Effects of prostaglandin D2, 15-deoxy-Δ12,14-prostaglandin J2, and selective DP1 and DP2 receptor agonists on pulmonary infiltration of eosinophils in Brown Norway rats

Prostaglandin (PG) D-2 is an arachidonic acid metabolite that is released by allergen-stimulated mast cells. It is a potent in vitro chemoattractant for human eosinophils, acting through the DP2 receptor/chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Furthermore, there is in vivo evidence that PGD(2) contributes to allergen-induced pulmonary eosinophilia via its classic DP1 receptor. The PGD(2)-derived product 15-deoxy-Delta(12,14)-PGJ(2) is widely used as a peroxisome proliferator-activated receptor gamma agonist and has been shown to have anti-inflammatory properties. However, this substance can also activate eosinophils in vitro through the DP2 receptor. The objectives of the present study were to determine whether PGD(2) and 15-deoxy-Delta(12,14)-PGJ(2) can induce pulmonary eosinophilia, and, if so, to examine the abilities of selective DP1 and DP2 receptor agonists to induce this response. Brown Norway rats were treated by intratracheal instillation of PGs. Vehicle and 5-oxo-6,8,11,14-eicosatetraenoic acid were used as negative and positive controls, respectively. Lung eosinophils were identified by immunostaining of lung sections with an antibody to major basic protein. Both PGD(2) and 15-deoxy-Delta(12,14)-PGJ(2) induced robust eosinophilic responses that were apparent by 12 h and persisted for at least 48 h. Two selective DP2 receptor agonists, 15R-methyl-PGD(2) and 13-14-dihydro-15-keto-PGD(2), induced similar responses, the former being more potent than PGD(2), whereas the latter was less potent. The selective DP1 receptor agonist BW245C [(4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid] was completely inactive. We conclude that PGD(2) and 15-deoxy- Delta(12,14)-PGJ(2) induce eosinophil infiltration into the lungs through the DP2 receptor. The potent in vitro DP2 receptor agonist 15R-methyl-PGD(2) is also very active in vivo and should be a useful tool in examining the role of this receptor.