Extended preservation of rat liver graft by induction of heme oxygenase-1.
Livers can be preserved only for a short period without jeopardizing the transplantation outcome. Heat shock proteins (HSPs) protect against ischemia and reperfusion injury. We studied whether their induction and, in particular, the induction of heme oxygenase 1 (HO-1), improves transplantation survival after an extended time of cold storage. Rats were subjected to heat preconditioning (42 degrees C for 20 minutes). Livers were harvested 24 hours later, preserved in cold University of Wisconsin solution for 44 hours, and transplanted in isogeneic rats (arterialized transplantation). HO-1 was specifically induced and inhibited by cobalt protoporphyrin and tin protoporphyrin, respectively. All animals receiving a graft without preconditioning and subjected to 44 hours of cold preservation died within 3 days, whereas 89% of rats who received a graft exposed to heat survived for 3 weeks (P =.0004). Preconditioning reduced serum aspartate transaminase (AST) and lactate dehydrogenase activities after reperfusion, improved bile flow, and decreased the histologic lesions of reperfusion injury. These significant effects of heat preconditioning were prevented by administration of tin protoporphyrin and could be reproduced by administration of cobalt protoporphyrin. In grafts without preconditioning, only a small fraction (<5%) of hepatocytes were positive with the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay, and even less expressed activated caspase 3. Preconditioning tended to reduce the number of positive cells and to stimulate the expression of antiapoptotic Bcl-X(L). In conclusion, heat preconditioning and, specifically, overexpression of HO-1 improve posttransplantation survival and graft function after prolonged cold ischemia preservation. The mechanism underlying these beneficial effects does not appear to be prevention of apoptosis.
Redaelli
Claudio A
CA
Department of Visceral and Transplantation Surgery, Institute for Clinical Pharmacology, University of Bern, Bern, Switzerland.
Tian
Ying-Hua
YH
Schaffner
Thomas
T
Ledermann
Monika
M
Baer
Hans U
HU
Dufour
Jean-François
JF
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003080:Cold Temperature; D006085:Graft Survival / Q000502:physiology*; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006358:Hot Temperature; D020287:In Situ Nick-End Labeling; D019194:Ischemic Preconditioning / Q000379:methods*; D016031:Liver Transplantation; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009926:Organ Preservation / Q000379:methods*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008665:Metalloporphyrins; D019253:Proto-Oncogene Proteins c-bcl-2; D011524:Protoporphyrins; D051020:bcl-X Protein; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases