title: Prostaglandin D2-induced eosinophilic airway inflammation is mediated by CRTH2 receptor.
abstract: Mast cell-derived prostaglandin D(2) (PGD(2)) is one of the essential modulators of eosinophilic airway inflammation in asthma and allergic rhinitis. Two G protein-coupled receptors for PGD(2), prostaglandin D(2) receptor (DP) and chemoattractant receptor-homologous molecule expressed on Th(2) cells (CRTH2), are both expressed on the surface of eosinophils, and CRTH2 has been demonstrated to mediate PGD(2)-induced eosinophil mobilization in vitro. However, it has not yet been determined whether PGD(2) and its receptors mediate in vivo eosinophil trafficking into the airways or other organs. We demonstrated that intratracheal administration of PGD(2) in rats pretreated with systemic interleukin-5 (IL-5) injection induced marked airway eosinophilia, determined by the differential counts of cells in bronchoalveolar lavage (BAL) fluid and lung histology, within 2 h. Systemic IL-5 alone significantly increased the number of eosinophils in the peripheral blood but showed no effect on airway eosinophilia. Three CRTH2-specific agonists (13,14-dihydro-15-keto-PGD(2), 11-deoxy-11-methylene-15-keto-PGD(2), and indomethacin) demonstrated equivalent induction of BAL eosinophilia to that of PGD(2), but a DP agonist (BW 245C [5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin]) or a thromboxane A(2) receptor (TP) agonist ([1S-1alpha,2beta(5Z), 3alpha(1E,3R*),4alpha)]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid) showed no effect. PGD(2) or CRTH2 agonist-induced BAL eosinophilia was almost completely inhibited by pretreatment with a CRTH2/TP antagonist, ramatroban [BAY-u3405; (+)-(3R)-3-(4-fluorobenzenesulfonamido)-1,2,3,4-tetra-hydrocarbazole-9-propionic acid], whereas a TP-specific antagonist, SQ29,548 (5-heptenoic, 7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-[1S-[1alpha,2alpha(Z),3alpha,4alpha]]), or a DP-specific antagonist, BW A868C [3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexy-2-hydroxyethylamino)-hydantoin], did not inhibit the effects of PGD(2). These results suggest that CRTH2 plays a significant role in the eosinophil trafficking from the bloodstream into the airways in PGD(2)-related airway inflammation.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. ko-asano@qa2.so-net.ne.jp
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Asano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakajima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Oguma
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiomi
authors.forename: Koichi
authors.initials: K
authors.lastname: Sayama
authors.forename: Kyoko
authors.initials: K
authors.lastname: Niimi
authors.forename: Misa
authors.initials: M
authors.lastname: Wakaki
authors.forename: Junko
authors.initials: J
authors.lastname: Kagyo
authors.forename: Eiji
authors.initials: E
authors.lastname: Ikeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Ishizaka
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D004305:Dose-Response Relationship, Drug; D015848:Interleukin-5 / Q000494:pharmacology; D008297:Male; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011657:Pulmonary Eosinophilia / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D011971:Receptors, Immunologic / Q000502:physiology*; D011982:Receptors, Prostaglandin / Q000502:physiology*
chemical_list: D015848:Interleukin-5; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor