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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Sodium Salicylate Inhibits Prostaglandin Formation without Affecting the Induction of Cyclooxygenase-2 by Bacterial Lipopolysaccharide in Vivo

Francesco Giuliano, Jane A. Mitchell and Timothy D. Warner
Journal of Pharmacology and Experimental Therapeutics December 2001, 299 (3) 894-900;
Francesco Giuliano
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Jane A. Mitchell
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Timothy D. Warner
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Abstract

The mechanisms underlying the anti-inflammatory properties of salicylate are not well understood. In particular, while salicylate inhibits prostaglandin production in vivo it only weakly inhibits cyclooxygenase (COX)-1 or -2 activity in vitro. Thus, it has often been suggested that in vivo salicylate may inhibit the expression rather than the activity of COX, particularly COX-2. Using a model of acute COX-2 expression in the rat, we show that salicylate inhibits COX-2 activity in vivo without affecting COX-2 expression. In anesthetized rats LPS (6 mg kg−1, i.p.) increased the expression of COX-2 as evidenced by increased circulating levels of 6-keto-prostaglandin F1α (6-keto-PGF1α, a stable breakdown product of PGI2), greatly exaggerated formation of 6-keto-PGF1α following arachidonic acid (AA) challenge (3 mg kg−1, i.v.), and increased expression of COX-2, but not COX-1, protein. Diclofenac (3 mg kg−1, i.p.) or the COX-2 selective agent diisopropyl fluorophosphate (10 mg kg−1, i.p.) decreased the LPS-induced increase in circulating 6-keto-PGF1α and the exaggerated 6-keto-PGF1α production following AA challenge. Sodium salicylate (20 or 120 mg kg−1, i.p.) (administered either 1 h prior, or once per day for 3 days prior, to LPS injection) reduced only the LPS-induced increase in circulating 6-keto-PGF1α, but not the exaggerated 6-keto-PGF1α production following AA challenge or the expression of COX-2. Thus, salicylate inhibits LPS-induced COX-2 activity in a manner that is overcome by provision of excess substrate and independent of effects on COX-2 expression. In conclusion, our results exclude mechanisms other than direct enzyme inhibition as responsible for the anti-COX effects of salicylate.

Footnotes

  • This work was supported by a grant from Boehringer Ingelheim Pharma KG.

  • J.A.M. is a Wellcome Career Development Fellow.

  • Abbreviations:
    COX
    cyclooxygenase
    AA
    arachidonic acid
    NO
    nitric oxide
    iNOS
    inducible NO synthase
    LPS
    lipopolysaccharide
    NF-κB
    nuclear factor κB
    NSAIDs
    nonsteroidal anti-inflammatory drugs
    PG
    prostaglandin, ANOVA, analysis of variance
    DFP
    diisopropyl fluorophosphate
    • Received May 25, 2001.
    • Accepted August 15, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 3
1 Dec 2001
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Sodium Salicylate Inhibits Prostaglandin Formation without Affecting the Induction of Cyclooxygenase-2 by Bacterial Lipopolysaccharide in Vivo

Francesco Giuliano, Jane A. Mitchell and Timothy D. Warner
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 894-900;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Sodium Salicylate Inhibits Prostaglandin Formation without Affecting the Induction of Cyclooxygenase-2 by Bacterial Lipopolysaccharide in Vivo

Francesco Giuliano, Jane A. Mitchell and Timothy D. Warner
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 894-900;
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