Prostaglandin D2-induced eosinophilic airway inflammation is mediated by CRTH2 receptor
Prostaglandin D2-induced eosinophilic airway inflammation is mediated by CRTH2 receptor
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DOI：
10.1124/jpet.104.078212
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发表时间：
2005-03-01
影响因子：
3.5
通讯作者：
Ishizaka, A
中科院分区：
文献类型：
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作者：
Shiraishi, Y;Asano, K;Ishizaka, A
肥大细胞衍生的前列腺素D-2（PGD（2））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剂之一。PGD（2）的两种G蛋白偶联受体，即前列腺素D-2受体（DP）和Th-2细胞上表达的趋化因子受体同源分子（CRTH 2），均表达于嗜酸性粒细胞表面，CRTH 2已被证明在体外介导PGD（2）诱导的嗜酸性粒细胞动员。然而，尚未确定PGD（2）及其受体是否介导体内嗜酸性粒细胞运输到气道或其他器官。我们证明，在全身注射白细胞介素-5（IL-5）的大鼠中，肺内注射PGD（2）可在2小时内诱导明显的气道嗜酸性粒细胞增多，这可通过支气管肺泡灌洗液（BAL）中细胞的分类计数和肺组织学来确定。单独的全身IL-5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没有影响。三种CRTH 2特异性激动剂（13，14-二氢-15-酮-PGD（2）、11-脱氧-11-亚甲基-15-酮-PGD（2）和吲哚美辛）显示出与PGD（2）相同的BAL嗜酸性粒细胞增多诱导作用，但是DP激动剂（BW 245 C [5-（6-羧基己基）-1-甲基-IH-吡唑-4-基]-2-甲基-IH-吡唑-4-甲酰胺）（3-环己基-3-羟丙基）-乙内酰脲]）或血栓烷A（2）受体（TP）激动剂（[1 S-1 α，2 β（5 Z），3 α（1 E，3R*），4 α）]-7-[3-（3-羟基-4-（4 '-碘苯氧基）-1-丁烯基）-7-氧杂双环-[2.2.1]庚-2-基]-5-庚烯酸）显示无影响。PGD（2）或CRTH 2激动剂诱导的BAL嗜酸性粒细胞增多几乎完全被CRTH 2/TP拮抗剂雷马曲班预处理抑制[BAY-u3405;（+）-（3R）-3-（4-氟苯磺酰氨基）1，2，3，4-四氢咔唑-9-丙酸]，而TP特异性拮抗剂SQ 29，548（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]-[1 S-[1 α，2 α（Z），3 α，4 α]]）或DP特异性拮抗剂，BW A868 C [3-苄基-5-（6-羧基己基）-1-（2-环己基-2-羟乙基氨基）-乙内酰脲]不抑制PGD的作用（2）。这些结果表明，在PGD（2）相关的气道炎症中，CRTH 2在嗜酸性粒细胞从血流进入气道中起重要作用。
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.