Inhibition of NF-kappa B activation by dimethyl sulfoxide correlates with suppression of TNF-alpha formation, reduced ICAM-1 gene transcription, and protection against endotoxin-induced liver injury.
The effect of the free radical scavenger dimethyl sulfoxide (DMSO) on activation of the nuclear transcription factor kappa B (NF-kappa B) was investigated in an experimental model of endotoxin-induced liver failure. In galactosamine-sensitized C3Heb/FeJ mice, DMSO (10 mL/kg) effectively inhibited endotoxin-induced hepatic NF-kappa B activation, suppressed TNF-alpha levels in plasma by 86%, attenuated intercellular adhesion molecule-1 (ICAM-1) mRNA formation, blocked hepatic neutrophil accumulation by 79%, and reduced liver injury by 80%. In galactosamine-sensitized mice treated with 20 micrograms/kg murine TNF-alpha, DMSO moderately reduced hepatic NF-kappa B and decreased ICAM-1 mRNA formation and liver injury by 83%, but had no significant effect on hepatic neutrophil accumulation. Thus, DMSO was able to inhibit, at least in part, two critical NF-kappa B-dependent steps in the pathophysiology, i.e., TNF-alpha formation and ICAM-1 gene transcription. Our data suggest the involvement of redox-sensitive events in the signal transduction pathway of NF-kappa B activation in the liver. Inhibition of NF-kappa B activation correlates with the reduced activation of proinflammatory genes in vivo and the subsequent attenuation of inflammatory liver injury. Thus, antioxidants that are NF-kappa B inhibitors may have therapeutic potential in endotoxin shock and sepsis.
Essani
N A
NA
Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007, USA.
Fisher
M A
MA
Jaeschke
H
H
D000287:Administration, Topical; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004731:Endotoxins / Q000633:toxicity*; D005688:Galactosamine / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D004731:Endotoxins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D005688:Galactosamine; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D004121:Dimethyl Sulfoxide