The role of hepatovenous back-perfusion in maintaining hepatic viability was investigated during inflow occlusion (Pringle manoeuvre) of the pig liver. The study compared two ischaemia procedures of 60 min duration: hepatic inflow occlusion and inflow plus outflow occlusion (vascular exclusion). Each procedure was carried out in six pigs and liver tissue perfusion, energy metabolism, lipid peroxidation and 7-day survival were assessed. Although all pigs survived after inflow occlusion, five of six died after vascular exclusion (P < 0.01). Exclusion induced a significant decrease in perfusion to 15.3 per cent of the value before ischaemia compared with 32.4 per cent after hepatic inflow occlusion alone (P < 0.01). Although cellular adenosine 5'-triphosphate levels were significantly decreased by ischaemia in both groups, the fall was less in pigs with inflow occlusion alone (to 55 per cent of the preclamp value) than in those with exclusion (to 24 per cent of the preclamp value) (P < 0.01). The plasma phosphatidylcholine hydroperoxide level rose immediately after reperfusion in pigs with exclusion, while the level remained constant after inflow occlusion alone. There is a fundamental difference between the two ischaemia procedures: back-perfusion from the vena cava contributes to the maintenance of liver function during inflow occlusion.

The mechanism by which FK506 (FK) prevents hepatic injury induced by ischemia/reperfusion was studied. Adult Sprague-Dawley rats were subjected to 60-min normothermic liver ischemia. Animals were divided into two groups: group I, controls, saline vehicle treatment; group II, FK treatment. FK (1 mg/kg/day, p.o.) was given for 4 consecutive days prior to inducing ischemia. In addition to a survival study, plasma levels of endotoxin and serum activities of tumor necrosis factor-α (TNF) and aspartate aminotransferase (AST) were assessed in the blood collected from suprahepatic vena cava. Results showed: (1) FK therapy significantly improved 7-day survival (80.0%) compared with nontreated animals (50.0%, p < 0.05); (2) both TNF and endotoxin were elevated following reperfusion, reaching maximum values at 3 h after reperfusion (217.0 ± 40.6 and 280.5 ± 31.4 pg/ml, respectively, in the control; mean ± SEM), and (3) serum activities of TNF and AST following reperfusion were substantially suppressed with FK treatment, whereas FK did not reduce the rise in endotoxin. These findings suggest that suppression of TNF production in response to endotoxemia might account at least in part for the protective effect of FK against ischemia-induced hepatic injury.

No abstract

The present work was undertaken to study whether the immunosuppressive agents cyclosporin (CyA) and azathioprine (AZA) ameliorate hepatic injury after warm ischemia. A temporary, normothermic liver ischemia was induced in female Sprague-Dawley rats. The rats were treated with CyA (10 mg/kg per day p.o.), AZA (8 mg/kg per day p.o.), or vehicles for 4 days before surgery. Seven-day survival rates after 60 min of ischemia improved significantly with CyA (76.2%, P < 0.005) and AZA (78.6%, P < 0.001) treatment, compared with 43.0% for the control group. The highest levels of serum aminotransferases in the treatment groups tended to be lower than those in the control group. The peak values for the percentage of liver necrosis, an indicator of the extent of hepatic necrosis, in the animals treated with CyA (26.1% +/- 7.2%, mean +/- SEM) and AZA (32.1% +/- 5.7%) were significantly lower than in the control group (47.4% +/- 3.7%). Lipid peroxidative damage after reperfusion, assessed as the hepatic malondialdehyde (MDA) concentration, was significantly suppressed by pretreatment with CyA and AZA. Histological findings coincided with other parameters. This study demonstrates that both AZA and CyA have beneficial effects on normothermic liver ischemia in rats. It is suggested that the diminished lipid peroxidative damage with these agents might be one of the mechanisms responsible for this.

We studied the relationship between augmentation of liver regeneration with immunosuppressants and malondialdehyde (MDA, an end-product of lipid peroxides) production. MDA was determined using the thiobarbituric acid reaction. Rats underwent a 4-day treatment of FK506 (FK, 1 mg/kg per day), cyclosporine (Cs, 10 mg/kg) or azathioprine (AZA, 1 mg/kg) by gavage prior to 70% hepatectomy. They were then divided into four groups: (1) controls (vehicle-treated); (2) FK; (3) Cs; (4) AZA. MDA levels, uptake of BrdU (5-bromo-2-deoxyuridine) in the liver and serum biochemistry were investigated 24 h after hepatectomy. Immunosuppressant pretherapy significantly stimulated BrdU uptake by hepatocytes, in association with increased MDA production, while there were no differences in serum liver injury parameters among the groups given or not given immunosuppressants. The implications of the rising MDA values during liver regeneration are discussed with respect to immunosuppression and a measure of lipid peroxidation. Additional study indicated that one immunodepressant pretreatment (24 h prior to hepatectomy) was effective for up-regulation of liver regeneration.