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Differential effects of inhibition of isoforms of cyclooxygenase (COX-1, COX-2) in chronic inflammation
D W Gilroy1, A Tomlinson, D A Willoughby
1Department of Experimental Pathology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, UK.
Objective And Design:
The anti-inflammatory effects of therapeutic dosing of drugs with greater selectivity for the inhibition of the constitutive (COX-1) or inducible isoform (COX-2) of cyclooxygenase were assessed in a model of chronic inflammation.
Methods:
The murine chronic granulomatous tissue air pouch model involves the subcutaneous injection of air into the dorsum of mice followed 24 h later by the intrapouch injection of an inflammatory stimulus (0.5 ml of Freund's complete adjuvant containing 0.1% croton oil). Aspirin, more selective in vitro for the inhibition of COX-1 (10,200 (mg/kg) and nimesulide, a selective in vitro inhibitor of COX-2 (0.5, 5 mg/kg) were dosed p.o. daily from 3 days after injection of the inflammatory stimulus. Granuloma dry weight, vascularity and COX activity (measured as PGE2) were assessed at various time points throughout the inflammatory lesion to resolution at day 28. A second COX-2 inhibitor, NS 398 (0.1, 1, 10 mg/kg), was dosed p.o. daily from 3 days after the injection of the inflammatory stimulus and its effects on granuloma dry weight, vascularity and COX activity were measured at 7 days.
Results:
Aspirin (200 mg/kg) significantly inhibited levels of PGE2 throughout the time course and at the lower dose (10 mg/kg) from day 14. Nimesulide (5 mg/kg) however, significantly increased levels of PGE2 at days 5 and 21, but at 0.5 mg/kg was without effect. Aspirin (200 mg/kg) significantly reduced granuloma dry weight at day 14 but had no effect on granuloma vascularity at day 7. In contrast, nimesulide (5 mg/kg) significantly increased granuloma vascularity at day 7 and granuloma dry weight at day 14. NS-398 at all doses had no effect on granuloma dry weight, vascularity or COX activity 7 days after the injection of the inflammatory stimulus.
Conclusion:
In this model of chronic inflammation, aspirin, more selective for the inhibition of COX-1 is more effective than the selective COX-2 inhibitors nimesulide and NS-398 at inhibiting granuloma dry weight, vascularity and COX activity.
Insights
Aspirin, which inhibits cyclooxygenase-1 (COX-1), proved more effective than selective cyclooxygenase-2 (COX-2) inhibitors in reducing chronic inflammation markers in a mouse model. This suggests COX-1 inhibition plays a key role in managing chronic inflammatory conditions.
Area of Science:
- Pharmacology
- Inflammation Research
- Drug Discovery
Background:
- Cyclooxygenase (COX) enzymes, specifically COX-1 and COX-2, are key targets for anti-inflammatory drugs.
- Understanding the differential effects of COX-1 and COX-2 inhibition is crucial for developing effective anti-inflammatory therapies.
Purpose of the Study:
- To compare the anti-inflammatory efficacy of drugs selectively inhibiting COX-1 versus COX-2 in a chronic inflammation model.
- To assess the impact of selective COX inhibition on granuloma formation, vascularity, and prostaglandin E2 (PGE2) production.
Main Methods:
- A murine chronic granulomatous tissue air pouch model was utilized.
- Aspirin (COX-1 selective), nimesulide (COX-2 selective), and NS-398 (COX-2 selective) were administered orally.
- Assessed outcomes included granuloma dry weight, vascularity, and COX activity (measured as PGE2).
Main Results:
- Aspirin (200 mg/kg) significantly inhibited PGE2 levels and reduced granuloma dry weight.
- Nimesulide (5 mg/kg) paradoxically increased PGE2 levels and granuloma vascularity.
- NS-398 showed no significant effects on measured parameters at any dose.
Conclusions:
- In this chronic inflammation model, aspirin's inhibition of COX-1 was more effective than selective COX-2 inhibition by nimesulide and NS-398.
- These findings highlight the importance of COX-1 in mediating chronic inflammatory responses.