A prostaglandin D2 receptor antagonist modifies experimental asthma in sheep

M. Shichijo, A. Arimura, Y. Hirano, K. Yasui, N. Suzuki, M. Deguchi, W. M. Abraham

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background Prostaglandin (PG) D2 is the major cylooxygenase metabolite released by mast cells upon allergen stimulation, and elicits responses through either the prostanoid DP1 receptor and/or the chemoattractant receptor homologous molecule expressed on T-helper type 2 (Th2) cells (CRTH2/DP2). Experimental evidence suggests that stimulation of one or both these receptors contributes to asthma pathophysiology. Objective The aim of this study was to test the hypothesis that the prostanoid DP1 receptor contributes to asthma pathophysiology by determining the efficacy of an orally active antagonist for this receptor, S-5751, on allergen-induced bronchoconstriction, airway hyperresponsiveness (AHR) and cellular inflammation in the sheep model of asthma. Methods PGD2-induced cyclic adenosine monophosphate (cAMP) production in platelet-rich plasma was used to establish the in vitro efficacy of S-5751. In vivo, sheep naturally allergic to Ascaris suum were challenged with an aerosolized antigen with and without S-5751 treatment (given 4 days before and for 6 days after the challenge). Results S-5751 inhibited PGD 2-induced cAMP production in platelet-rich plasma with an IC 50 value of 0.12 μm. S-5751 at 30 mg/kg, but not at 3 mg/kg, reduced the early bronchoconstriction and inhibited the late bronchoconstriction. AHR and inflammatory cell infiltration in bronchoalveolar lavage fluid at days 1 and 7 were also inhibited with the 30 mg/kg dose. The responses observed with S-5751 at 30 mg/kg were comparable with those with montelukast treatment (0.15 mg/kg, twice a day, intravenous); however, S-5751 did not block inhaled leukotrieneD4-induced broncoconstriction. Conclusion Prostanoid DP1 receptor inhibition may represent an alternative target for asthma therapy.

Original languageEnglish
Pages (from-to)1404-1414
Number of pages11
JournalClinical and Experimental Allergy
Volume39
Issue number9
DOIs
StatePublished - Sep 1 2009
Externally publishedYes

Fingerprint

7(2-(5-hydroxybenzo(b)thiophen-3-ylcarbonylamino)-10-norpinan-3-yl)hept-5-enoic acid
Sheep
Asthma
Bronchoconstriction
Prostaglandins
Prostaglandin D2
Platelet-Rich Plasma
montelukast
Cyclic AMP
Allergens
Formyl Peptide Receptor
Ascaris suum
Prostaglandins D
Th2 Cells
Bronchoalveolar Lavage Fluid
prostaglandin D2 receptor
Mast Cells
Therapeutics

Keywords

  • Asthma
  • PGD
  • Prostanoid DP1 receptor
  • S-5751
  • Sheep

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Shichijo, M., Arimura, A., Hirano, Y., Yasui, K., Suzuki, N., Deguchi, M., & Abraham, W. M. (2009). A prostaglandin D2 receptor antagonist modifies experimental asthma in sheep. Clinical and Experimental Allergy, 39(9), 1404-1414. https://doi.org/10.1111/j.1365-2222.2009.03275.x

A prostaglandin D2 receptor antagonist modifies experimental asthma in sheep. / Shichijo, M.; Arimura, A.; Hirano, Y.; Yasui, K.; Suzuki, N.; Deguchi, M.; Abraham, W. M.

In: Clinical and Experimental Allergy, Vol. 39, No. 9, 01.09.2009, p. 1404-1414.

Research output: Contribution to journalArticle

Shichijo, M, Arimura, A, Hirano, Y, Yasui, K, Suzuki, N, Deguchi, M & Abraham, WM 2009, 'A prostaglandin D2 receptor antagonist modifies experimental asthma in sheep', Clinical and Experimental Allergy, vol. 39, no. 9, pp. 1404-1414. https://doi.org/10.1111/j.1365-2222.2009.03275.x
Shichijo, M. ; Arimura, A. ; Hirano, Y. ; Yasui, K. ; Suzuki, N. ; Deguchi, M. ; Abraham, W. M. / A prostaglandin D2 receptor antagonist modifies experimental asthma in sheep. In: Clinical and Experimental Allergy. 2009 ; Vol. 39, No. 9. pp. 1404-1414.
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