Skip to main content
SpringerLink
Log in

A Novel Thromboxane Synthetase Inhibitor, Dp-1904, Inhibits Human Blood Eosinophil Degranulation

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Eosinophils have been recognized to be associated with various immune responses and disease processes including bronchial asthma. Eosinophils release a number of cytotoxic and neurotoxic mediators. However, the factors regulating such release and the underlying mechanisms are unclear. In this study, we investigated the effect of a selective and potent thromboxane synthase inhibitor, DP-1904, on the release of eosinophil cationic protein (ECP) in platelet activating factor (PAF) and IgG-stimulated human blood eosinophils. PAF (1 μM) and IgG both released ECP which constituted about 25–30% of the total ECP content. The control protein, ovalbumin, did not release any ECP over the basal values. DP-1904 in two different concentrations, 10 μM and 100 μM, significantly attenuated the release of ECP in response to PAF or IgG. The mean percent inhibition by 10 μM DP-1904 was 49 ± 10 and 31 ± 2 against PAF and IgG-induced ECP release, respectively. However, at 100 μM DP-1904 the percent inhibition was 76 ± 14 and 67 ± 2, respectively. These data suggest that TXA2 is an important mediator in the regulation of eosinophil degranulation, and DP-1904 thus might prove beneficial in the treatment of bronchial asthma.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. KAY, A. B. 1989. Inflammatory cells in bronchial asthma. J. Asthma. 23:335–344.

    Google Scholar 

  2. DURHAM, S. R., and A. B. KAY. 1985. Eosinophils, bronchial hyperreactivity, and late-phase asthmatic reactions. Clin. Allergy 15:411–416.

    Google Scholar 

  3. FRIGAS, E., and G. J. GLEICH. 1986. The eosinophil and the pathophysiology of asthma. J. Allergy Clin. Immunol. 77:527–533.

    Google Scholar 

  4. WELLER, P. F. 1991. The immunobiology of eosinophils. N. Engl. J. Med. 324:1110–1115.

    Google Scholar 

  5. TAYLOR, K. J. and A. R. LUKSZA. 1987. Peripheral blood eosinophil counts and bronchial responsiveness. Thorax 42:452–460.

    Google Scholar 

  6. TAMURA, N., D. K. AGRAWAL, and R. G. TOWNLEY. 1988. Leukotriene C4 production from human eosinophils in vitro: Role of eosinophil chemotactic factors on eosinophil activation. J. Immunol. 141:4291–4297.

    Google Scholar 

  7. TAYLOR, I. K., P. L. WARDS, K. M. O'SHAUGHNESSY, C. I. DOLLERY, P. BLACK, S. E. BARROW, G. W. TAYLOR, and R. W. FULLER. 1991. TXA2 biosynthesis in acute asthma and after antigen challenge. Am. Rev. Respir. Dis. 143:119–125.

    Google Scholar 

  8. KANAO, M., Y. WATANABE, Y. KIMURA, J. SAGUSA, K. YAMAMOTO, H. KANNO, N. KANAYA, H. KUBO, S. ASHIDA, and F. ISHIKAWA. 1989. Thromboxane A2 synthetase inhibitor. Syntheses and activities of Tetrahydronaphthalene and Indan derivatives. J. Med. Chem. 32:1326–1334.

    Google Scholar 

  9. TAKAMI, M., Y. TAKATA, K. MATSUMOTO, S. ONO, and W. TSUKADA. 1991. Effect of DP-1904, a new thromboxane A2 synthetase inhibitor, on guinea pig experimental asthma. Ann. N.Y. Acad. of Sci. 629:407–409.

    Google Scholar 

  10. AGRAWAL, D. K., M. TAKAMI, and S. ONO. 1993. DP-1904: a novel thromboxane A2 (TXA2) synthetase inhibitor attenuates the effect of inflammatory mediators in human monocytes and lymphocytes. Am. Rev. Respir. Dis. 147:A448.

    Google Scholar 

  11. TAKAMI, M., K. MATSUMOTO, Y. TAKATA, K. FURUHAMA, and W. TSUKADA. 1995. Possible role of thromboxane A2 in hyperresponsiveness of isolated rat lung tissue in a Sephadex-induced eosinophilia model. Int. Arch. Allergy Immunol. 106:401–409.

    Google Scholar 

  12. NUMAO, T. and D. K. AGRAWAL. 1992. Neuropeptides modulate human eosinophil chemotaxis. J. Immunol. 149:3309–3315.

    Google Scholar 

  13. MANNING, P. J., W. H. STEVENS, D. W. COCKCROFT, and P. M. O'BYRNE. 1991. The role of thromboxane in allergen-induced asthmatic responses. Eur. Respir. J. 4:667–673.

