THALIDOMIDE INHIBITS TNF RESPONSE AND INCREASES SURVIVAL FOLLOWING ENDOTOXIN INJECTION IN RATS

Sepsis is a leading Cause of death following major trauma and complica ted abdominal surgery. Tumor necrosis factor-cy (TNF) is believed to b e a central mediator in the inflammatory response syndrome. Numerous m ethods of blunting the TNF response in sepsis have been attempted with suggestion of increased survival and decreased organ injury. Thalidom ide, shown in vitro to selectively inhibit TNF production, has been us ed clinically in states of chronic TNF elevation with encouraging resu lts. In this study, we examined the effect of thalidomide administrati on in a rat model of acute septic shock. Femoral artery cannulation wa s performed and baseline TNF measured. Dose response was determined by giving varying doses of thalidomide by gavage. Rats were injected int raarterially with endotoxin and serial samples drawn. TNF was measured by ELISA. For survival, thalidomide was given by gavage and endotoxin injected intraperitoneally. Serum TNF elevation occurred after endoto xin injection with peak levels at 90 min. Thalidomide treated rats had lower TNF levels at all time points (P = <0.01 at 90 and 120 min), wi th the inhibition being dose dependent. Survival in treated rats excee ded that of untreated rats (53% vs 19%, P = <0.05) at 48 and 72 hr. In conclusion, we found that thalidomide administration leads to increas ed survival following acute endotoxemia, which may be due to the obser ved TNF inhibition. (C) 1996 Academic Press, Inc.