Leukotriene inhibitors modulate hepatic injury induced by lipopolysaccharide-activated macrophages.
In an attempt to elucidate the effect of lipoxygenase inhibitors on hepatic injury, we investigated D-galactosamine (GalN)-treated C57BL/6 mice receiving an intravenous (i.v.) injection of lipopolysaccharide (LPS)-activated autologous spleen cells. As compared with control spleen cells, the number of monocytes in the spleen cells isolated from LPS-treated mice and their oxidative free radical production increased markedly. Oxygen radical production by the dish-adherent cells (macrophage-rich population) was enhanced a further 4-fold. Although hepatotoxicity was not demonstrated in mice treated with 20 mg GalN alone, marked hepatic injury was found in the GalN-treated mice with a supplementation of LPS-activated spleen cells. The dish-adherent cells aggravated this hepatic injury, in contrast to minor hepatotoxicity by the nonadherent cells. Oxygen radical production by LPS-activated spleen cells was markedly reduced by the lipoxygenase inhibitors (azelastine, ketotifen and AA861). Hepatotoxicity was scarcely detected in the GalN-treated mice with a supplementation of the LPS-activated spleen cells which had been previously treated with lipoxygenase inhibitors. From these results, LPS-activated spleen macrophages contributed to hepatic injury induced by GalN, and lipoxygenase inhibitors which reduced oxygen radical production by the activated cells, protected against macrophage-induced hepatic injury in mice.
Shiratori
Y
Y
2nd Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Tanaka
M
M
Umihara
J
J
Kawase
T
T
Shiina
S
S
Sugimoto
T
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D005609:Free Radicals; D005688:Galactosamine / Q000494:pharmacology; D020024:Leukotriene Antagonists; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology; D014700:Verapamil / Q000494:pharmacology
D005609:Free Radicals; D020024:Leukotriene Antagonists; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D005688:Galactosamine; D014700:Verapamil; D000410:Alanine Transaminase