Comparison of the effects of some compounds on human neutrophil degranulation and leukotriene B4 and thromboxane B2 synthesis.

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 B4 (LTB4) and thromboxane B2 (TXB2) synthesis by these cells to elucidate the relationship between LTB4 formation and degranulation. All compounds inhibited TXB2 synthesis by 50% at concentrations between 0.0016 and 50 microM. The synthesis of LTB4 was inhibited by 50% by ETYA (1.9 microM) and by NDGA (0.52 microM). Degranulation induced by A23187 and FMLP was inhibited by 50% by ETYA (16 and 11 microM respectively) and by NDGA (1.5 and 6.5 microM respectively). In the case of ETYA the concentrations required to inhibit degranulation were significantly higher than those required to inhibit LTB4 synthesis. In contrast, BW755C inhibited LTB4 synthesis by 50% at 2.8 microM but did not affect A23187-induced degranulation and was only a weak inhibitor of FMLP-induced degranulation (50% inhibition at 89 microM). The effects of the above compounds on the omega-oxidation of LTB4 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 LTB4 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 LTB4 synthesis.