TUMOR-NECROSIS-FACTOR AND ENDOTOXIN IN THE PATHOGENESIS OF LIVER AND PULMONARY INJURIES AFTER ORTHOTOPIC LIVER-TRANSPLANTATION IN THE RAT

This study examines whether tumor necrosis factor and endotoxin are involved in the pathogenesis of primary nonfunction of graft and pulmonary complication after orthotopic liver transplantation. Livers from Lewis rats were stored for either 1 or 4 hr in ice-cold Euro-Collins solution (1-hr storage and 4-hr storage group, respectively). Subsequently, donor livers were implanted orthotopically. In some experiments, anti-tumor necrosis factor antibody was administered intravenously before and immediately after the surgery into animals that received livers stored for 4 hr. Blood samples for the measurement of tumor necrosis factor and endotoxin were collected by way of an indwelling catheter placed in the suprahepatic vena cava. Serum tumor necrosis factor was elevated at all time points studied postoperatively in rats of the 4-hr storage group; however, tumor necrosis factor was not detected in the serum in the 1-hr storage group. Endotoxin was also elevated significantly in the serum of the former group compared with levels in the serum of the latter group. The peak value of endotoxin occurred 1 hr earlier than that of tumor necrosis factor, suggesting that the rise in endotoxin stimulated release of tumor necrosis factor. The histological study of livers stored for 4 hr showed substantial hepatocellular degeneration 24 hr after surgery, whereas hepatocellular damage was minimal in the 1-hr storage group. Serum ALT levels 24 hr after the operation in the 1-hr and 4-hr storage groups were 169 +/- 46 IU/L and 374 +/- 41 IU/L (mean +/- S.E.M., p < 0.05), respectively. Histological studies of the lung revealed substantial alveolar edema, leukocyte infiltration and alveolar hemorrhage in the 4-hr storage group; however, these findings were minimal in the lungs in the 1-hr storage group. Anti-tumor necrosis factor antibody treatment effectively attenuated both the liver and pulmonary injuries and the serum ALT activities (163 +/- 9 IU/L, p < 0.05) compared with nontreated animals. Thus this study demonstrates that endotoxemia occurred in the early postoperative stage, followed by elevation of levels of tumor necrosis factor in blood. These events may contribute to the pathogenesis of primary nonfunction of the graft and pulmonary complications after orthotopic liver transplantation.