Effects of Iron Loading and Iron Chelation Therapy on Innate Immunity During Human Endotoxemia
- Conditions
- AnemiaSystemic Inflammatory Process
- Interventions
- Registration Number
- NCT01349699
- Lead Sponsor
- Radboud University Medical Center
- Brief Summary
Iron affects immunity. However, the exact effect of iron on the innate immune response is not known. Animal data suggest that iron administration induced oxidative stress which enhances the innate immune response, whereas iron chelation has the opposite effect. The investigators tested the hypothesis that administration of iron sucrose 1.25 mg/kg augments the innate immune response, and iron chelation by deferasirox 30 mg/kg attenuates the innate immune response during human experimental endotoxemia.
- Detailed Description
Systemic inflammation is accompanied by profound changes in iron distribution, mainly under the influence of hepcidin, leading to sequestration of iron in macrophages of the reticuloendothelial system, and ultimately anemia of inflammation. This redistribution of iron may represent an effective defense mechanism against a variety of pathogens, that need iron for replication and growth. The fact that iron withholding strategy is such a highly conserved part of the innate immune response illustrates that iron homeostasis and immunity are closely related. Concordantly, several studies in animal models have revealed immune modulatory effects of both iron and iron chelation: Iron sucrose has been shown to potentiate the inflammatory response and associated mortality, while iron chelation appears to attenuate inflammation and improve outcome in murine models of inflammation and sepsis. The immune modulatory effects of iron supplements and chelators are mainly attributed to their ability to potentiate or reduce the formation of reactive oxygen species (ROS). A subfraction of non-transferrin bound catalytically active iron, labile plasma iron, is thought to be responsible as this free iron is able to easily donate or accept electrons, thereby fueling redox reactions. Oxidative stress is associated with propagation of the immune response, endothelial dysfunction, and contributes to the organ damage that occurs during systemic inflammation. In accordance, anti-oxidants exert anti-inflammatory effects. As such, iron chelation has been suggested to be a valuable adjuvant therapy during infection for two distinct reasons: inhibition of bacterial growth and protection of organs against inflammation induced oxidative stress.
Effects of iron status on the immune response has up till now mainly been investigated in in vitro and in animal models, often using supra-therapeutic dosages of iron donors or iron chelators. Data on the effect of iron loading and iron chelation during systemic inflammation in humans are lacking. The objectives of the present study were to investigate the acute effect of therapeutic dosages of iron loading and iron chelation therapy on iron homeostasis, oxidative stress, the innate immune response, and subclinical organ injury during systemic inflammation induced by experimental endotoxemia in humans in vivo.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 30
- male
- healthy
- between 18 and 35 years of age
- smoking
- use of prescription drugs
- febrile illness < 2 weeks before the study date
- abnormalities found at screening
- participation in another trial in the preceding 6 months
- iron disorders in the family
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Iron loading iron sucrose Subjects will receive 1.25 mg/kg iron sucrose intravenously 1 hour before endoxin administration 2ng/kg. Iron loading endotoxin Subjects will receive 1.25 mg/kg iron sucrose intravenously 1 hour before endoxin administration 2ng/kg. Placebo endotoxin Subjects will receive placebo instead of iron chelation or iron loading before endotoxin administration Placebo Placebo Subjects will receive placebo instead of iron chelation or iron loading before endotoxin administration Iron chelation endotoxin Subjects will receive 30mg/kg deferasirox orally 2 hours before endotoxin administration 2ng/kg. Iron chelation Deferasirox Subjects will receive 30mg/kg deferasirox orally 2 hours before endotoxin administration 2ng/kg.
- Primary Outcome Measures
Name Time Method TNF-alfa Level of TNF-alfa 90 minutes after endotoxin administration Level of TNF-alfa 90 minutes after endotoxin administration
- Secondary Outcome Measures
Name Time Method Cytokines 24 hrs after the administration of endotoxin Levels of TNF-alfa, IL-6, IL-10 IL-1RA, ICAM and VCAM.
Oxidative stress 24 hrs after the administration of iron / iron chelator / placebo Several parameters of oxidative stress are measured:
TBARS,carbonyls,oxidative radical production of neutrophils, ferric reducing ability of plasma.Hemodynamic response 24 hours after the administration of endotoxin Hemodynamic sequelae of endotoxin administration are monitored (heart rate, blood pressure) and the response of fore arm vessels to the infusion of vasoactive medication (norepinephrine, acetycholine, and nitroglycerine) is measured.