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Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation.
Respir Res. 2007 Feb 28; 8:16.RR

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.

Authors+Show Affiliations

Dept. Experimental Medical Science, Lund University, Sweden. lena.Uller@med.lu.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17328802

Citation

Uller, Lena, et al. "Antagonism of the Prostaglandin D2 Receptor CRTH2 Attenuates Asthma Pathology in Mouse Eosinophilic Airway Inflammation." Respiratory Research, vol. 8, 2007, p. 16.
Uller L, Mathiesen JM, Alenmyr L, et al. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation. Respir Res. 2007;8:16.
Uller, L., Mathiesen, J. M., Alenmyr, L., Korsgren, M., Ulven, T., Högberg, T., Andersson, G., Persson, C. G., & Kostenis, E. (2007). Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation. Respiratory Research, 8, 16.
Uller L, et al. Antagonism of the Prostaglandin D2 Receptor CRTH2 Attenuates Asthma Pathology in Mouse Eosinophilic Airway Inflammation. Respir Res. 2007 Feb 28;8:16. PubMed PMID: 17328802.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation. AU - Uller,Lena, AU - Mathiesen,Jesper Mosolff, AU - Alenmyr,Lisa, AU - Korsgren,Magnus, AU - Ulven,Trond, AU - Högberg,Thomas, AU - Andersson,Gunnar, AU - Persson,Carl G A, AU - Kostenis,Evi, Y1 - 2007/02/28/ PY - 2006/10/10/received PY - 2007/02/28/accepted PY - 2007/3/3/pubmed PY - 2007/3/30/medline PY - 2007/3/3/entrez SP - 16 EP - 16 JF - Respiratory research JO - Respir. Res. VL - 8 N2 - 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. SN - 1465-993X UR - https://www.unboundmedicine.com/medline/citation/17328802/Antagonism_of_the_prostaglandin_D2_receptor_CRTH2_attenuates_asthma_pathology_in_mouse_eosinophilic_airway_inflammation_ L2 - https://respiratory-research.biomedcentral.com/articles/10.1186/1465-9921-8-16 DB - PRIME DP - Unbound Medicine ER -