Comparison of the effects of some compounds on human neutrophil degranulation and leukotriene B 4 and thromboxane B 2 synthesis

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The effects of aspirin, indomethacin, phenylbutazone, eicosatetraynoic acid (ETYA), nordihydroguaiaretic acid (NDGA) and 3-amino-1-[3-(trifluoromethyl)-phenyl]-2-pyrazoline (BW755C) on human neutrophil degranulation induced by A23187 and F-Met-Leu-Phe (FMLP) have been studied. These effects have been compared with those on A23187 induced leukotriene B 4 (LTB 4) and thromboxane B 2 (TXB 2) synthesis by these cells to elucidate the relationship between LTB 4 formation and degranulation. All compounds inhibited TXB 2 synthesis by 50% at concentrations between 0.0016 and 50 μM. The synthesis of LTB 4 was inhibited by 50% by ETYA (1.9 μM) and by NDGA (0.52 μM). Degranulation induced by A23187 and FMLP was inhibited by 50% by ETYA (16 and 11 μM respectively) and by NDGA (1.5 and 6.5 μM respectively). In the case of ETYA the concentrations required to inhibit degranulation were significantly higher than those required to inhibit LTB 4 synthesis. In contrast, BW755C inhibited LTB 4 synthesis by 50% at 2.8 μM but did not affect A23187-induced degranulation and was only a weak inhibitor of FMLP-induced degranulation (50% inhibition at 89 μM). The effects of the above compounds on the ω-oxidation of LTB 4 by human neutrophils has also been studied to investigate the mechanism of action of these compounds. None of the above compounds affected the metabolism of LTB 4 by these cells suggesting that their actions are not as non-specific anti-oxidants. These data indicate that human neutrophil degranulation induced by FMLP and A23187 is independent of LTB 4 synthesis.