehydration shifts the cytokine response towards a more anti-inflammatory balance in human endotoxemia

Cited by 26 publications

References 22 publications

The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial

The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial

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

Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans

Contact Info

Product

Resources

About