Skip to main content
Log in

Inhibition of Prostaglandin \({\text{F}}_{{{\text{2}}\alpha }} \) by Selective Cyclooxygenase 2 Inhibitors Accounts for Reduced Rat Leukocyte Migration

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

To investigate whether selective COX 2 inhibitors (celecoxib, rofecoxib) would play a role in a model of leukocyte migration in rats. Bacterial endotoxin (Escherichia coli LPS) was intraperitoneally injected at time zero in rats that were previously treated with unspecific and selective cyclooxygenase inhibitors. LPS induced a dose and time-dependent increase in leukocyte number, which was predominantly related to the presence of PMN neutrophils. Only rats treated with selective COX 2 inhibitors and indomethacin showed a significant reduction in leukocyte numbers following LPS administration. Prostaglandins E2 and \( {\text{F}}_{{2\alpha }} \) were injected into the peritoneum and the chemoatractant effect was studied. Only \( {\text{PGF}}_{{2\alpha }} \) was able to induce neutrophil increase following injection. Intraperitoneal reposition of \( {\text{PGF}}_{{2\alpha }} \) restored the abrogated leukocyte response to LPS, shown by rats pretreated with rofecoxib. It can be concluded that COX 2, through \( {\text{PGF}}_{{2\alpha }} \) release, is the isoform responsible for neutrophil recruitment in the rat model of LPS-induced inflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hellewell, P. G., and P. M. Henson. 1991. Mechanisms of granulocyte accumulation and emigration in vivo. In: Vascular Endothelium: Interactions with Circulating Cells, Gordon ed. Elsevier, Amsterdam, pp. 143–160.

    Google Scholar 

  2. Lin, T. J., R. Garduno, R. T. M. Boudreau, and A. C. Issekutz. 2002. Pseudomonas aeruginosa activates human mast cells to induce neutrophil transendothelial migration via mast cell-derived IL-1 alpha and beta. J. Immunol. 169:4522–4530.

    PubMed  CAS  Google Scholar 

  3. Arnould, T., R. Thibaut-Vercruyssen, N. Bouaziz, M. Dieu, J. Remacie, and C. Michiels. 2001. \( {\text{PGF}}_{{2\alpha }} \), a prostanoid released by endothelial cells activated by hypoxia, is a chemoattractant candidate for neutrophil recruitment. Am. J. Pathol. 159(1):345–357.

    PubMed  CAS  Google Scholar 

  4. Lee, W., S. Aitken, J. Sodek, and C. A. McCulloch. 1995. Evidence of a direct relationship between neutrophil collagenase activity and periodontal tissue destruction in vivo: role of active enzyme in human periodontitis. J. Periodontal. Res. 30:23–33.

    Article  PubMed  CAS  Google Scholar 

  5. Chan, C. C., S. Boyce, C. Brideau, S. Charleson, W. Cromlish, D. Ethier, et al. 1999. Rofecoxib (Vioxx, MK-0966; 4-(4′-Methylsulfonylphenyl)-3-phenyl-2- (5H)-furanone): a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and Biochemical profiles. J. Pharmacol. Exp. Ther. 290:551–560.

    PubMed  CAS  Google Scholar 

  6. Penning, T. B., J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. W. Collins, S. Docter, et al. 1997. Synthesis and biological evaluation of the 1,5-Diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-(5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y1) benzenesulfonamide (SC-58635, Celecoxib). J. Med. Chem. 40:1347–1365.

    Article  PubMed  CAS  Google Scholar 

  7. Kuritz, L., and A. Weaver. 2003. Advances in rheumatology: coxibs and beyond. J. Pain. Symp. Manage. 25S:S6–S20.

    Article  Google Scholar 

  8. Whittle, B. J. R. 2003. Gastrointestinal effects of nonsteroidal anti-inflammatory drugs. Fundam. Clin. Pharmacol. 17:301–313.

    Article  PubMed  CAS  Google Scholar 

  9. Vane, J. R., Y. S. Bakhle, and R. M. Botting. 1998. Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 38:97–120.

    Article  PubMed  CAS  Google Scholar 

  10. Francischi, J. N., C. T. Chaves, A. C. L. Moura, A. S. Lima, D. L. Ferreira-Alves, A. O. Rocha, et al. 2002. Selective inhibitors of cyclooxygenase-2 (COX-2) induce hypoalgesia in a rat paw model of inflammation. Br. J. Pharmacol. 137(6):837–844.

    Article  PubMed  CAS  Google Scholar 

  11. Déciga-Campos, M., and F. J. López-Muñoz. 2004. Participation of the L-arginine-nitric oxide-cyclic GMP-ATP-sensitive K+ channel cascade in the antinociceptive effect of rofecoxib. Eur. J. Pharmacol. 484:193–199.

    Article  PubMed  Google Scholar 

  12. Allcock, G. H., M. Allegra, R. J. Flower, and M. Perreti. 2001. Neutrophil accumulation induced by bacterial lipopolysaccharide: effects of dexamethasone and annexin 1. Clin. Exp. Invest. 123(1):62–67.

