title: Donor brain death exacerbates complement-dependent ischemia/reperfusion injury in transplanted hearts.
abstract: BACKGROUND
  Brain death (BD) can immunologically prime the donor organ and is thought to lead to exacerbated ischemia/reperfusion injury after transplantation. Using a newly developed mouse model of BD, we investigated the effect of donor BD on posttransplantation cardiac ischemia/reperfusion injury. We further investigated the therapeutic effect of a targeted complement inhibitor in recipients of BD donor hearts and addressed the clinical relevance of these studies by analyzing human heart biopsies from BD and domino (living) donors.
  
  
  RESULTS
  Hearts from living or BD donor C57BL/6 mice were transplanted into C57BL/6 or BALB/c recipients. Recipient mice were treated with the complement inhibitor CR2-Crry or vehicle control (n=6). Isografts were analyzed 48 hours after transplantation for injury, inflammation, and complement deposition, and allografts were monitored for graft survival. Human cardiac biopsies were analyzed for complement deposition and inflammatory cell infiltration. In the murine model, donor BD exacerbated ischemia/reperfusion injury and graft rejection, as demonstrated by increased myocardial injury, serum cardiac troponin, cellular infiltration, complement deposition, inflammatory chemokine and cytokine levels, and by decreased graft survival. CR2-Crry treatment of recipients significantly reduced all measured outcomes in grafts from both BD and living donors compared with controls. Analysis of human samples documented the relevance of our experimental findings and revealed exacerbated complement deposition and inflammation in grafts from BD donors compared with grafts from living donors.
  
  
  CONCLUSIONS
  BD exacerbates posttransplantation cardiac ischemia/reperfusion injury in mice and humans and decreases survival of mouse allografts. Furthermore, targeted complement inhibition in recipient mice ameliorates BD-exacerbated ischemia/reperfusion injury.
authors: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Carl
authors: C
authors: Atkinson
authors: Bernhard
authors: B
authors: Floerchinger
authors: Fei
authors: F
authors: Qiao
authors: Sarah
authors: S
authors: Casey
authors: Tucker
authors: T
authors: Williamson
authors: Ellen
authors: E
authors: Moseley
authors: Serban
authors: S
authors: Stoica
authors: Martin
authors: M
authors: Goddard
authors: Xupeng
authors: X
authors: Ge
authors: Stefan G
authors: SG
authors: Tullius
authors: Stephen
authors: S
authors: Tomlinson
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001706:Biopsy; D001926:Brain Death / Q000503:physiopathology*; D003165:Complement System Proteins / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects; D016027:Heart Transplantation / Q000401:mortality / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000503:physiopathology*; D012189:Retrospective Studies; D015996:Survival Rate; D014019:Tissue Donors; D055815:Young Adult
chemical_list: C527099:CR2-Crry fusion protein, mouse; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D003165:Complement System Proteins