title: Long-term preconditioning with erythropoietin reduces ischemia-induced skin necrosis.
abstract: OBJECTIVE
  Recent findings have attested to EPO tissue-protective effects in ischemically challenged tissues. Therefore, the study aimed at elaborating the effect of systemic pre- and postconditioning using EPO in a mouse model of persistent ischemia of the skin.
  
  
  METHODS
  Three groups of nine C57Bl/6-mice each were analyzed. The experimental groups consisted of untreated controls, EPO preconditioning, and EPO postconditioning (500 IU EPO/kg bw/day for 10 days). Critically perfused skin flaps undergoing necrosis, if kept untreated, were mounted into dorsal skinfold chambers. Intravital epi-fluorescence microscopy was performed for 10 days to assess tissue necrosis, microcirculation, inflammation, and angiogenesis. Protein expression analysis of eNOS was performed. Hematocrit analyses were carried out separately in eight animals.
  
  
  RESULTS
  Only EPO preconditioning was able to significantly reduce necrosis, when compared with controls. This correlated with a significantly increased CD in the critically perfused tissue. Administration of EPO only slightly increased eNOS expression at day 10, when compared with controls. EPO induced angiogenesis and increased hematocrit. Finally, EPO significantly reduced leukocytic inflammation in arterioles in all EPO receiving mice.
  
  
  CONCLUSIONS
  EPO preconditioning effectively reduces skin necrosis predominantly by capillary maintenance and reperfusion, as well as improved tissue regeneration. Thus, EPO preconditioning might represent a promising, non-invasive approach to reduce complications in ischemically challenged skin.
authors.affiliation: Department of Plastic Surgery and Hand Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Department of Plastic Surgery and Hand Surgery, University of Zurich, Zurich, Switzerland.
authors.forename: Farid
authors.initials: F
authors.lastname: Rezaeian
authors.forename: Reto
authors.initials: R
authors.lastname: Wettstein
authors.forename: Claudia
authors.initials: C
authors.lastname: Scheuer
authors.forename: Thilo L
authors.initials: TL
authors.lastname: Schenck
authors.forename: Jose T
authors.initials: JT
authors.lastname: Egaña
authors.forename: Hans-Günther
authors.initials: HG
authors.lastname: Machens
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Yves
authors.initials: Y
authors.lastname: Harder
mesh_terms: D000818:Animals; D004921:Erythropoietin / Q000494:pharmacology*; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012867:Skin / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
chemical_list: D004921:Erythropoietin
keywords: angiogenesis; capillary reperfusion; flap; intravital epi-fluorescence microscopy; persistent ischemia