Reduction of hepatotoxicity of tumor necrosis factor in isolated hepatic perfusion by administration of glucocorticoid as well as lipopolysaccharide

Background: The application of an isolation procedure with tumor necrosis f actor (TNF) To the liver is quit attractive, however; one of problems to ov ercome is reducing the toxicity to the liver caused by high closes of TNF. Materials and Methods: Rats underwent isolated hepatic perfusion (IHP) with TNF and pre-treatment of subcutaneous administration of dexamethasone (4 m g/kg) and/or intradermal administration of LPS (50 mu g/rat). After a 10 mi n perfusion, a washout procedure was performed for 5 min, after which isola tion was terminated. Results: SD or Wister rats and F344 mts tolerated up t o 120 mg/rat or 4 mu g/rat, respectively. Dexamethasone and/or LPS was tole rated at 40 mu g/rat of TNF in F344 mt and showed a significant reduction o f hepatotoxicity, and indicated histologically the suppression of balloonin g and of necrosis during and after perfusion by TNF. Conclusion: We propose new a protocol for IHP as follows: 1. the intradermal administration of LP S for protection against toxicity of TNF, 2. IHP with TNF-SAM2 a mutain of TNF-alpha, having less toxicity than conventional TNF-alpha, and 3. simulta neous perfusion with chemotherapeutic agents such as 5-fluorouracil (5-FU).