DP2 Receptor Antagonists: Novel Therapeutic Target for COPD

Chronic obstructive pulmonary disease (COPD) is a chronic and progressive disease of the small airways and lung parenchyma that is characterized by chronic airway inflammation, airway remodeling and parenchymal destruction. Current treatment options for patients with COPD consist primarily of long acting bronchodilators. Inhaled corticosteroids provide benefit for exacerbations but have little impact on the persistent inflammation. At present, there are no approved drugs that are disease modifying to treat the underlying causes of COPD. One pharmacological mechanism we and others are exploring as a therapeutic target for COPD is antagonism of the DP2 receptor (also known as chemoattractant receptor-homologous molecule expressed on Th2 cells, CRTh2). Since cigarette smoking is a risk factor for COPD, we used mouse models of acute and subchronic cigarette smoke exposure to explore the role of DP2 in COPD. We observed an increase in prostaglandin D2 (PGD2), the natural ligand for DP2, in the mouse lungs following subchronic smoke exposure. We demonstrated that DP2 antagonism alleviated much of the cigarette smoke-induced lung phenotype, including cellular inflammation, mucus cell metaplasia and epithelial hyperplasia. Although the role of PGD2 and DP2 in COPD is yet to be fully elucidated, our results support the development of DP2 antagonists clinically as a novel pharmacological mechanism to treat COPD.