Chemotactic factor-induced generation of superoxide radicals by human neutrophils: effect of metabolic inhibitors and antiinflammatory 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 4 X 10(-5)M), 2-iodoacetate (ID50 5 X 10(-5)M), and N-ethyl-maleimide (ID50 5 X 10(-6)M), 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 1 X 10(-4)M), ibuprofen (ID50 9 X 10(-4)M, and phenylbutazone (ID50 1 X 10(-5)M) 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) microgram/ml) and aurothioglucose (10(-3)-10(-6)M) were without appreciable effects. Superoxide generation was inhibited only by relatively high concentrations of hydrocortisone (ID50 greater than 10(-3)M). 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.
D015120:6-Aminonicotinamide / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D006051:Aurothioglucose / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D003847:Deoxyglucose / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005033:Ethylmaleimide / Q000494:pharmacology; D005609:Free Radicals; D006019:Glycolysis; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007461:Iodoacetates / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D010653:Phenylbutazone / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D000963:Antimetabolites; D005609:Free Radicals; D007461:Iodoacetates; D013481:Superoxides; D006051:Aurothioglucose; D015120:6-Aminonicotinamide; D010042:Ouabain; D003847:Deoxyglucose; D010653:Phenylbutazone; D005033:Ethylmaleimide; D001241:Aspirin; D010100:Oxygen; D006854:Hydrocortisone; D007052:Ibuprofen; D007213:Indomethacin