DP 2 antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment

• Published in: Science translational medicine 2019-02, Vol.11 (479)
• Main Authors: Saunders, Ruth, Kaul, Himanshu, Berair, Rachid, Gonem, Sherif, Singapuri, Amisha, Sutcliffe, Amanda J, Chachi, Latifa, Biddle, Michael S, Kaur, Davinder, Bourne, Michelle, Pavord, Ian D, Wardlaw, Andrew J, Siddiqui, Salman H, Kay, Richard A, Brook, Bindi S, Smallwood, Rod H, Brightling, Christopher E
• Format: Article
• Language: English
• Subjects: Airway Remodeling - drug effects; Asthma - complications; Asthma - pathology; Asthma - physiopathology; Cell Movement - drug effects; Eosinophilia - complications; Eosinophilia - pathology; Eosinophilia - physiopathology; Eosinophils - drug effects; Eosinophils - pathology; Humans; Indoleacetic Acids - pharmacology; Models, Biological; Muscle, Smooth - drug effects; Muscle, Smooth - pathology; Myofibroblasts - drug effects; Myofibroblasts - pathology; Pyridines - pharmacology; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; Receptors, Prostaglandin - antagonists & inhibitors; Receptors, Prostaglandin - metabolism
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aao6451

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 D type 2 receptor (DP ) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP in airway smooth muscle cells. We report that the DP 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 DP -specific antagonists in an airway smooth muscle cell culture model. Our analyses suggest that fevipiprant, through antagonism of DP , 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.