Uller Lena, Mathiesen Jesper Mosolff, Alenmyr Lisa, Korsgren Magnus, Ulven Trond, Högberg Thomas, Andersson Gunnar, Persson Carl G A, Kostenis Evi
Dept. Experimental Medical Science, Lund University, Sweden.
Respir Res. 2007 Feb 28;8(1):16. doi: 10.1186/1465-9921-8-16.
Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology.
Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model.
TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia.
This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban.
肥大细胞衍生的前列腺素D2（PGD2）可能在过敏性哮喘的嗜酸性粒细胞炎症和黏液分泌中起作用。TH2细胞上表达的趋化因子受体同源分子（CRTH2）是前列腺素D2的高亲和力受体，介导TH2细胞、肥大细胞和嗜酸性粒细胞向炎症部位的迁移，最近作为过敏性气道疾病的治疗靶点受到关注。本项涉及小鼠的研究探讨了与双重TP/CRTH2拮抗剂雷马曲班结构密切相关的TM30089对CRTH2拮抗作用的特异性，并比较了雷马曲班和TM30089抑制哮喘样病理的能力。
在体外重组表达系统中测定TM30089对多种小鼠受体的亲和力和拮抗效力，这些受体包括血栓素A2受体mTP、CRTH2受体以及选定的过敏毒素和趋化因子受体。在小鼠哮喘模型中研究TM30089和雷马曲班对组织嗜酸性粒细胞增多和黏液细胞组织病理学的体内作用。
TM30089对小鼠CRTH2表现出高选择性和拮抗效力，但对TP以及许多其他受体缺乏亲和力，这些受体包括相关的过敏毒素C3a和C5a受体、选定的趋化因子受体以及环氧化酶同工型1和2，而这些都是过敏性疾病中公认的相关因子。此外，TM30089和雷马曲班（本文中用作对照）通过减少支气管周围嗜酸性粒细胞增多和黏液细胞增生，在体内同样抑制哮喘病理。
这是首份证明高选择性小分子CRTH2拮抗剂具有体内抗过敏疗效的报告。我们的数据表明，单独的CRTH2拮抗作用对小鼠过敏性气道炎症有效，甚至在某种程度上，这一机制可以解释雷马曲班的疗效。