    CAS  Google Scholar 

  13. Muller, W. A. 2002. Leukocyte-endothelial cell interactions in the inflammatory response. Lab. Invest. 82(5):521–533.

    Article  PubMed  CAS  Google Scholar 

  14. Smith, C. J., Y. Zhang, C. M. Koboldt, J. Muhammad, B. S. Zweifel, A. Shaffer, et al. 1998. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc. Natl. Acad. Sci. USA 95:13313–13318.

    Article  PubMed  CAS  Google Scholar 

  15. Vane, J. R. 1971. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin like drugs. Nat. New. Biol. 231:232–235.

    PubMed  CAS  Google Scholar 

  16. Sachs, D., F. Q. Cunha, S. H. Ferreira. 2004. Peripheral analgesic blockade of hypernociception: activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+ channel pathway. Proc. Natl. Acad. Sci. USA 101(10):3680–3685.

    Article  PubMed  CAS  Google Scholar 

  17. Ivanov, A. I., and A. A. Romanovsky. 1977. Prostaglandin E2 as a mediator of fever: synthesis and catabolism. Front Biosci. 9:1977–1993.

    Google Scholar 

  18. Aronoff, D. M., and E. G. Neilson. 2001. Antipyretics: mechanisms of action and clinical use in fever suppression. Am. J. Med. 111:304–315.

    Article  PubMed  CAS  Google Scholar 

  19. Menezes, G. B., K. L. M. Maltos, J. M. M. Santos, I. D. G. Duarte, and J. N. Francischi. 2003. Cyclooxygenase (COX)-2 isoform accounts for neutrophil migration in a model of leukocyte recruitment induced by bacterial lipopolyssacaride in rats. Inflamm. Res. 52:S88.

    Google Scholar 

  20. Pereira, L. S. M., D. L. Ferreira-Alves, M. A. Resende, V. A. Romualdo, W. G. P. Reis, M. T. P. Lopes, et al. 2003. Reduced production of hyperalgesic substances by mononuclear cells from aged rats incubated with carrageenan: role of interleukin-2 and prostaglandins. Inflamm. Res. 52(3):119–125.

    Article  PubMed  CAS  Google Scholar 

  21. Giuliano, F., and T. D. Warner. 2002. Origins of prostaglandin E2: Involvements of cyclooxygenase (COX)-1 and COX 2 in human and rat systems. J. Pharmacol. Exp. Ther. 303:1001–1006.

    Article  PubMed  CAS  Google Scholar 

  22. Lauffenburger, D. A., and A. F. Horwitz. 1996. Cell migration: a physically integrated molecular process. Cell 84(3):359–369.

    Article  PubMed  CAS  Google Scholar 

  23. Vane, J. R., and R. M. Botting. 1997. Mechanism of action of aspirin-like drugs. Semin. Arthritis. Rheum. 26:2–10.

    Article  PubMed  CAS  Google Scholar 

  24. Warner, T. D., I. Vojnovic, F. Giuliano, R. Jiménez, D. Bishop-Bailey, and J. A. Mitchell. 2004. Cyclooxygenases 1, 2, and 3 and the production of prostaglandin I2: investigating the activities of acetaminophen and cyclooxygenase-2-selective inhibitors in rat tissues. J. Pharmacol. Exp. Ther. 310:642–647.

    Article  PubMed  CAS  Google Scholar 

  25. Foster, S. J., M. E. McCormick, A. Howart, and D. Aked. 1986. Leukocyte recruitment in the subcutaneous sponge implant model of acute inflammation in rat is not mediated by leukotriene B4. Biochem. Pharmacol. 35:1709–1717.

    Article  PubMed  CAS  Google Scholar 

  26. Ockilnd, A., S. Lake, K. Krook, I. Hallin, M. Nistér, and B. Westermark. 1997. Localization of the prostaglandin F2 alpha on rat tissues. Prostaglandins, Leukot. Essent. Fat. Acids. 57:6527–6532.

    Google Scholar 

  27. Kammerl, M. C., J. Debler, G. A. Riegger, and B. K. Kramer. 2004. COX 2 inhibitors and risk of heart failure. Lancet. 364:1486–1487.

    Article  PubMed  Google Scholar 

  28. Topol, E. J. 2004. Failing the Public Health—Rofecoxib, Merck, and the FDA. N. Engl. J. Med. 351:1707–1709.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

We wish to thank YS Bakhle for his suggestions regarding this project.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Janetti Nogueira de Francischi.

Additional information

Project supported by the Conselho Nacional de Pesquisa (CNPq).

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Menezes, G.B., dos Reis, W.G.P., Santos, J.M.M. et al. Inhibition of Prostaglandin \({\text{F}}_{{{\text{2}}\alpha }} \) by Selective Cyclooxygenase 2 Inhibitors Accounts for Reduced Rat Leukocyte Migration. Inflammation 29, 163–169 (2005). https://doi.org/10.1007/s10753-006-9013-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-006-9013-z

Key words

Navigation