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Role of prostaglandin D 2 and CRTH 2 blockade in early‐ and late‐phase nasal responses
Author(s) -
Shiraishi Y.,
Takeda K.,
Domenico J.,
Gelfand E. W.
Publication year - 2014
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.12280
Subject(s) - prostaglandin d2 , ovalbumin , allergic inflammation , immunology , antagonist , medicine , receptor , inflammation , prostaglandin , nasal administration , receptor antagonist , pharmacology , immune system
Summary Background Prostaglandin D 2 ( PGD 2 ) plays an important role in allergic inflammation. The PGD 2 receptor, CRTH 2, is expressed on basophils, eosinophils, and Th2 lymphocytes and mediates chemotactic activity. Objective To define the role of CRTH 2 in allergen‐induced nasal responses in a mouse model of allergic rhinitis ( AR ), a potent, selective CRTH 2 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 ( R NA ) 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 CRTH 2 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 R NA 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 CRTH 2 prevents the development of both the EPR and LPR as well as nasal inflammation.