CHEMOTACTIC FACTOR-INDUCED GENERATION OF SUPEROXIDE RADICALS BY HUMAN-NEUTROPHILS - EFFECT OF METABOLIC-INHIBITORS AND ANTI-INFLAMMATORY DRUGS

Human peripheral neutrophils generated superoxide radicals as assessed by ferricytochrome C reduction in response to activation by the synthetic chemotactic factor, N‐formyl‐methionyl‐leucyl‐phenylalanine. Superoxide generation was inhibited by 2‐deoxy‐D‐glucose (ID50 4X10−5M), 2‐iodoacetate (ID50 5X10−5M), and N‐ethyl‐maleimide (ID50 5X10−6M), suggesting a dependence on anaerobic glycolysis and sulfhydryl groups. Ouabain, microtubule‐disrupting agents, inhibitors of respiration, oxidative phosphorylation, and protein and nucleic acid synthesis were without appreciable effects. Indomethacin (ID50 1X10−4M), ibuprofen (ID50 9X10−4M), and phenylbutazone (ID50 1X10−5M) all caused dose‐dependent inhibition of superoxide generation at concentrations approximating those plasma and tissue levels obtained in human beings at therapeutic doses. Acetylsalicylic acid (125–500 ug/ml) and aurothioglucose (10−3−10−6M) were without appreciable effects. Superoxide generation was inhibited only by relatively high concentrations of hydrocortisone (ID50 > 10−3M). Because superoxide radicals have been implicated in the pathogenesis of tissue injury in several forms of inflammation and arthritis in vivo, these studies suggest that the production of a potential cytotoxic factor may be subject to pharmacologic manipulation and that at least some of the antiphlogistic effects of the nonsteroidal antiinflammatory agents may be mediated through effects on superoxide production. Copyright © 1979 American College of Rheumatology