Prostaglandin receptors in the treatment of allergy

A growing demand for additional treatments of allergic diseases exists, particularly for patients who need to avoid corticosteroids (e.g. children), and those who are insufficiently treated with corticosteroids. Accumulation of eosinophils in the lung tissue is a hallmark of asthma and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Thus, eosinophils are currently considered a major therapeutic target in allergic diseases and asthma. However, drugs that selectively target the accumulation and activation of eosinophils in tissue are unavailable so far. Prostaglandin (PG) E2 , the predominant cyclooxygenase product of airway macrophages, epithelial cells and smooth muscle cells and PGI2 , the main prostaglandin released from endothelial cells, have been suggested to limit the immunological and inflammatory responses to allergens in the lung by activating G- protein coupled receptors. PGE 2 exerts its biological effects via activation of EP1, EP2, EP3 and EP4 receptors, while PGI2 targets a single receptor, IP, all of which couple into diverse intracellular signaling pathways. The usefulness of PGE 2 as a therapeutic agent is limited because of its various side effects thought to arise from EP1 or EP3 receptor stimulation. In contrast, selective EP2 or EP4 agonists might have more favourable pharmacological profiles. Therefore, we will set out to investigate the hypothesis that PGE 2 and PGI2 are highly potent inhibitors of the trafficking and activation of eosinophils and that EP2, EP4 and IP receptors are mediating these effects. We will further focus on the IP, EP2 and EP4 receptors as potential novel therapeutic targets, and we will elucidate the effects of selective receptor agonists on eosinophil function at three specific levels, (i) effector functions of eosinophils such as chemotaxis, respiratory burst, and mediator release, (ii) eosinophil trafficking including mobilization of eosinophils from bone marrow and interaction of eosinophils with the endothelium as a rate- limiting steps for eosinophil accumulation in the tissue, and (iii) in vivo models of allergic disease. Hence we may be able to propose a novel pharmacological approach to controlling eosinophilic inflammation.

A growing demand for additional treatments of allergic diseases exists, particularly for patients who need to avoid corticosteroids (e.g. children), and those who are insufficiently treated with corticosteroids. Accumulation of eosinophils in the lung tissue is a hallmark of asthma and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Thus, eosinophils are currently considered a major therapeutic target in allergic diseases and asthma. However, drugs that selectively target the accumulation and activation of eosinophils in tissue are unavailable so far. Prostaglandin (PG) E2, the predominant cyclooxygenase product of airway macrophages, epithelial cells and smooth muscle cells and PGI2, the main prostaglandin released from endothelial cells, have been suggested to limit the immunological and inflammatory responses to allergens in the lung by activating G- protein coupled receptors. PGE2 exerts its biological effects via activation of EP1, EP2, EP3 and EP4 receptors, while PGI2 targets a single receptor, IP, all of which couple into diverse intracellular signaling pathways. The usefulness of PGE2 as a therapeutic agent is limited because of its various side effects thought to arise from EP1 or EP3 receptor stimulation. In contrast, selective EP2 or EP4 agonists might have more favourable pharmacological profiles. Therefore, we set out to investigate the hypothesis that PGE2 and PGI2 are highly potent inhibitors of the trafficking and activation of eosinophils and that EP2, EP4 and IP receptors are mediating these effects. In this project we highlighted IP, EP2 and EP4 receptors as potential novel therapeutic targets, as we could show that selective receptor agonists of these receptors modulate eosinophil function at three specific levels, (i) effector functions of eosinophils such as chemotaxis, respiratory burst, and mediator release, (ii) eosinophil trafficking including mobilization of eosinophils from bone marrow and interaction of eosinophils with the endothelium as a rate-limiting steps for eosinophil accumulation in the tissue, and (iii) in vivo models of allergic disease. Hence we propose a novel pharmacological approach to controlling eosinophilic inflammation.