The inactivation of the polymorphonuclear leukocyte by non-steroidal anti-inflammatory drugs

Abstract

When human neutrophils (PMNs) are activated by appropriate stimuli, they aggregate, generate Superoxide anion (O 2 ) and secrete lysosomal enzymes. Pre-incubation of PMNs in vitro with the cyclo-oxygenase (COx) inhibitor piroxicam (50μM) before stimulation with the chemotactic peptide f-met-leu-phe (FMLP, 10−7 M) inhibited all of these responses. The COx inhibitor ibuprofen inhibited FMLP-induced aggregation and lysozyme secretion, leaving O 2 generation unaffected. Binding of3H-FMLP was inhibited by piroxicam. When the plant iectin concanavalin A (Con-A, 30μg/ml) or the tumor promoter phorbol myristate acetate (PMA, 50μml) was used as a stimulus, ibuprofen had no effect on PMN response, while piroxicam inhibited only O 2 generation. To determine whether such inhibition might also occur in vivo, we tested neutrophil aggregation and O 2 generation in response to FMLP in 26 normal subjects. These subjects were then administered therapeutic doses of piroxicam (20 mg/ day), ibuprofen (2400 mg/day) or indomethacin (100 mg/day), and neutrophil functions were retested after 3 days. Piroxicam inhibited FMLP-induced aggregation by 31% (5.2 cm2/min versus 3.6cm2/min,P<0.004) and O 2 generation by 35% (15.8 nmol cytochrorae c reduced versus 10.2 nmol,P<0.002). Ibuprofen inhibited FMLP-induced aggregation by 44% (5.2 versus 3.0,P<0.03) but had no effect on O 2 production. Indomethacin inhibited FMLP-induced aggregation (6,4 versus 2.9,P<0.01) but had no effect on O 2 generation. These studies suggest that: (a) multiple pathways exist for the activation of the neutrophil, since inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) is stimulus-dependent; (b) NSAIDs have cellular effects that are not dependent on COx inhibition; (c) unique effects on cellular function may account for the clinical variability in responsiveness to different NSAIDs.

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Abramson, S., Edelson, H., Kaplan, H. et al. The inactivation of the polymorphonuclear leukocyte by non-steroidal anti-inflammatory drugs. Inflammation 8, S103–S108 (1984). https://doi.org/10.1007/BF00915717

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Keywords

  • Indomethacin
  • Ibuprofen
  • Lysozyme
  • Phorbol
  • Piroxicam