The role of prostaglandin D2 in eosinophil recruitment

Prostaglandin (PG) D2 is released by activated mast cells during the allergic response. Others and our group have recently produced considerable evidence that PGD 2 might be a key candidate for the initiation and perpetuation of allergic inflammation by orchestrating the recruitment of eosinophil granulocytes to the tissue, where they cause tissue damage and induce the symptoms of allergic inflammation. The biological effects of PGD 2 are mediated by three distinct receptors, (i) the D-type prostaglandin (DP) receptor, (ii) chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), or at higher concentrations (iii) by the thromboxane receptor ( TP). Small molecule antagonists of these receptors have recently become available and are currently being developed for the treatment of inflammatory diseases. However, the relative contributions of DP, CRTH2 and TP to PGD 2 - induced biological responses have still remained unclear. In order to predict which of these receptors might be the most promising targets for the treatment of allergic disease and to highlight their potential limitations, we will investigate the roles of PGD 2 and its receptors in eosinophil function with respect to the release of eosinophils and their precursors from the bone marrow, the regulation of eosinophil locomotion, their life span, and mediator release. Furthermore, we will test the potential clinical usefulness of CRTH2 and DP antagonists, or a combination of them, in vivo using a murine model of ovalbumin-induced allergic pulmonary inflammation and airway hyperresponsiveness. We hope that the study will lead to novel therapeutic regimens for the treatment of allergic inflammation and asthma.

Prostaglandin (PG) D2 is released by activated mast cells during the allergic response. Others and our group have recently produced considerable evidence that PGD 2 might be a key candidate for the initiation and perpetuation of allergic inflammation by orchestrating the recruitment of eosinophil granulocytes to the tissue, where they cause tissue damage and induce the symptoms of allergic inflammation. The biological effects of PGD 2 are mediated by three distinct receptors, (i) the D-type prostaglandin (DP) receptor, (ii) chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), or at higher concentrations (iii) by the thromboxane receptor ( TP). Small molecule antagonists of these receptors have recently become available and are currently being developed for the treatment of inflammatory diseases. However, the relative contributions of DP, CRTH2 and TP to PGD 2 - induced biological responses have still remained unclear. In order to predict which of these receptors might be the most promising targets for the treatment of allergic disease and to highlight their potential limitations, we will investigate the roles of PGD 2 and its receptors in eosinophil function with respect to the release of eosinophils and their precursors from the bone marrow, the regulation of eosinophil locomotion, their life span, and mediator release. Furthermore, we will test the potential clinical usefulness of CRTH2 and DP antagonists, or a combination of them, in vivo using a murine model of ovalbumin-induced allergic pulmonary inflammation and airway hyperresponsiveness. We hope that the study will lead to novel therapeutic regimens for the treatment of allergic inflammation and asthma.