Abstract
BackgroundMast 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.MethodsAffinity 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.ResultsTM30089, 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.ConclusionThis 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.
Highlights
Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma
In vitro pharmacological profile of TM30089 and ramatroban We have recently reported that the ramatroban analog TM30089 displays high affinity to human CRTH2 but completely lacks affinity to the human thromboxane A2 receptor hTP (TP, T prostanoid receptor), unlike ramatroban which antagonizes both receptors well [27]
To investigate whether TM30089 represents a suitable tool compound to explore the role of CRTH2 in a mouse model of allergic inflammation in vivo, we cloned the mouse orthologs of CRTH2 and TP and evaluated TM30089 and ramatroban in their ability to displace [3H]PGD2 and 3 [H]SQ29548 from mouse CRTH2 (mCRTH2) and mouse TP (mTP), respectively, in competition binding
Summary
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. PGD2 elicits biological responses by interaction with three specific seven-transmembrane receptors, referred to as DP/DP1, DP2/CRTH2, and TP (DP, D prostanoid receptor; CRTH2, chemoattractant receptor homologous molecule expressed on T helper type 2 cells; TP, thromboxane A2 receptor) [6,7,8]. Via interaction with one (or a combination) of its three specific receptors PGD2 may contribute to bronchoconstriction, eosinophilia and mucus production in allergic asthma. It is possible that the contribution of PGD2 to allergic airway inflammation is missed if the load of allergen in challenge studies is too large [9]
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