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

https://doi.org/10.1016/j.jaci.2014.08.027Get rights and content
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Background

The 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.

Objectives

We sought to investigate the bronchial submucosal DP2 expression in asthmatic patients and healthy control subjects and to explore its functional role in epithelial cells.

Methods

DP2 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.

Results

Numbers 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.

Conclusions

DP2 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.

Key words

Expression
asthma
immunohistochemistry
prostaglandin D2
biopsy

Abbreviations used

ALI
Air-liquid interface
COPD
Chronic obstructive pulmonary disease
CRTH2
Chemoattractant receptor–homologous molecule expressed on TH2 cells
DK-PGD2
13, 14-Dihydro-15-keto prostaglandin D2
DP1
D prostanoid receptor 1
DP2
D prostanoid receptor 2
PGD2
Prostaglandin D2

Cited by (0)

Supported by AstraZeneca. C.E.B. is a Wellcome Trust Senior Clinical Fellow. The research was performed in laboratories funded in part by the European Regional Development Fund (ERDF 05567). This study was also supported in part by the National Institute for Health Research Leicester Respiratory Biomedical Research Unit and AirPROM (FP7-270194). The views expressed are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health. The European Regional Development Fund had no involvement in the design of the study, data collection, analysis and interpretation of the data, in the writing of the manuscript, or in the decision to submit the manuscript.

Disclosure of potential conflict of interest: S. E. Stinson has received research support from and owns shares of AstraZeneca. C. E. Brightling has received research support from GlaxoSmithKline, MedImmune, Novartis, Roche, and Chiesi; has consultant arrangements with GlaxoSmithKline, MedImmune, Boehringer Ingelheim, Novartis, Roche, and Chiesi; and has received travel support from Boehringer Ingelheim. Y. Amrani declares no relevant conflicts of interest.

∗

These authors contributed equally to this work as co-senior authors.

Copyright © 2014 The Authors. Published by Mosby, Inc.