DIMETHYLTHIOUREA PROTECTS RATS AGAINST GRAM-NEGATIVE SEPSIS AND DECREASES TUMOR-NECROSIS-FACTOR AND NUCLEAR FACTOR KAPPA-B ACTIVITY

The thiol-containing compound dimethylthiourea (DMTU) is a known prote ctant in various models of oxidant-mediated tissue damage, Protective effects of DMTU have also been reported in studies on endotoxin-induce d (LPS-induced) tissue injury. DMTU may exert this protective effect b y reducing oxidative stress. In this study we investigated the effect of DMTU on survival, oxidative stress, and tumor necrosis factor (TNF) activity in two rat models of gram-negative bacterial sepsis. Intrape ritoneal injection of 500 mg DMTU/kg protected against the lethal effe cts of intraperitoneally injected LPS (5 mg/kg) and live Salmonella ty phimurium (3.3 x 10(10) CFU/kg). LPS injection resulted in oxidative s tress, as indicated by an elevated concentration of hydrogen peroxide (H2O2) in normal and carbon monoxide-treated deproteinized blood. We a lso observed increased H2O2 levels in animals injected with live Salmo nella typhimurium. Although DMTU improved survival in both models, H2O 2 concentrations were not affected by it. This is consistent with our in vitro observation that DMTU is a weak H2O2 scavenger. Serum TNF act ivity, however, was substantially decreased by DMTU, and this was asso ciated with a reduced activation of nuclear factor KB in the peritonea l cells of LPS-treated rats. In addition, LPS-induced TNF production i n vitro by rat peritoneal macrophages was inhibited by DMTU (p < 0.05) . These results suggest that the protective effect of DMTU in gram-neg ative bacterial sepsis may be the result of a reduction in TNF activit y. DMTU does not exert this effect by H2O2 scavenging but may inactiva te toxic H2O2 metabolites.