D prostanoid receptor 2 (chemoattractant receptor–homologous molecule expressed on TH2 cells) protein expression in asthmatic patients and its effects on bronchial epithelial cells

Abstract

BackgroundThe D prostanoid receptor 2 (DP2; also known as chemoattractant receptor–homologous molecule expressed on TH2 cells) is implicated in the pathogenesis of asthma, but its expression within bronchial biopsy specimens is unknown.ObjectivesWe sought to investigate the bronchial submucosal DP2 expression in asthmatic patients and healthy control subjects and to explore its functional role in epithelial cells.MethodsDP2 protein expression was assessed in bronchial biopsy specimens from asthmatic patients (n = 22) and healthy control subjects (n = 10) by using immunohistochemistry and in primary epithelial cells by using flow cytometry, immunofluorescence, and quantitative RT-PCR. The effects of the selective DP2 agonist 13, 14-dihydro-15-keto prostaglandin D2 on epithelial cell migration and differentiation were determined.ResultsNumbers of submucosal DP2+ cells were increased in asthmatic patients compared with those in healthy control subjects (mean [SEM]: 78 [5] vs 22 [3]/mm2 submucosa, P < .001). The bronchial epithelium expressed DP2, but its expression was decreased in asthmatic patients compared with that seen in healthy control subjects (mean [SEM]: 21 [3] vs 72 [11]/10 mm2 epithelial area, P = .001), with similar differences observed in vitro by primary epithelial cells. Squamous metaplasia of the bronchial epithelium was increased in asthmatic patients and related to decreased DP2 expression (rs = 0.69, P < .001). 13, 14-Dihydro-15-keto prostaglandin D2 promoted epithelial cell migration and at air-liquid interface cultures increased the number of MUC5AC+ and involucrin-positive cells, which were blocked with the DP2-selective antagonist AZD6430.ConclusionsDP2 is expressed by the bronchial epithelium, and its activation drives epithelial differentiation, suggesting that in addition to its well-characterized role in inflammatory cell migration, DP2 might contribute to airway remodeling in asthmatic patients.

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

“…Stimulation of CRTh2 receptors found in the bronchial epithelium has been shown to drive epithelial differentiation, suggesting that, in addition to its well-characterized role in inflammatory cell migration, CRTh2 may contribute to airway remodeling in asthmatic patients (Stinson et al, 2015). Preclinical studies suggest that CRTh2 antagonism may also dx.doi.org/10.1124/mol.115.101832. s This article has supplemental material available at molpharm.…”

Eosinophil Production of PGD2 in Aspirin-Exacerbated Respiratory Disease

“…In addition to defining a more severe subgroup, PGD 2 likely contributes to the severity of AERD through its myriad of biological activities that include inducing vasodilation and vascular leakage as well as bronchoconstriction. Many stromal and inflammatory cells found in AERD tissue express receptors for PGD 2 , including eosinophils, basophils, mast cells, epithelium, endothelium, and dendritic cells [32][33][34][35] . In addition to producing PGD 2 , eosinophils chemotax in response to PGD 2 which thereby worsen tissue eosinophilia 32,34 .…”

“…PGD 2 also activates basophils driving upregulated expression of CD203c and CD11b 37 . On epithelium, PGD 2 acts to alter their differentiation 35 . Perhaps the most important potential impact of PGD 2 in allergic inflammation is through its ability to recruit, activate, and promote cytokine secretion from both Th2-like lymphocytes and type 2 innate lymphoid cells 8,910,11 .…”

Are emerging PGD2 antagonists a promising therapy class for treating asthma?

“…Both COX-2 [7] and hematopoietic PGDS [8] are more highly expressed in asthmatic lungs, suggesting a greater capacity for producing PGD 2 , and there are greater numbers of CRTH2 + cells [9], increasing sensitivity to PGD 2 . These observations are more pronounced in patients with poor asthma control [8].…”