Augmentation of human neutrophil and alveolar macrophage LTB 4 production by N ‐acetylcysteine: role of hydrogen peroxide

1 The actions of N ‐acetylcysteine (NAC) on hydrogen peroxide (H 2 O 2 ) and leukotriene B 4 (LTB 4 ) production by human resting and stimulated peripheral blood neutrophils and alveolar macrophages were investigated. 2 At a concentration of 100 μ M , NAC significantly ( P <0.01) suppressed the accumulation of H 2 O 2 in the incubation medium of resting and opsonized zymosan (OZ; 0.5 mg ml −1 )‐ or N ‐formylmethionyl‐leucyl‐phenylalanine (fMLP; 1 μ M )‐stimulated neutrophils and of resting and OZ‐stimulated macrophages. At concentrations of 10 μ M and above, NAC augmented significantly the level of LTB 4 in the supernatants of OZ‐ and fMLP‐stimulated neutrophils ( P <0.01 and P <0.05, respectively) and OZ‐stimulated macrophages ( P <0.05 at 10 μ M , P <0.01 at 100 μ M NAC). 3 NAC (100 μ M ) caused a significant ( P <0.01) reduction in the quantity of measurable H 2 O 2 when incubated with exogenous H 2 O 2 concentrations equivalent to those released from OZ‐stimulated neutrophils and macrophages. At no concentration did NAC affect quantitites of measurable LTB 4 when incubated with exogenous LTB 4 . 4 Superoxide dismutase (SOD), which catalyzes the conversion of superoxide anion to H 2 O 2 had no significant effect on LTB 4 production by human neutrophils. In contrast, catalase, which catalyzes the conversion of H 2 O 2 to H 2 O and O 2 , caused a pronounced, statistically significant ( P <0.01) increase in the levels of LTB 4 measured in the supernatants of OZ‐ and fMLP‐stimulated neutrophils. 5 H 2 O 2 (12.5 μ M and 25 μ M , concentrations equivalent to those measured in the supernatants of activated neutrophils and alveolar macrophages, respectively) caused a small (13%) decrease in the quantity of measurable LTB 4 ( P =0.051 and P <0.05 at 12.5 μ M and 25 μ M , respectively) that was inhibited by NAC (100 μ M ) but not by catalase (400 u ml −1 ). 6 In conclusion, the anti‐oxidant drug, NAC, increases LTB 4 production by human neutrophils and alveolar macrophages, probably through the elimination of cell‐derived H 2 O 2 . LTB 4 undergoes a H 2 O 2 ‐dependent oxidation that is inhibited by NAC but this is unlikely to account fully for the increased levels of LTB 4 , suggesting that NAC may increase LTB 4 production by blocking the H 2 O 2 ‐dependent inhibition of a synthetic enzyme, such as 5‐lipoxygenase.British Journal of Pharmacology (1997) 122 , 758–764; doi: 10.1038/sj.bjp.0701428