CRTH2 and D-Type Prostanoid Receptor Antagonists as Novel Therapeutic Agents for Inflammatory Diseases

Abstract

Accumulation of type 2 T helper (Th2) lymphocytes and eosinophils is a hallmark of bronchial asthma and other allergic diseases, and it is believed that these cells play a crucial pathogenic role in allergic inflammation. Thus, Th2 cells and eosinophils are currently considered a major therapeutic target in allergic diseases and asthma. However, drugs that selectively target the accumulation and activation of Th2 cells and eosinophils in tissues are unavailable so far. Prostaglandin (PG)D₂ is a key mediator in various inflammatory diseases including allergy and asthma. It is generated by activated mast cells after allergen exposure and subsequently orchestrates the recruitment of inflammatory cells to the tissue. PGD₂ induces the chemotaxis of Th2 cells, basophils and eosinophils, stimulates cytokine release from these cells and prolongs their survival, and might hence indirectly promote IgE production. PGD₂ mediates its biologic functions via 2 distinct G protein-coupled receptors, D-type prostanoid receptor (DP), and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). DP and CRTH2 receptors are currently being considered as highly promising therapeutic targets for combating allergic diseases and asthma. Here, we revisit the roles of PGD₂ receptors in the regulation of eosinophil and Th2 cell function and the efforts towards developing candidate compounds for clinical evaluation.

Role of prostaglandin D2 in mast cell activation-induced sensitization of esophageal vagal afferents

“…In addition, it may potentiate the inflammatory response induced by other relevant mediators. The biological effects of PGD 2 are mediated by two G protein-coupled receptors, DP 1 and DP 2 (23). Expression of DP 1 and DP 2 receptors has been identified in central and peripheral neurons (7,17,22).…”

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

“…2011. 41: 2379-2389 DOI 10.1002 Leukocyte signaling 2379 phils, basophils, and Th2 lymphocytes to the sites of allergic inflammation [12], PGE 2 seems to attenuate inflammatory responses and reduce tissue injury in airways [13]. PGE 2 was found to exert bronchoprotective effects in patients with asthma [14].…”

Preclinical Evaluation of an Inhibitor of Cytosolic Phospholipase A2α for the Treatment of Asthma

“…With these mediators also being implicated in the pathogenesis of asthma (Drazen et al, 1999), it seems logical that inhibition of the enzyme might be a useful therapeutic option for the treatment of this common disease. In addition, although it is unlikely to be a direct effect, downstream inhibition of cytokine release from a variety of immune cells might be expected as a result of inhibition of cPLA 2 ␣-mediated prostanoid release, which strengthens the rationale for effective treatment of asthma (Schuligoi et al, 2010). To our knowledge, however, this publication is the first to demonstrate clearly a convincing rationale, with primary human lung cell and tis- sue data, for why a potent specific inhibitor of cPLA 2 ␣ should be effective in the treatment of asthma.…”