BackgroundMast cell localization within the airway smooth muscle (ASM)-bundle plays an important role in the development of airway hyper-responsiveness (AHR). Genomewide association studies implicate the ‘alarmin’ IL-33 in asthma, but its role in mast cell–ASM interactions is unknown.ObjectivesWe examined the expression and functional role of IL-33 in bronchial biopsies of patients with and without asthma, ex vivo ASM, mast cells, cocultured cells and in a mouse model system.MethodsIL-33 protein expression was assessed in human bronchial tissue from 9 healthy controls, and 18 mild-to-moderate and 12 severe asthmatic patients by immunohistochemistry. IL-33 and ST2 mRNA and protein expression in human-derived ASM, epithelial and mast cells were assessed by qPCR, immunofluorescence and/or flow cytometry and ELISA. Functional assays were used to assess calcium signalling, wound repair, proliferation, apoptosis and contraction. AHR and inflammation were assessed in a mouse model.ResultsBronchial epithelium and ASM expressed IL-33 with the latter in asthma correlating with AHR. ASM and mast cells expressed intracellular IL-33 and ST2. IL-33 stimulated mast cell IL-13 and histamine secretion independent of FcεR1 cross-linking and directly promoted ASM wound repair. Coculture of mast cells with ASM activated by IL-33 increased agonist-induced ASM contraction, and in vivo IL-33 induced AHR in a mouse cytokine installation model; both effects were IL-13 dependent.ConclusionIL-33 directly promotes mast cell activation and ASM wound repair but indirectly promotes ASM contraction via upregulation of mast cell-derived IL-13. This suggests that IL-33 may present an important target to modulate mast cell–ASM crosstalk in asthma.

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.

Airway remodelling in asthma remains poorly understood. This study aimed to determine the association of airway remodelling measured on bronchial biopsies with i) lung function impairment and ii) quantitative thoracic CT (QCT)-derived morphometry and densitometry measures of proximal airway remodelling and air-trapping. Subjects were recruited from a single centre Bronchial biopsy remodelling features that were the strongest predictors of lung function impairment and QCT-derived proximal airway morphometry and air-trapping markers were determined by step-wise multiple regression. The best predictor of air-trapping was validated in an independent replication group. Airway smooth muscle percentage (ASM %) was the only predictor of post-bronchodilator FEV1 % predicted, while both ASM % and vascularity were predictors of FEV1/FVC. Epithelial thickness and ASM % were predictors of mean segmental bronchial luminal area (R2=0.12; p=0.02 and R2=0.12; p=0.015). Whereas epithelial thickness was the only predictor of % wall area (R2=0.13; p=0.018). Vascularity was the only significant predictor of air-trapping (R2=0.24; p=0.001), which was validated in the replication group (R2=0.19; p=0.031). In asthma, airway smooth muscle content and vascularity were both associated with airflow obstruction. QCT-derived proximal airway morphometry was most strongly associated with epithelial thickness and airway smooth muscle content, whereas air-trapping was related to vascularity.

Asthma remains a major health problem with significant morbidity, mortality and economic costs. In asthma, airway remodelling, which refers to all the microscopic structural changes seen in the airway tissue, has been recognised for many decades and remains one of the defining characteristics of the disease; however, it is still poorly understood. The detrimental pathophysiological consequences of some features of remodelling, like increased airway smooth muscle mass and subepithelial fibrosis, are well documented. However, whether targeting these by therapy would be beneficial is unknown. Although the prevailing thinking is that remodelling is an abnormal response to persistent airway inflammation, recent evidence, especially from studies of remodelling in asthmatic children, suggests that the two processes occur in parallel. The effects of asthma therapy on airway remodelling have not been studied extensively due to the challenges of obtaining airway tissue in the context of clinical trials. Corticosteroids remain the cornerstone of asthma therapy, and their effects on remodelling have been better studied than other drugs. Bronchial thermoplasty is the only asthma therapy to primarily target remodelling, although how it results in the apparent clinical benefits seen is not exactly clear. In this article we discuss the mechanisms of airway remodelling in asthma and review the effects of conventional and novel asthma therapies on the process.