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

Autor: Lena Uller, Jesper Mosolff Mathiesen, Carl G. A. Persson, Lisa Alenmyr, Gunnar Andersson, Magnus Korsgren, Thomas Högberg, Trond Ulven, Evi Kostenis
Rok vydání: 2006
Předmět:
Pathology
Chemokine
Respiratory Medicine and Allergy
antagonists & inhibitors [Immunologic]
Receptors
Prostaglandin
Pharmacology
pathology [Pulmonary Eosinophilia]
chemistry.chemical_compound
Chemokine receptor
Mice
Radioligand Assay
pharmacology [Sulfonamides]
Receptors
Receptors
Immunologic
Receptor
Inbred BALB C
Cells
Cultured
Mice
Inbred BALB C
Sulfonamides
Cultured
biology
cytology [Bronchoalveolar Lavage Fluid]
Female
Prostaglandin D2
medicine.symptom
Bronchial Hyperreactivity
drug therapy [Asthma]
Bronchoalveolar Lavage Fluid
medicine.drug
Pulmonary and Respiratory Medicine
medicine.medical_specialty
pharmacology [Prostaglandin Antagonists]
Prostaglandin Antagonists
pathology [Asthma]
Cells
antagonists & inhibitors [Prostaglandin]
Carbazoles
immunology [Asthma]
Inflammation
Enzyme-Linked Immunosorbent Assay
In Vitro Techniques
Sensitivity and Specificity
medicine
Animals
Anaphylatoxin
immunology [Pulmonary Eosinophilia]
Pulmonary Eosinophilia
Prostaglandin D2 receptor
pharmacology [Carbazoles]
pathology [Inflammation]
lcsh:RC705-779
business.industry
Animal
Research
drug therapy [Inflammation]
lcsh:Diseases of the respiratory system
Asthma
Disease Models
Animal
chemistry
immunology [Bronchial Hyperreactivity]
Immunology
Disease Models
biology.protein
Immunization
Ramatroban
physiopathology [Bronchial Hyperreactivity]
business
Zdroj: Respiratory Research
Respiratory Research; 8:16 (2007)
Uller, L, Mathiesen, J M, Alenmyr, L, Korsgren, M, Ulven, T, Högberg, T, Andersson, G, Persson, C G A & Kostenis, E 2007, ' Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation ', Respiratory research (Online), vol. 8, no. 16 . https://doi.org/10.1186/1465-9921-8-16
Respiratory Research, Vol 8, Iss 1, p 16 (2007)
ISSN: 1465-993X
1465-9921
DOI: 10.1186/1465-9921-8-16
Popis: 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.
Databáze: OpenAIRE
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