title: Carbon monoxide inhibits apoptosis during cold storage and protects kidney grafts donated after cardiac death.
abstract: Ischemia/reperfusion (I/R) injury remains as a serious deleterious factor in kidney transplantation (KTx). We hypothesized that carbon monoxide (CO), an endogenous potent cytoprotective molecule, inhibits hypothermia-induced apoptosis of kidney grafts. Using the rat KTx model mimicking the conditions of donation after cardiac death (DCD) as well as nontransplantable human kidney grafts, this study examined effects of CO in preservation solution in improving the quality of marginal kidney grafts. After cardiac cessation, rat kidneys underwent 40 min warm ischemia (WI) and 24 h cold storage (CS) in control UW or UW containing CO (CO-UW). At the end of CS, kidney grafts in control UW markedly increased mitochondrial porin release into the cytosol and resulted in increased cleaved caspase-3 and PARP expression. In contrast, grafts in CO-UW had significantly reduced mitochondrial breakdown and caspase pathway activation. After KTx, recipient survival significantly improved with CO-UW with less TUNEL(+) cells and reduced mRNA upregulation for proinflammatory mediators (IL-6, TNF-α, iNOS). Furthermore, when nontransplantable human kidney grafts were stored in CO-UW for 24 h, graft PARP expression, TUNEL(+) cells, and proinflammatory mediators were less than those in control UW. CO in UW inhibited hypothermia-induced apoptosis and significantly improved kidney graft function and outcomes of KTx.
authors: Department of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Kikumi S
authors: KS
authors: Ozaki
authors: Junichi
authors: J
authors: Yoshida
authors: Shinya
authors: S
authors: Ueki
authors: Gaetan L
authors: GL
authors: Pettigrew
authors: Nisanne
authors: N
authors: Ghonem
authors: Rita M
authors: RM
authors: Sico
authors: Lung-Yi
authors: LY
authors: Lee
authors: Ron
authors: R
authors: Shapiro
authors: Fadi G
authors: FG
authors: Lakkis
authors: Alvaro
authors: A
authors: Pacheco-Silva
authors: Noriko
authors: N
authors: Murase
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002248:Carbon Monoxide / Q000494:pharmacology*; D003080:Cold Temperature; D003600:Cytosol / Q000378:metabolism; D003643:Death; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011887:Raffinose / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury; D016896:Treatment Outcome
chemical_list: D007328:Insulin; D019188:Organ Preservation Solutions; D012333:RNA, Messenger; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D002248:Carbon Monoxide; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose