Reduction of hepatotoxicity of tumor necrosis factor in isolated hepatic perfusion by administration of glucocorticoid as well as lipopolysaccharide.
The application of an isolation procedure with tumor necrosis factor (TNF) to the liver is quit attractive, however, one of problems to overcome is reducing the toxicity to the liver caused by high doses of TNF. Rats underwent isolated hepatic perfusion (IHP) with TNF and pre-treatment of subcutaneous administration of dexamethasone (4 mg/kg) and/or intradermal administration of LPS (50 micrograms/rat). After a 10 min perfusion, a washout procedure was performed for 5 min, after which isolation was terminated. SD or Wister rats and F344 rats tolerated up to 120 mg/rat or 4 micrograms/rat, respectively. Dexamethasone and/or LPS was tolerated at 40 micrograms/rat of TNF in F344 rat and showed a significant reduction of hepatotoxicity, and indicated histologically the suppression of ballooning and of necrosis during and after perfusion by TNF. We propose new a protocol for IHP as follows: 1. the intradermal administration of LPS 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. simultaneous perfusion with chemotherapeutic agents such as 5-fluorouracil (5-FU).