Effects of Iron Loading and Iron Chelation Therapy on Innate Immunity During Human Endotoxemia
Condition: Systemic Inflammatory Process; Anemia
MeSH terms: Endotoxemia
Study type: Interventional

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.
    

Intervention name(s): iron sucrose; Deferasirox; endotoxin; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 1.25 mg/kg iron sucrose is administered intravenously 1 hr before endotoxin administration; 30 mg/kg deferasirox is administered orally 2 hrs before endotoxin administration.; at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously; At t=-2 hrs starch is dissolved in water to serve as a placebo for exjade. It is prepared and administered orally by a research nurse that is unblinded to the protocol.
At t=-1 hrs 0.9% NaCl is administered intravenously serving as a placebo for iron sucrose. The infused volume is identical, and the syringes en tubes are blinded by aluminum foil. The administration is carried out by a research nurse that is unblinded to the protocol.
Other intervention name(s): Venofer; Exjade; LPS
Intervention MeSH terms: Ferric Oxide, Saccharated; Deferasirox
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: endotoxemia; inflammation; iron; iron chelation; cytokines