Research

Antagonism of the prostaglandin D₂ receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

Lena Uller¹ , Jesper Mosolff Mathiesen² , Lisa Alenmyr³ , Magnus Korsgren³ , Trond Ulven² , Thomas Högberg² , Gunnar Andersson² , Carl GA Persson³ and Evi Kostenis²

¹  Dept. Experimental Medical Science, Lund University, Sweden

²  7TM Pharma A/S, Fremtidsvej 3, 2970 Hørsholm, Denmark

³  Dept. Clinical Pharmacology, Lund University Hospital, Lund, Sweden

author email corresponding author email

Respiratory Research 2007, 8:16doi:10.1186/1465-9921-8-16

Published:	28 February 2007

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.