title: Carbon monoxide releasing molecules inhibit cell death resulting from renal transplantation related stress.
abstract: OBJECTIVE
  Organ cold storage and subsequent transplantation are associated with significant ischemia-reperfusion injury, leading to cell death, graft inflammation and decreased graft function.
  
  
  METHODS
  CORM-3s reduce oxidative stress and prevent inflammation in kidneys stored at 4C and subsequently transplanted. Graft survival and function are markedly improved compared to kidneys preserved and stored in University of Wisconsin solution alone. We determined whether CORM-3 has direct antiapoptotic effects on in vitro preparations of human HUVECs exposed to anoxic conditions. We also determined whether direct administration of CORM-3 to renal grafts before and/or after cold storage would prevent renal damage during the transplantation process.
  
  
  RESULTS
  CORM-3 supplementation led to a significantly increased frequency of live cells (mean ± SD 72.3% ± 1.9%, p <0.01), reduced apoptosis (14.9% ± 6.1%, p <0.01) and decreased mitochondrial transmembrane potential (40.2% ± 7.2%, p <0.05) in HUVECs exposed to 20 hours of cold storage compared to controls (11.6% ± 3.5%, 82.2% ± 2.3% and 78.2% ± 3.2%, respectively). In keeping with this antiapoptotic effect CORM-3 supplementation led to a mean 7.4 ± 2.1-fold up-regulation in Bcl-2 gene expression. CORM-3 supplementation in standard preservation solution was most beneficial at initial ischemic injury and before cold storage exposure. However, additional reflushing before vascular reperfusion showed an additive benefit to graft survival and function after transplantation. This was confirmed by decreased glomerular and tubular necrosis, and apoptosis in double flushed grafts.
  
  
  CONCLUSIONS
  CORM-3 supplementation in standard University of Wisconsin solution has a significant impact on decreasing cellular and graft injury, and improving survival through its antiapoptotic effects, which are likely mediated through mitochondrial membrane stabilization.
authors.affiliation: Division of Urology, Department of Surgery, London Health Sciences Center, London, Ontario, Canada.
authors.forename: Alp
authors.initials: A
authors.lastname: Sener
authors.forename: Kim-Chi
authors.initials: KC
authors.lastname: Tran
authors.forename: Jian P
authors.initials: JP
authors.lastname: Deng
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Zhu
authors.initials: Z
authors.lastname: Lan
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.forename: Jacquie
authors.initials: J
authors.lastname: Arp
authors.forename: Michael
authors.initials: M
authors.lastname: Salna
authors.forename: Phillip
authors.initials: P
authors.lastname: Acott
authors.forename: Gediminas
authors.initials: G
authors.lastname: Cepinskas
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Jevnikar
authors.forename: Patrick P W
authors.initials: PP
authors.lastname: Luke
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D006085:Graft Survival; D007249:Inflammation / Q000517:prevention & control; D007328:Insulin / Q000494:pharmacology; D016030:Kidney Transplantation; D008297:Male; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology*; D018384:Oxidative Stress; D011887:Raffinose / Q000494:pharmacology; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D007328:Insulin; D019188:Organ Preservation Solutions; D009942:Organometallic Compounds; C055206:University of Wisconsin-lactobionate solution; C476530:tricarbonylchloro(glycinato)ruthenium(II); D000493:Allopurinol; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose