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

Eijk, Lucas T. van; Heemskerk, Suzanne; Pluijm, Rob W van der; Wijk, Susanne M. van; Peters, Wilbert H.M.; Hoeven, Johannes G. van der; Kox, Matthijs; Swinkels, Dorine W.; Pickkers, Peter

doi:10.3324/haematol.2013.088047

Cited by 20 publications

(13 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This immediate increase was previously observed during experimental endotoxemia 18 and may be due to an acute inflammation-induced abrogation of erythropoiesis and iron uptake by the bone marrow, whereas the export of iron from iron storing cells persists as long as ferroportin is expressed. In concordance, Transferrin saturation (TSAT).…”

Section: Resultssupporting

confidence: 64%

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

Eijk¹,

John²,

Schwoebel

et al. 2014

Blood

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

Section: Resultssupporting

confidence: 64%

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

Eijk¹,

John²,

Schwoebel

et al. 2014

Blood

View full text Add to dashboard Cite

show abstract

“…This study was part of a larger endotoxemia trial ( clinicaltrials.gov identifier : NCT01349699 ) [20] . Our analyses were performed on data of the ten placebo-LPS-treated subjects only.…”

Section: Methodsmentioning

confidence: 99%

“…The trial was approved by the local ethics committee, and carried out according to GCP standards and the declaration of Helsinki. A detailed protocol of the human endotoxemia trial was previously described [20] . Blood was collected at various time points after the injection of purified endotoxin (LPS) prepared from E. coli O:113 (Clinical Center Reference Endotoxin, National Institute of Health (NIH), Bethesda, MD, USA) [20] .…”

Section: Methodsmentioning

confidence: 99%

Inflammation-associated changes in lipid composition and the organization of the erythrocyte membrane

et al. 2016

View full text Add to dashboard Cite

BackgroundReduced erythrocyte survival and deformability may contribute to the so-called anemia of inflammation observed in septic patients. Erythrocyte structure and function are affected by both the membrane lipid composition and the organization. We therefore aimed to determine whether these parameters are affected during systemic inflammation.MethodsA sensitive matrix-assisted laser desorption and ionization time-of-flight mass spectrometric method was used to investigate the effect of plasma components of 10 patients with septic shock and of 10 healthy volunteers subjected to experimental endotoxemia on erythrocyte membrane lipid composition.ResultsIncubation of erythrocytes from healthy control donors with plasma from patients with septic shock resulted in membrane phosphatidylcholine hydrolysis into lysophosphatidylcholine (LPC). Plasma from volunteers undergoing experimental human endotoxemia did not induce LPC formation. The secretory phospholipase A2 IIA concentration was enhanced up to 200-fold in plasma of septic patients and plasma from endotoxin-treated subjects, but did not correlate with the ability of these plasmas to generate LPC. Erythrocyte phosphatidylserine exposure increased up to two-fold during experimental endotoxemia.ConclusionsErythrocyte membrane lipid remodeling as reflected by LPC formation and/or PS exposure occurs during systemic inflammation in a secretory phospholipase A2 IIA-independent manner.General significanceSepsis-associated inflammation induces a lipid remodeling of the erythrocyte membrane that is likely to affect erythrocyte function and survival, and that is not fully mimicked by experimental endotoxemia.

show abstract

“…Furthermore, repeated endotoxin administration studies have demonstrated the development of endotoxin tolerance, representing an immune suppressed state that resembles sepsis-induced immunoparalysis13. 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 interventions14151617, and to evaluate the effects of inflammation on other biologic processes, such as iron homeostasis18.…”

mentioning

confidence: 99%

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

Kiers

Koch

Hamers

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 20 publications

References 43 publications

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

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

Inflammation-associated changes in lipid composition and the organization of the erythrocyte membrane

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

Contact Info

Product

Resources

About