title: Anti-inflammatory signaling during ex vivo liver perfusion improves the preservation of pig liver grafts before transplantation.
abstract: Normothermic ex vivo liver perfusion (NEVLP) improves graft preservation by avoiding cold ischemia injury. We investigated whether the protective effects of NEVLP can be further improved by applying strategies targeted on reducing the activation of proinflammatory cytokines during perfusion. Livers retrieved under heart-beating conditions were perfused for 4 hours. Following the preservation period, a pig liver transplantation was performed. In group 1 (n = 5), anti-inflammatory strategies (alprostadil, n-acetylcysteine, carbon monoxide, sevoflurane, and subnormothermic temperature [33°C]) were applied. This was compared with a perfused control group (group 2) where livers (n = 5) were perfused at 37°C without anti-inflammatory agents, similar to the setup used in current European clinical trials, and to a control group preserved with static cold storage (group 3). During 3-day follow-up, markers of reperfusion injury, bile duct injury, and liver function were examined. Aspartate aminotransferase (AST) levels during perfusion were significantly lower in the study versus control group at 1 hour (52 ± 6 versus 162 ± 86 U/L; P = 0.01), 2 hours (43 ± 5 versus 191 ± 111 U/L; P = 0.008), and 3 hours (24 ± 16 versus 218 ± 121 U/L; P = 0.009). During perfusion, group 1 versus group 2 had reduced interleukin (IL) 6, tumor necrosis factor α, and galactosidase levels and increased IL10 levels. After transplantation, group 1 had lower AST peak levels compared with group 2 and group 3 (1400 ± 653 versus 2097 ± 1071 versus 1747 ± 842 U/L; P = 0.47) without reaching significance. Bilirubin levels were significantly lower in group 1 versus group 2 at day 1 (3.6 ± 1.5 versus 6.60 ± 1.5 μmol/L; P = 0.02) and 3 (2 ± 1.1 versus 9.7 ± 7.6 μmol/L; P = 0.01). A trend toward decreased hyaluronic acid, as a marker of improved endothelial cell function, was observed at 1, 3, and 5 hours after reperfusion in group 1 versus group 2. Only 1 early death occurred in each group (80% survival). In conclusion, addition of anti-inflammatory strategies further improves warm perfused preservation. Liver Transplantation 22 1573-1583 2016 AASLD.
authors.affiliation: Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goldaracena
authors.affiliation: Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.|Programa de Doctorat en Cirurgia i Ciències Morfològiques, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Echeverri
authors.affiliation: Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vinzent N
authors.initials: VN
authors.lastname: Spetzler
authors.affiliation: Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kaths
authors.affiliation: Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Barbas
authors.affiliation: Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kristine S
authors.initials: KS
authors.lastname: Louis
authors.affiliation: Department of Pathology, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Oyedele A
authors.initials: OA
authors.lastname: Adeyi
authors.affiliation: Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Grant
authors.affiliation: Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nazia
authors.initials: N
authors.lastname: Selzner
authors.affiliation: Departments of Surgery, Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. markus.selzner@uhn.ca.
authors.forename: Markus
authors.initials: M
authors.lastname: Selzner
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use; D064591:Allografts / Q000378:metabolism*; D000527:Alprostadil / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001659:Biliary Tract / Q000473:pathology; D001663:Bilirubin / Q000032:analysis; D050377:Cold Ischemia / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D008738:Methyl Ethers / Q000627:therapeutic use; D023421:Models, Animal; D009926:Organ Preservation / Q000379:methods*; D010477:Perfusion / Q000379:methods*; D015427:Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D000077149:Sevoflurane; D034421:Sus scrofa; D013552:Swine; D013696:Temperature; D020858:Tissue and Organ Harvesting / Q000379:methods*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008738:Methyl Ethers; D000077149:Sevoflurane; D006820:Hyaluronic Acid; D001219:Aspartate Aminotransferases; D000527:Alprostadil; D001663:Bilirubin; D000111:Acetylcysteine