EVALUATION OF THE SIGNIFICANCE OF ELEVATED LEVELS OF SYSTEMIC AND LOCALIZED TUMOR-NECROSIS-FACTOR IN DIFFERENT ANIMAL-MODELS OF INFLAMMATION

Elevated tumor necrosis factor (TNF) levels have been reported in vari ous models of acute and chronic inflammation and used by many investig ators to determine the stage of disease and effectiveness of treatment . Because of the documented involvement of TNF in the mechanism of sep tic shock, experiments were done to determine whether serum TNF levels paralleled the pathology in endotoxic shock and other models of infla mmation. When mice received an intraperitoneal injection of lipopolysa ccharide, serum TNF levels increased dramatically, peaking 90 minutes after injection. In a dose-response experiment with lipopolysaccharide alone, we found no correlation between serum levels of TNF and surviv al rate of mice. All three lipopolysaccharide concentrations resulted in comparable elevations of serum TNF, yet only in the high-dose group did the animals die. In a second model of endotoxic shock, TNF-alpha. levels in serum were again compared with the survival rate of mice re ceiving lipopolysaccharide plus galactosamine. As in the first model, we found no relationship between the level of TNF in mouse serum and m ouse survival rate. The two lowest concentrations of lipopolysaccharid e/galactosamine induced identically low levels of serum TNF, yet in on e group all of the animals survived and in the other all died. Discrep ancies between serum TNF level and mortality rate were also seen in dr ug treatment experiments. Gl 147404X, a standard phosphodiesterase typ e IV inhibitor, inhibited lipopolysaccharide/galactosamine-induced ele vation of serum TNF by 90% at doses of 1 and 10 mg/kg. However, the hi gh dose resulted in 66% protection while the low dose afforded no prot ection. Taken together these experiments show that serum TNF is not a good predictor in determining the outcome of septic shock. Perhaps loc alized levels of TNF are more important in the pathology of inflammati on than levels of TNF in the circulation. In a different model of acut e inflammation, a significant level of TNF was measured in the inflame d paws of carrageenan-injected rats and mice, although no TNF was dete cted in the serum of these same rodents. Because systemic levels of TN F do not appear to be directly related to the degree of inflammatory d amage, future work will focus on the role of localized TNF in the path ology of inflammatory diseases.