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.

Highlights

  • Asthma affects over 300 million people worldwide, and its prevalence is increasing [1] despite currently available therapies [2]

  • Using an agent-based computational model representing an asthmatic airway in human patients and supported by in vitro airway smooth muscle (ASM) cell–based observations, we propose that the reduced ASM mass observed in the bronchial biopsies after fevipiprant treatment may be a consequence of inhibition of eosinophilic airway inflammation together with reduced recruitment of myofibroblasts and fibrocytes to the ASM bundle

  • We report that a drug intervention in asthma, namely, fevipiprant, reduced ASM mass in bronchial biopsies from patients with asthma who had participated in a previous randomized placebo-controlled trial [4]

Read more

Summary

Introduction

Asthma affects over 300 million people worldwide, and its prevalence is increasing [1] despite currently available therapies [2]. Increased airway smooth muscle (ASM) mass is an important component of airway remodeling in asthma, contributing substantially to symptoms and disordered airway physiology [3,4,5]. No drug has affected the increased ASM mass observed in asthma in randomized placebo-controlled trials [3, 4]. Bronchial thermoplasty has demonstrated a potential reduction in ASM mass in asthma in uncontrolled studies [6, 7]. The role of the PGD2/DP2 axis in ASM dysfunction in asthma has not been extensively studied. We hypothesized that the PGD2/DP2 axis may contribute to increased ASM mass in asthma and that antagonism of DP2 with fevipiprant might result in a decrease in ASM mass

Objectives
Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call