    Google Scholar 

  14. IWAMOTO, I., C. RA, T. SATO, H. TOMIOKA, and S. YOSHIDA. 1988. Thromboxane A2 production in allergen-induced immediate and late asthmatic responses. Its possible role in inducing the late response. J. Asthma 25: 117–124.

    Google Scholar 

  15. SLADEK, K., R. DWORSKI, G. A. FITZGERALD. 1990. Allergen-stimulated release of thromboxane A2 and leukotriene E4 in humans. Effect of indomethacin. Am. Rev. Respir. Dis. 141:1441–1445.

    Google Scholar 

  16. LUPINETTI, M. D., J. R. SHELLER, F. CATELLA, and G. A. FITZGERALD. 1989. Thromboxane biosynthesis in allergen-induced bronchospasm. Evidence for platelet activation. Am. Rev. Respir. Dis. 140:932–935.

    Google Scholar 

  17. KUMLIN, M., B. DAHLEN T. BJOERCK, O. ZETTERSTROEM, E. GRANSTROEM, and S. E. DAHLEN. 1992. Urinary excretion of LTE4 and 11-dehydro TXB2 in response to bronchial provocations with allergen, aspirin, LTD4, and histamine in asthmatics. Am. Rev. Respir. Dis. 146:96–103.

    Google Scholar 

  18. BUTCHERS, P. R. and C. J. VARDEY. 1990. The effect of prostanoids on the function of human eosinophils. Agents and Actions suppl.31:103–l12.

  19. PARSONS, W. G., and L. J. ROBERTS. 1988. Transformation of prostaglandin D2 to isomeric prostaglandin F2 compounds by human eosinophils: a potent mast cell-eosinophil interaction. J. Immunol. 141:2413–2419.

    Google Scholar 

  20. FOEGH, M. L., Y. T. MADDOX, and P. W. RAMWELL. 1986. Human peritoneal eosinophils and formation of arachidonate cyclooxygenase products. Scand. J. Immunol. 23:599–603.

    Google Scholar 

  21. WHITE, S. R., M. E. STREK, G. V. P. KULP, S. M. SPAETHE, R. A. BURCH, S. P. NEELEY, and A. R. LEFF. 1993. Regulation of human eosinophil degranulation and activation by endogenous phospholipase A2. J. Clin. Invest. 91:2118–2125.

    Google Scholar 

  22. DVORAK, A. M., P. F. WELLER, V. S. HARVEY, E. S. MORGAN, and H. F. DVORAK. 1993. Ultrastructural localization of prostaglandin endoperoxide synthase (cyclooxygenase) to isolated, purified fractions of guinea pig peritoneal macrophage and line 10 hepatocarcinoma cell lipid bodies. Int. Arch. Allergy Immunol. 101:136–142.

    Google Scholar 

  23. DWORSKI, R., G. A. FITZGERALD, and J. R. SHELLER. 1992. Thromboxane synthetase inhibitor in allergen challenged sheep lung: effect on eicosanoid synthesis. Eicosanoids 5:35–37.

    Google Scholar 

  24. TROCHTENBERG, D. S., P. L. LEFFERTS, G. A. KING, Y. S. HWANG, B. W. CHRISTMAN, and J. R. SNAPPER. 1992. Effect of thromboxane synthetase and cyclooxygenase inhibition on PAF-induced changes in lung function and arachidonic acid metabolism. Prostaglundins 44:555–577.

    Google Scholar 

  25. AGRAWAL, D. K. and T. NUMAO. 1993. Transmembrane signaling in cosinophils. In Eosinophils, S. Makino and T. Fukuda, editors. CRC Press, Boca Raton, Florida, pp. 171–192.

    Google Scholar 

  26. SPRY, C. J. F. 1988. In Eosinophils: a comprehensive review and guide to the scientific and medical literature, Oxford Univ Press, Oxford, UK, 1988, pp. 43–80.

    Google Scholar 

  27. NUESSE O., M. LINDAU, O. CROMWELL, A. B. KAY, and B. D. GOMPERTS. 1990. Intracellular application of guanosine-5′-O-(3-thiotriphosphate) induces exocytotic granule fusion in guinea pig eosinophils. J. Exp. Med 171:775–781.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Creighton University School of Medicine, Omaha, Nebraska

    Devendra K. Agrawal

  2. Daiichi Pharmaceutical Co., Tokyo, Japan

    Mitsutaka Takami & Shin-Etsu Ono

Authors
  1. Devendra K. Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitsutaka Takami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shin-Etsu Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Agrawal, D.K., Takami, M. & Ono, SE. A Novel Thromboxane Synthetase Inhibitor, Dp-1904, Inhibits Human Blood Eosinophil Degranulation. Inflammation 21, 1–8 (1997). https://doi.org/10.1023/A:1027330506697

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1027330506697

Keywords

Search

Navigation