CRTh2 (DP2) is implicated in the pathogenesis of asthma; however, currently there is a lack of data describing the protein expression of CRTh2 in bronchial biopsies in asthma. This has limited the cell types that CRTh2 function has been explored within. A thorough understanding of CRTh2 expression within the airways and whether changes in receptor expression correlates with disease severity, may aid in the design of future CRTh2 antagonist clinical studies. This study aimed to investigate the expression of CRTh2 expression in bronchial biopsies of subjects with asthma and healthy controls. The novel finding that CRTh2 was expressed on bronchial epithelial cells in asthma prompted further investigation into the expression and activation of CRTh2 on bronchial epithelial cells in vitro, using the selective CRTh2 agonist 13, 14-dihydro-15-keto prostaglandin D2 (DK-PGD2) and the CRTh2 selective antagonist AZD6430. This study is the first to describe differential CRTh2 expression within bronchial tissue in asthma compared to healthy controls. The number of sub-mucosal CRTh2+ cells was found to be increased in asthma compared to healthy controls. CRTh2 was found to be expressed on the bronchial epithelium and its expression was decreased in asthma compared to healthy controls with similar differences observed in vitro by primary epithelial cells. Squamous metaplasia of the bronchial epithelium was increased in asthma and related to decreased CRTh2 expression. DK-PGD2 promoted epithelial cell migration, and in air-liquid interface cultures increased the number of MUC5AC+ and involucrin+ cells, which were blocked with the CRTh2 antagonist, AZD6430. This study describes the novel findings that CRTh2 is expressed by the bronchial epithelium in both health and asthma, and its activation drives epithelial differentiation. These data suggests that CRTh2 could contribute to airway remodelling in asthma and this information may contribute to the understanding of the effects of CRTh2 antagonists in asthmatic patients.
|Stinson, Sally Elizabeth
|Brightling, Christopher; Amrani, Yassine
|University of Leicester
|Electronic Thesis or Dissertation
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