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Modification of tumor necrosis factor-induced acute toxicity D-galactosamine challenge by polymyxin B, an
S Sakaguchi1, S Furusawa, K Yokota
1First Department of Hygienic Chemistry, Tohoku Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, 981-8558, Sendai, Japan.
Abstract:
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.
Insights
Polymyxin B (PMB) protected mice from lethal toxicity induced by recombinant human tumor necrosis factor (rhTNF) and D-galactosamine (GalN). This suggests endotoxin plays a key role in rhTNF/GalN-induced liver injury and lethality.
Area of Science:
- Immunology
- Pharmacology
- Toxicology
Background:
- Recombinant human tumor necrosis factor (rhTNF) induces severe toxicity in D-galactosamine (GalN)-sensitized mice.
- Endogenous endotoxins are suspected to enhance this rhTNF-induced toxicity.
Purpose of the Study:
- To investigate the role of endogenously produced endotoxin in rhTNF/GalN-induced lethality and liver injury.
- To evaluate the protective effect of Polymyxin B (PMB), an antibiotic with anti-endotoxin activity.
Main Methods:
- Mice were sensitized with GalN and treated with rhTNF, with or without prior administration of PMB.
- Biochemical markers of liver injury, including alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) isozyme leakage, were measured.
- Lipid peroxide formation in the liver was assessed.
Main Results:
- PMB pretreatment significantly reduced rhTNF/GalN-induced mortality and liver damage.
- PMB administration decreased ALT and LDH leakage and hepatic lipid peroxide formation.
- Low-dose endotoxin administration exacerbated rhTNF/GalN-induced lethality.
Conclusions:
- Endogenously produced endotoxin plays a significant role in the synergistic toxicity of rhTNF and GalN.
- PMB demonstrates protective effects against rhTNF/GalN-induced liver injury and lethality, likely by neutralizing endotoxin.