piriprost and esculetin

The effects of five inhibitors of the lipoxygenase pathway were evaluated on oxygen radical production, degranulation, chemotaxis, leukotriene B4 (LTB4) production by neutrophils. The lipoxygenase inhibitors tested were nordihydroguaiaretic acid (NDGA), esculetin, eicosatetraynoic acid (ETYA), 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-1,4-benzoqu inone (AA-861), and 6,9-deepoxy-6, 9-(phenylimino)-delta 6.8-prostaglandin I1 (U-60,257). Neutrophils were activated by n-formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol myristate acetate (PMA), A23187, or platelet activating factor (PAF). The effects of these inhibitors on NADPH oxidase activity and phospholipase A2 activity of isolated particulate fraction of neutrophils were also evaluated. ETYA inhibited neutrophil function induced by all the stimulators except PMA. AA-681 was unique in that it did not inhibit PAF-induced neutrophil activation. U-60,257 had virtually no effect on oxygen radical production and degranulation, but chemotaxis was moderately suppressed. NDGA effectively inhibited neutrophil function, except for chemotaxis. Esculetin inhibited only oxygen radical production, but this was due to inhibition on NADPH oxidase activity of neutrophil membrane. The inhibitory effect on neutrophil function and that of LTB4 production were not closely correlated. It is suggested that lipoxygenase inhibitors may modify neutrophil function by the mechanism not involving the lipoxygenase pathway. It is also suggested that LTB4 may not be a mediator in neutrophil oxygen radical production and degranulation induced by the stimulators used in the present study.

Topics: 5,8,11,14-Eicosatetraynoic Acid; Benzoquinones; Calcimycin; Chemotaxis, Leukocyte; Epoprostenol; Humans; Hydroxides; Hydroxyl Radical; Leukotriene B4; Lipoxygenase Inhibitors; Masoprocol; N-Formylmethionine Leucyl-Phenylalanine; NADH, NADPH Oxidoreductases; NADPH Oxidases; Neutrophils; Phospholipases A; Phospholipases A2; Platelet Activating Factor; Quinones; Tetradecanoylphorbol Acetate; Umbelliferones

In this study we demonstrated that natural killer (NK) cell lysis by human peripheral blood nonadherent (NA) cells against K562 target cells was rapidly inhibited by four agents that inhibit the lipoxygenase pathway of arachidonic acid metabolism, nordihydroguaiaretic acid (NDGA), U-60257, alpha-phenanthroline, and esculetin. However, human NK cells activated by interferons (IFN) or poly I:C were partially resistant to suppression by NDGA and U-60257. Pretreatment of the NA cells with the four lipoxygenase inhibitors at 37 degrees C for 18 h led to suppression of NK activity. The inhibition of NK activity by NDGA was not reversed by aspirin at a concentration that inhibits PGE2 synthesis. Thus, suppression of NK activity by NDGA was not mediated by the effects on PGE2 synthesis. However, the inhibition of endogenous NK activity by NDGA, U-60257, alpha-phenanthroline, or esculetin was partially reversed by IFN or poly I:C. These results suggest that products of lipoxygenation are required for maintenance of human NK activity.

Topics: Arachidonate 12-Lipoxygenase; Arachidonate Lipoxygenases; Aspirin; Cytotoxicity, Immunologic; Epoprostenol; Humans; Interferon Type I; Killer Cells, Natural; Lipoxygenase Inhibitors; Masoprocol; Phenanthrolines; Poly I-C; Umbelliferones