Continuous infusion of tumor necrosis factor: mechanisms of toxicity in the rat

This study was designed to assess the toxicity of continuous infusion of tumor necrosis factor (TNF) in the rat model. The effect of TNF on cell membranes was assessed by diffusion of radiolabeled inulin (RI). The effect of concomitant administration of the cytoprotectant prostaglandin E1 (PGE1) was also assessed. Eighty rats were anesthetized and two osmotic pumps were implanted in the peritoneal cavity of each rat. One pump contained either TNF (0.1 mg/kg/day) or vehicle and the other either PGE1 (0.1 mcg/kg/min) or vehicle. Four groups resulted: vehicle alone, PGE1 alone, TNF alone, and TNF + PGE1. After 5 days, half of each group received intravenous RI and organ/blood radioactivity ratios were compared at sacrifice 7 min later. Remaining animals had serum drawn for CBC and electrolyte determination. Organ weights were determined in all animals. The effects of TNF and PGE1 were assessed by two-way ANOVA. Mortality in animals infused with TNF was 20%. One animal in the control group died. TNF infusion increased lung weight by 38% (697 +/- 49 vs 937 +/- 77 mg; P less than 0.05). Liver weight was also increased in animals infused with TNF (6.7 +/- 0.2 vs 7.0 +/- 0.3 g; P less than 0.05). TNF infusion increased blood urea nitrogen and decreased serum bicarbonate compared to controls. TNF had no effect on RI diffusion. PGE1 did not alter the response to TNF.

Continuous infusion of TNF does not affect membrane permeability as assessed by inulin diffusion. PGE1 does not cytoprotect against the toxicity of TNF. Evidence of direct hepatic toxicity suggests that regional therapy via the hepatic artery or portal vein is contraindicated.