Primary graft nonfunction and Kupffer cell activation after liver transplantation from non-heart-beating donors in pigs.
More extensive use of non-heart-beating donors (NHBD) could reduce mortality on liver transplantation waiting lists, but this is associated with more primary nonfunction (PNF). We assessed which parameters are involved in the development of PNF in livers from NHBD in a previously validated pig liver transplantation model, in which livers were transplanted after exposure to incremental periods of warm ischemia. The risk of PNF was unacceptably high (>50%) when livers were exposed to >30 minutes' warm ischemia before a short cold ischemic period. This study examined how PNF is affected by Kupffer cell activation (beta-galactosidase), the generation of cytokines tumor necrosis factor alpha and interleukin 6, antioxidant mechanisms (ascorbic acid, alpha-tocopherol, reduced glutathione), circulating redox-active iron, and sinusoidal endothelial cell function (hyaluronic acid clearance). Kupffer cells were more activated in PNF recipients, as suggested by higher beta-galactosidase levels (15 minutes after reperfusion), and secondarily, by higher production of tumor necrosis factor alpha and interleukin 6 (180 minutes after reperfusion). In addition, alpha-tocopherol and reduced glutathione were lower, and ascorbic acid and redox-active iron higher in PNF recipients. Finally, PNF grafts displayed progressively decreasing hyaluronic acid clearance (suggesting sinusoidal endothelial cell dysfunction) and parenchymal edema. Consequently, a reduced-flow phenomenon was documented. In grafts from NHBD that are destined to fail, beta-galactosidase activity (a surrogate of Kupffer cell activation) is higher, proinflammatory cytokines are overproduced, some antioxidant mechanisms fail, and circulating redox-active iron is more rapidly released. A no-flow phenomenon is eventually observed in these failing grafts.
Monbaliu
Diethard
D
Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium. Diethard.Monbaliu@uz.kuleuven.ac.be
van Pelt
Jos
J
De Vos
Rita
R
Greenwood
Joanne
J
Parkkinen
Jaakko
J
Crabbé
Tina
T
Zeegers
Marcel
M
Vekemans
Katrien
K
Pincemail
Joël
J
Defraigne
Jean-Olivier
JO
Fevery
Johan
J
Pirenne
Jacques
J
D000818:Animals; D000975:Antioxidants / Q000032:analysis; D001205:Ascorbic Acid / Q000097:blood; D016207:Cytokines / Q000032:analysis; D051799:Delayed Graft Function / Q000276:immunology*; D005978:Glutathione / Q000097:blood; D007501:Iron; D007728:Kupffer Cells / Q000201:enzymology / Q000276:immunology*; D008099:Liver / Q000098:blood supply; D016031:Liver Transplantation; D008262:Macrophage Activation; D010084:Oxidation-Reduction; D012039:Regional Blood Flow; D013552:Swine; D052096:Warm Ischemia; D024502:alpha-Tocopherol / Q000097:blood; D001616:beta-Galactosidase / Q000032:analysis / Q000378:metabolism
D000975:Antioxidants; D016207:Cytokines; D007501:Iron; D001616:beta-Galactosidase; D005978:Glutathione; D024502:alpha-Tocopherol; D001205:Ascorbic Acid