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INFLAMMATION AND IMMUNOPHARMACOLOGY

Effects of Prostaglandin D₂, 15-Deoxy-^12,14-prostaglandin J₂, and Selective DP₁ and DP₂ Receptor Agonists on Pulmonary Infiltration of Eosinophils in Brown Norway Rats

Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada (W.A., C.C., J.G.M., Q.H., W.S.P.); and Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida (J.R.)

Prostaglandin (PG) D₂ 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 PGD₂ contributes to allergen-induced pulmonary eosinophilia via its classic DP₁ receptor. The PGD₂-derived product 15-deoxy-^12,14-PGJ₂ is widely used as a peroxisome proliferator-activated receptor 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 PGD₂ and 15-deoxy-^12,14-PGJ₂ 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 PGD₂ and 15-deoxy-^12,14-PGJ₂ induced robust eosinophilic responses that were apparent by 12 h and persisted for at least 48 h. Two selective DP₂ receptor agonists, 15R-methyl-PGD₂ and 13–14-dihydro-15-keto-PGD₂, induced similar responses, the former being more potent than PGD₂, 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 PGD₂ and 15-deoxy-^12,14-PGJ₂ induce eosinophil infiltration into the lungs through the DP₂ receptor. The potent in vitro DP₂ receptor agonist 15R-methyl-PGD₂ is also very active in vivo and should be a useful tool in examining the role of this receptor.

Address correspondence to: Dr. William S. Powell, Meakins-Christie Laboratories, McGill University, 3626 St. Urbain St., Montreal, QC, Canada H2X 2P2. E-mail: william.powell{at}mcgill.ca

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