Role of prostaglandin D2 and CRTH2 blockade in early- and late-phase nasal responses

Background Prostaglandin D-2 (PGD(2)) plays an important role in allergic inflammation. The PGD(2) receptor, CRTH2, is expressed on basophils, eosinophils, and Th2 lymphocytes and mediates chemotactic activity. Objective To define the role of CRTH2 in allergen-induced nasal responses in a mouse model of allergic rhinitis (AR), a potent, selective CRTH2 receptor antagonist, ARRY-063 was administered in a model of allergic rhinitis in mice. Methods ARRY-063 was administered orally to ovalbumin (OVA) sensitized and challenged mice. To assess nasal obstruction, respiratory frequency (RF) was monitored by whole-body plethysmography immediately after the 4th challenge (early-phase response, EPR) and 24 h after the 6th challenge (late-phase response, LPR). Nasal resistance (RNA) was also measured in the LPR. PGD(2) was administered with or without OVA to determine the effect of PGD(2) on nasal responsiveness. Cytokine levels and histopathological changes in nasal tissue were analysed. Results Instillation of PGD(2) in the nose of sensitized mice together with a low concentration of OVA induced both an EPR and LPR. Treatment with the CRTH2 receptor antagonist prevented the decreases in RF seen immediately following the 4th challenge of sensitized mice (EPR). In the LPR, decreases in RF and increases in RNA were also prevented by antagonist treatment associated with reduced cytokine levels and inflammation in nasal tissues. Conclusions These data identify PGD(2) as a mediator of both the EPR and LPR in this model of AR and suggest that antagonism of CRTH2 prevents the development of both the EPR and LPR as well as nasal inflammation.