DP2 antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment

Science Translational Medicine

Vol 11, Issue 479 13 February 2019

Ruth Saunders1,*, 

Himanshu Kaul1,2,*,†,‡, 

Rachid Berair1,*, 

Sherif Gonem1, 

Amisha Singapuri1, 

Amanda J. Sutcliffe1, 

Latifa Chachi1, 

Michael S. Biddle1, 

Davinder Kaur1, 

Michelle Bourne1, 

Ian D. Pavord3, 

Andrew J. Wardlaw1, 

Salman H. Siddiqui1, 

Richard A. Kay4,§, 

Bindi S. Brook5, 

Rod H. Smallwood2,|| and 

Christopher E. Brightling1,†,||

 See all authors and affiliations

Science Translational Medicine  13 Feb 2019:
Vol. 11, Issue 479, eaao6451
DOI: 10.1126/scitranslmed.aao6451

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Smoothing out muscle in asthma

Asthma is often treated with drugs that reduce airway inflammation. Saunders et al. now show that fevipiprant, a prostaglandin D2 type 2 receptor antagonist, reduced smooth muscle mass in bronchial biopsies from asthma patients. Computational simulations of an asthmatic airway predicted that this decrease in airway smooth muscle mass was due to both amelioration of inflammation observed in a prior clinical trial together with direct effects on migration of myofibroblasts.

Treating smooth muscle cells from bronchial biopsies from asthma patients with fevipiprant in vitro revealed that the drug-induced decrease in airway smooth muscle mass may be due to reduced migration of myofibroblasts and fibrocytes.

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.

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