Shiraishi Yoshiki, Asano Koichiro, Nakajima Takeshi, Oguma Tsuyoshi, Suzuki Yusuke, Shiomi Tetsuya, Sayama Koichi, Niimi Kyoko, Wakaki Misa, Kagyo Junko, Ikeda Eiji, Hirai Hiroyuki, Yamaguchi Kazuhiro, Ishizaka Akitoshi
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
J Pharmacol Exp Ther. 2005 Mar;312(3):954-60. doi: 10.1124/jpet.104.078212. Epub 2004 Nov 4.
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.
肥大细胞衍生的前列腺素D2（PGD2）是哮喘和变应性鼻炎中嗜酸性粒细胞气道炎症的重要调节因子之一。PGD2的两种G蛋白偶联受体，前列腺素D2受体（DP）和Th2细胞上表达的趋化因子受体同源分子（CRTH2），均表达于嗜酸性粒细胞表面，并且CRTH2已被证实在体外介导PGD2诱导的嗜酸性粒细胞动员。然而，PGD2及其受体是否介导体内嗜酸性粒细胞向气道或其他器官的转运尚未确定。我们证明，在全身注射白细胞介素-5（IL-5）预处理的大鼠中，气管内给予PGD2在2小时内可诱导明显的气道嗜酸性粒细胞增多，这通过支气管肺泡灌洗（BAL）液中的细胞分类计数和肺组织学检查来确定。单独全身给予IL-5可显著增加外周血中嗜酸性粒细胞的数量，但对气道嗜酸性粒细胞增多无影响。三种CRTH2特异性激动剂（13,14-二氢-15-酮-PGD2、11-脱氧-11-亚甲基-15-酮-PGD2和吲哚美辛）对BAL嗜酸性粒细胞增多的诱导作用与PGD2相当，但DP激动剂（BW 245C [5-(6-羧基己基)-1-(3-环己基-3-羟丙基)-乙内酰脲]）或血栓素A2受体（TP）激动剂（[1S-1α,2β(5Z), 3α(1E,3R*),4α)]-7-[3-(3-羟基-4-(4'-碘苯氧基)-1-丁烯基)-7-氧杂双环-[2.2.1]庚烷-2-基]-5-庚烯酸）无此作用。PGD2或CRTH2激动剂诱导的BAL嗜酸性粒细胞增多几乎完全被CRTH2/TP拮抗剂雷马曲班[BAY-u3405；(+)-(3R)-3-(4-氟苯磺酰胺基)-1,2,3,4-四氢咔唑-9-丙酸]预处理所抑制，而TP特异性拮抗剂SQ29,548（5-庚烯酸，7-[3-[[2-[(苯基氨基)羰基]肼基]甲基]-7-氧杂双环[2.2.1]-庚-2-基]-[1S-[1α,2α(Z),3α,4α]]）或DP特异性拮抗剂BW A868C [3-苄基-5-(6-羧基己基)-1-(2-环己基-2-羟乙氨基)-乙内酰脲]不能抑制PGD2的作用。这些结果表明，在与PGD2相关的气道炎症中，CRTH2在嗜酸性粒细胞从血流向气道的转运中起重要作用。
