Modification of tumor necrosis factor-induced acute toxicity D-galactosamine challenge by polymyxin B, an anti-endotoxin.
Polymyxin B (PMB), an antibiotic with anti-endotoxin activity, was used to examine the participation of endogenously produced endotoxin in the enhancement of recombinant human tumor necrosis factor (rhTNF)-induced toxicity in D-galactosamine (GalN)-sensitized mice. GalN-sensitized mice (700 mg/kg, intraperitoneally (i.p.)) injected together with rhTNF (1x10(4) U/mouse, intravenously (i.v.)) exhibited severe symptoms, with 100% mortality at 18 h. However, mice pretreated with PMB (20 mg/kg, i.p.) showed protection against the rhTNF-induced lethality following GalN sensitization. Little or no effects were observed on alanine aminotransferase (ALT) activity or lactate dehydrogenase (LDH) isozyme leakage in serum in mice 7 h after administration of rhTNF alone. Administration of rhTNF to GalN-sensitized mice resulted in marked increases in ALT activity and LDH isozyme leakage relative to those in mice treated with rhTNF alone. In mice pretreated with PMB, the levels of ALT and LDH isozyme leakage 7 h after rhTNF/GalN injection were significant decreased as compared with those in mice treated with rhTNF/GalN. Similarly, injection of PMB markedly decreased lipid peroxide formation in the liver of the GalN-sensitized mice treated with rhTNF. The injection of a low endotoxin dose (0.1 mg/kg, i.p.) markedly increased the lethality in mice treated with rhTNF (5x10(3) U/mouse, i.v.) and GalN, and these animals showed 100% mortality at 8 h. These findings suggested that the extent of TNF-induced toxicity caused by GalN administration may be a result of synergism between TNF and gut-derived endotoxin. It is likely that endogenously produced endotoxin play a significant role in rhTNF/GalN-hypersensitized mice.
Sakaguchi
S
S
First Department of Hygienic Chemistry, Tohoku Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, 981-8558, Sendai, Japan.
Furusawa
S
S
Yokota
K
K
Takayanagi
M
M
Takayanagi
Y
Y
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005688:Galactosamine / Q000633:toxicity*; D007527:Isoenzymes / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D011112:Polymyxin B / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D004731:Endotoxins; D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D011112:Polymyxin B