A prostaglandin D2 receptor antagonist modifies experimental asthma in sheep


Michitaka Shichijo, Discovery Research Laboratories, Shionogi & Co. Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
E-mail: michitaka.shichijou@shionogi.co.jp


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 PGD2-induced cAMP production in platelet-rich plasma with an IC50 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.