Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/43623
Title: DP2 antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment
Authors: Saunders, R
Kaul, H
Berair, R
Gonem, S
Singapuri, A
Sutcliffe, AJ
Chachi, L
Biddle, MS
Kaur, D
Bourne, M
Pavord, ID
Wardlaw, AJ
Siddiqui, SH
Kay, RA
Brook, BS
Smallwood, RH
Brightling, CE
First Published: 13-Feb-2019
Publisher: American Association for the Advancement of Science
Citation: Sci Transl Med, 2019, 11 (479)
Abstract: Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D2 type 2 receptor (DP2) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP2 in airway smooth muscle cells. We report that the DP2 antagonist fevipiprant reduced airway smooth muscle mass in bronchial biopsies from patients with asthma who had participated in a previous randomized placebo-controlled trial. We developed a computational model to capture airway remodeling. Our model predicted that a reduction in airway eosinophilia alone was insufficient to explain the clinically observed decrease in airway smooth muscle mass without a concomitant reduction in the recruitment of airway smooth muscle cells or their precursors to airway smooth muscle bundles that comprise the airway smooth muscle layer. We experimentally confirmed that airway smooth muscle migration could be inhibited in vitro using DP2-specific antagonists in an airway smooth muscle cell culture model. Our analyses suggest that fevipiprant, through antagonism of DP2, reduced airway smooth muscle mass in patients with asthma by decreasing airway eosinophilia in concert with reduced recruitment of myofibroblasts and fibrocytes to the airway smooth muscle bundle. Fevipiprant may thus represent a potential therapy to ameliorate airway remodeling in asthma.
DOI Link: 10.1126/scitranslmed.aao6451
eISSN: 1946-6242
Links: http://stm.sciencemag.org/content/11/479/eaao6451
http://hdl.handle.net/2381/43623
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2019 The Authors. Deposited with reference to the publisher’s open access archiving policy. (http://www.rioxx.net/licenses/all-rights-reserved)
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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