THE EFFECT OF INHIBITION OF LEUKOTRIENE-B4 RELEASE ON LIPOPOLYSACCHARIDE-INDUCED PRODUCTION OF NEUTROPHIL ATTRACTANT ACTIVATION PROTEIN-1 (INTERLEUKIN-8) BY HUMAN ALVEOLAR MACROPHAGES

Whereas we observed previously that concentrations of the lipoxygenase inhibitor nordihydroguaiaretic acid that inhibited leukotriene B4 release from lipopolysaccharide-stimulated human alveolar macrophages in vitro also inhibited subsequent interleukin-8 release, we hypothesized that leukotriene B4 release was required for the release of interleukin-8. Alveolar macrophages from normal nonsmoking volunteers were adhered to plastic and incubated with varying concentrations(25-250 nM) of the 5-lipoxygenase activating protein inhibitor MK-886 prior to stimulation with lipopolysaccharide. MK-886 inhibited leukotriene B4 release in a concentration-dependent manner. The concentration of MK-886 that inhibited release by 50% was 53.3+/-23.1nM (mean+/-SD), n=4. Interleukin-8 concentrations in 24hr supernatants were not inhibited by incubation of the cells with any concentration of MK-886, including those that inhibited leukotriene B4 release by >95%. Thus, MK-886 is an effective inhibitor of human alveolar macrophage release of leukotriene B4, and the release of leukotriene B4 is not a prerequisite for alveolar macrophage release of interleukin-8.