THE ENHANCING EFFECT OF TUMOR-NECROSIS-FACTOR-ALPHA ON OXIDATIVE STRESS IN ENDOTOXEMIA

The enhancing effect of tumour necrosis factor-alpha (TNF-alpha) on ox idative stress with or without a sublethal dose of endotoxin was exami ned. The mortality of mice treated with recombinant human TNF-alpha (1 x10(4) units/mouse, intravenously) and endotoxin (0.01-1 mg/kg, intrap eritoneally) was dependent on the dose of endotoxin. The liver lipid p eroxide level, superoxide anion generation and serum lactate dehydroge nase activity, especially serum lactate dehydrogenase-5 isozyme leakag e, in mice 2-4 hr after administration of recombinant human TNF to end otoxin-pretreated mice (0.5 mg/kg, intraperitoneally) were markedly hi gher than in those without endotoxin, whereas the administration of re combinant human TNF significantly decreased the non-protein sulfhydryl level, superoxide dismutase and glutathione peroxide activities in th e liver of endotoxin-injected mice compared with those in mice treated with recombinant human TNF or endotoxin alone. Furthermore, findings clearly demonstrated that J774A.1 cells stimulated with recombinant hu man TNF (1x10(4) units/ml) can effectively produce nitric oxide in the presence of endotoxin, and the production was dependent on the dose o f endotoxin (0.01-10 mu g/ml). The level of lipid peroxide in mice 4 h r after administration of recombinant human TNF and lead acetate (50 m g/kg, intravenously) was markedly higher than that in the mice treated with recombinant human TNF alone. By contrast, injection of polymyxin -B (20 mg/kg, intraperitoneally, an anti-endotoxin drug) markedly decr eased the lipid peroxide level in the liver of the mice treated with r ecombinant human TNF and lead acetate. These findings suggest that the oxidative stress caused by TNF occurs as a enhancing effect of endoto xion or by bacterial translocation from the intestinal gut under reduc tion of reticuloendothelial system function in various disease states, and that the effect of TNF may cause a marked increase of toxicity of oxidative stress by endotoxin.