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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 (O2-) and secrete lysosomal enzymes. Pre-incubation of PMNs in vitro with the cyclo-oxygenase (COx) inhibitor piroxicam (50 microM) 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 O2- generation unaffected. Binding of 3H-FMLP was inhibited by piroxicam. When the plant lectin concanavalin A (Con-A, 30 micrograms/ml) or the tumor promoter phorbol myristate acetate (PMA, 50 micrograms/ml) was used as a stimulus, ibuprofen had no effect on PMN response, while piroxicam inhibited only O2- generation. To determine whether such inhibition might also occur in vivo, we tested neutrophil aggregation and O2- 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 3.6 cm2/min, P less than 0.004) and O2- generation by 35% (15.8 nmol cytochrome c reduced versus 10.2 nmol, P less than 0.002). Ibuprofen inhibited FMLP-induced aggregation by 44% (5.2 versus 3.0, P less than 0.03) but had no effect on O2- production. Indomethacin inhibited FMLP-induced aggregation (6.4 versus 2.9, P less than 0.01) but had no effect on O2- generation.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Cyclo-oxygenase (COX) inhibitors like piroxicam and ibuprofen affect human neutrophil functions. Piroxicam significantly inhibited both aggregation and superoxide anion generation in vivo, while ibuprofen primarily impacted aggregation.
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Human neutrophils (PMNs) exhibit aggregation, superoxide anion (O2-) generation, and lysosomal enzyme secretion upon activation.
- Cyclo-oxygenase (COX) inhibitors are known to modulate inflammatory responses.
Purpose of the Study:
- To investigate the in vitro and in vivo effects of COX inhibitors piroxicam and ibuprofen on human neutrophil activation.
- To determine the impact of these inhibitors on FMLP-induced neutrophil aggregation and O2- generation.
Main Methods:
- In vitro studies involved pre-incubating PMNs with piroxicam or ibuprofen before stimulation with f-met-leu-phe (FMLP), concanavalin A (Con-A), or phorbol myristate acetate (PMA).
- In vivo studies assessed neutrophil aggregation and O2- generation in normal subjects after administration of therapeutic doses of piroxicam, ibuprofen, or indomethacin.
Main Results:
- In vitro, piroxicam inhibited all FMLP-induced PMN responses, while ibuprofen affected aggregation and lysozyme secretion but not O2- generation.
- In vivo, piroxicam significantly inhibited both FMLP-induced neutrophil aggregation (31%) and O2- generation (35%).
- Ibuprofen and indomethacin inhibited FMLP-induced aggregation but had no significant effect on O2- generation.
Conclusions:
- Piroxicam demonstrates a broad inhibitory effect on key human neutrophil functions, including both aggregation and O2- generation, in vivo.
- Ibuprofen and indomethacin primarily impact neutrophil aggregation, with limited effects on O2- production, suggesting differential mechanisms of action.