Split-liver procedure and inflammatory response: improvement by pharmacological preconditioning.

BACKGROUND: Final outcome of split-liver (SL) transplantation is impaired due to an increased rate of vascular complications and primary non-function. Herein, we hypothesized that an in situ split-liver procedure induces an inflammatory response and a deterioration of graft quality. We further studied whether graft quality can be improved by pharmacologic preconditioning. MATERIAL AND METHODS: SL-procedure was performed in rats. One group (SL-HPP; n = 8) was pretreated according to a defined protocol [Homburg preconditioning protocol (HPP)], including pentoxyphylline, glycine, deferoxamine, N-acetylcysteine, erythropoietin, melatonin, and simvastatin. A second SL group (SL-Con; n = 8) received NaCl. Untreated non-SL served as controls (Sham; n = 8). Cytokines release, leukocyte invasion, endothelial activation and liver morphology were studied directly after liver harvest and after 8 h cold storage. Lung tissue was studied to determine remote injury. RESULTS: The SL-procedure induced an increase of TNF-α concentration, intercellular-adhesion-molecule 1 (ICAM-1) expression, leukocytic-tissue infiltration and vacuolization. This was associated with an increased number of apoptotic hepatocytes. HPP reduced TNF-α release, ICAM-1 expression, the number of infiltrated leukocytes, as well as hepatocellular vacuolization and apoptosis. In lung tissue, the SL-procedure caused an increased IL-1 and IL-6 concentration and leukocyte infiltration. CONCLUSIONS: HPP was capable of abrogating cytokine-mediated leukocytic response. Pharmacologic preconditioning of liver donors prevents the SL procedure-mediated inflammatory response, resulting in an improved graft quality.

Multidrug donor preconditioning protects steatotic liver grafts against ischemia-reperfusion injury.

BACKGROUND: Graft dysfunction of steatotic livers (SL) still remains a major challenge in liver transplantation. Different mechanisms are thought to be involved in the impaired tolerance of SL to ischemia-reperfusion injury. Thus, different pharmacologic strategies may need to be combined to effectively protect SL and to reduce graft dysfunction after transplantation. Therefore, we analyzed the effectiveness of a multidrug donor preconditioning (MDDP) procedure to protect SL from cold ischemia-reperfusion injury. METHODS: Liver steatosis was induced by a high-carbohydrate, fat-free diet. A total of 24 Sprague-Dawley rats were divided into 3 groups (n = 8 each), including a control group with nonsteatotic livers (Con), a vehicle-treated SL group (SL-Con), and a SL group undergoing MDDP (SL-MDDP), including pentoxyphylline, glycine, deferoxamine, N-acetylcysteine, erythropoietin, melatonin, and simvastatin. MDDP was applied before liver perfusion with 4°C histidine-tryptophan-ketoglutarate (HTK) solution and organ harvest. After 24 hours of cold storage in HTK, postischemic reperfusion was performed in an isolated liver reperfusion model using 37°C Krebs-Henseleit bicarbonate buffer. RESULTS: After 60 minutes of reperfusion, SL showed a significant reduction of bile flow as well as a marked increase of liver enzyme levels and apoptotic cell death compared with Con. This was associated with an increased malondialdehyde formation, interleukin-1 production, and leukocytic tissue infiltration. MDDP completely abolished the inflammatory response and was capable of significantly reducing parenchymal dysfunction and injury. CONCLUSIONS: MDDP decreases SL injury after cold storage and reperfusion. The concept of MDDP as a simple and safe preoperative regime, thus may be of interest in clinical use, expanding the donor pool from marginal donors.