Targeting the PGD2-CRTH2-DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future PerspectivesReport as inadecuate




Targeting the PGD2-CRTH2-DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future Perspectives - Download this document for free, or read online. Document in PDF available to download.

Drugs

, Volume 77, Issue 12, pp 1281–1294

First Online: 13 June 2017

Abstract

Prostaglandin D2 PGD2 released by degranulating mast cells is believed to play a key role in orchestrating mechanisms of inflammation in allergies and asthma. The biological effects of PGD2 are mediated by D-prostanoid DP1, CRTH2 DP2, and thromboxane prostanoid TP receptors. The CRTH2 receptor is involved in induction of migration and activation of T helper type 2 Th2 lymphocytes, eosinophils, and basophils; up-regulation of adhesion molecules; and promotion of pro-inflammatory Th2-type cytokines interleukin IL-4, 5, 13, whereas the DP receptor is associated with relaxation of smooth muscles, vasodilation, inhibition of cell migration, and apoptosis of eosinophils. A number of CRTH2-PGD2 receptor antagonists have been investigated in asthma and allergic diseases. The CRTH2 antagonist OC000459 or dual CRTH2 and TP receptor antagonist ramatroban were effective in reducing eosinophilia, nasal mucosal swelling, and clinical symptoms of allergic rhinitis, with the latter drug registered for clinical use in this indication. OC000459 and setipiprant reduced the late but not early phase of response in an allergen challenge in atopic asthmatics. In persistent asthma, some molecules induced limited improvement in lung function, quality of life, and asthma symptoms OC000459, BI671800, but in other trials with AMG 853 and AZ1981 these findings were not confirmed. The clear discrepancy between animal studies and clinical efficacy of CRTH2 antagonism in allergic rhinitis, and lack of efficacy in a general cohort of asthmatics, highlight the issue of patient phenotyping. There is no doubt that the PGD2-CATH2-DP1 pathway plays a key role in allergic inflammation and further studies with selective or combined antagonisms in well defined cohorts of patients are needed.

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Author: Maciej Kupczyk - Piotr Kuna

Source: https://link.springer.com/







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