Anti-inflammatory Signaling During Ex Vivo Liver Perfusion Improves the Preservation of Pig Liver Grafts Before Transplantation

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 degrees C]) were applied. This was compared with a perfused control group (group 2) where livers (n = 5) were perfused at 37 degrees 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 6 121 U/L; P = 0.009). During perfusion, group 1 versus group 2 had reduced interleukin (IL) 6, tumor necrosis factor a, 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 mu mol/L; P = 0.02) and 3 (2 6 1.1 versus 9.7 +/- 7.6 mu mol/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.