Portal infusion of tumor necrosis factor increases mortality in rats

Tumor necrosis factor (TNF) is a protein found in the serum of mice presensitized with BCG following injection of endotoxin. Although TNF has been shown to cause hemorrhagic necrosis of certain tumors, the marked toxicity of recombinant human TNF has limited the clinical usefulness of this compound. This experiment was designed to determine whether hepatic metabolism would reduce the systemic toxicity of TNF delivered by the portal circulation. Twenty male Fischer rats received a continuous infusion of recombinant human TNF (100 micrograms/kg/day), 10 through a portal venous branch, and 10 through a branch of the inferior vena cava. Control animals received an infusion of carrier solution by the same route. After 7 days the animals were sacrificed and their organs weighed and sectioned. Mortality in the portal TNF group was 100%. The animals followed the clinical pattern seen with lethal TNF injection. Histologic sections revealed significant gastric and small intestinal mucosal injury, pulmonary edema, and acute tubular necrosis. Animals receiving TNF systemically lost more weight per day of infusion than controls, but followed a relatively benign course. Systemically infused animals had evidence of mild pulmonary edema, and a periportal mononuclear infiltrate in the liver, but no obvious renal or gastrointestinal injury. In a second experiment the effect of escalating doses of portal TNF infusion on liver enzymes was assessed. TNF was infused intraportally at 10, 50, or 100 micrograms/kg/day for 3 days. Control animals received a carrier solution. Mortality was dose-related with 100% mortality in animals receiving 100 micrograms/kg/day, and 40% mortality in the 50 micrograms/kg/day group.(ABSTRACT TRUNCATED AT 250 WORDS)