Differential protective activities of site specific lipoxygenase inhibitors in endotoxic shock and production of tumor necrosis factor

Abstract

Lipoxygenase inhibitors have been shown to exert beneficial effects in experimental models of endotoxin shock. In the present study it was found that lipoxygenase inhibitors prevented LPS, but not tumor necrosis factor α (TNF α)-evoked leukopenia in mice. These inhibitors protected against endotoxin lethality but not against TNF α induced lethality. When the protective potency of the specific 5-lipoxygenase inhibitors (MK 886, CGS 81585) was tested in endotoxin-induced leukopenia and shock, they were found to be ineffective. Site specificity of the inhibitors was assessed by comparison of their effects on the formation of LTC 4 and the conversion of linoleic acid to 13-hydroxyoctadecadienoic acid (13-HODD) by macrophages. The 5-lipoxygenase inhibitors interfered with LTC 4 formation in macrophages, however, they did not affect endotoxin-induced TNF α formation, neither in cell cultures nor in mice. The inhibitory strength of other, less specific lipoxygenase blockers to suppress TNF α formation correlated quantitatively with their ability to interfere with 13-HODD synthesis. From these findings it is concluded that lipoxygenase inhibitors interfere with endotoxic effects because they block TNF α formation. Since 5-lipoxygenase inhibitors neither prevented the formation of TNF α nor endotoxin leukopenia and lethality, it is suggested that a lipoxygenase product distinct from the leukotrienes is involved in TNF α synthesis. Based on the fact that a tight correlation exists between inhibition of TNF α synthesis and 13-HODD formation, activation of 15-lipoxygenase might be important for TNF α formation.