title: Xenon treatment protects against cold ischemia associated delayed graft function and prolongs graft survival in rats.
abstract: Prolonged hypothermic storage causes ischemia-reperfusion injury (IRI) in the renal graft, which is considered to contribute to the occurrence of the delayed graft function (DGF) and chronic graft failure. Strategies are required to protect the graft and to prolong renal graft survival. We demonstrated that xenon exposure to human proximal tubular cells (HK-2) led to activation of range of protective proteins. Xenon treatment prior to or after hypothermia-hypoxia challenge stabilized the HK-2 cellular structure, diminished cytoplasmic translocation of high-mobility group box (HMGB) 1 and suppressed NF-κB activation. In the syngeneic Lewis-to-Lewis rat model of kidney transplantation, xenon exposure to donors before graft retrieval or to recipients after engraftment decreased caspase-3 expression, localized HMGB-1 within nuclei and prevented TLR-4/NF-κB activation in tubular cells; serum pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced and renal function was preserved. Xenon treatment of graft donors or of recipients prolonged renal graft survival following IRI in both Lewis-to-Lewis isografts and Fischer-to-Lewis allografts. Xenon induced cell survival or graft functional recovery was abolished by HIF-1α siRNA. Our data suggest that xenon treatment attenuates DGF and enhances graft survival. This approach could be translated into clinical practice leading to a considerable improvement in long-term graft survival.
authors.affiliation: Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: H R
authors.initials: HR
authors.lastname: Watts
authors.forename: M
authors.initials: M
authors.lastname: Chong
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.forename: C
authors.initials: C
authors.lastname: Tralau-Stewart
authors.forename: P H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: M
authors.initials: M
authors.lastname: Maze
authors.forename: A J T
authors.initials: AJ
authors.lastname: George
authors.forename: D
authors.initials: D
authors.lastname: Ma
mesh_terms: D018685:Anesthetics, Inhalation / Q000008:administration & dosage; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D050377:Cold Ischemia; D051799:Delayed Graft Function / Q000209:etiology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D006085:Graft Survival; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D007035:Hypothermia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016030:Kidney Transplantation; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000150:complications*; D014184:Transplantation, Homologous; D014978:Xenon / Q000008:administration & dosage*
chemical_list: D018685:Anesthetics, Inhalation; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014978:Xenon
keywords: Delayed graft function (DGF); graft survival; renal graft loss; treatment