title: Phlebotomies or erythropoietin injections allow mobilization of iron stores in a mouse model mimicking intensive care anemia.
abstract: OBJECTIVE
  Anemia in critically ill patients is frequent and consists of chronic disease associated with blood losses. These two mechanisms have opposite effects on iron homeostasis, especially on the expression of the iron regulatory hormone hepcidin. We developed a mouse model mimicking the intensive care anemia to explore iron homeostasis.
  
  
  METHODS
  Experimental study.
  
  
  METHODS
  University-based research laboratory.
  
  
  METHODS
  C57BL/6 mice.
  
  
  METHODS
  Mice received either a single intraperitoneal injection of lipopolysaccharide followed 1 week later by zymosan, or were subjected to repeated phlebotomies by retro-orbital punctures, or both. Several subsets of mice were analyzed over a 14-day period to describe the mouse model of intensive care anemia. Additional mice received erythropoietin injections with or without the zymosan treatment and were killed at day 5, to perform a more detailed analysis.
  
  
  RESULTS
  We observed anemia as soon as 5 days after zymosan injection, together with increased messenger RNA (mRNA) levels for interleukin-6 and hepcidin. Phlebotomies alone fully suppressed hepcidin mRNA expression. Interestingly, in mice treated with zymosan and phlebotomies, hepcidin expression was suppressed, despite the persistent increase in interleukin-6. Stimulation of erythropoiesis by erythropoietin injections also led to a decrease in hepcidin mRNA in zymosan-treated mice. In these situations combining inflammation and erythropoiesis stimulation, there was no change in ferroportin, the membrane iron exporter, at the mRNA level, whereas ferroportin protein increased. Macrophage iron stores (assessed by histology using diaminobenzidine staining, or by quantification of nonheme iron and ferritin concentrations) were depleted in the spleen.
  
  
  CONCLUSIONS
  These results suggest that the erythroid factor dominates over inflammation for hepcidin regulation, and that iron could be mobilized in these situations combining inflammation and erythropoiesis stimulation.
authors.affiliation: INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon, Paris, France.
authors.forename: Sigismond
authors.initials: S
authors.lastname: Lasocki
authors.forename: Sarah
authors.initials: S
authors.lastname: Millot
authors.forename: Valérie
authors.initials: V
authors.lastname: Andrieu
authors.forename: Philippe
authors.initials: P
authors.lastname: Lettéron
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pilard
authors.forename: Françoise
authors.initials: F
authors.lastname: Muzeau
authors.forename: Olivier
authors.initials: O
authors.lastname: Thibaudeau
authors.forename: Philippe
authors.initials: P
authors.lastname: Montravers
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000627:therapeutic use*; D064451:Hepcidins; D006706:Homeostasis / Q000187:drug effects*; D015850:Interleukin-6 / Q000235:genetics; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018962:Phlebotomy; D012333:RNA, Messenger / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D015850:Interleukin-6; D012333:RNA, Messenger; D000098742:Ferroportin; D004921:Erythropoietin; D007501:Iron