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Review
. 2023 Jan 19:14:1113100.
doi: 10.3389/fphys.2023.1113100. eCollection 2023.

Airway remodeling heterogeneity in asthma and its relationship to disease outcomes

Aileen Hsieh  1   2 , Najmeh Assadinia  1   2 , Tillie-Louise Hackett  1   2
Affiliations
Review

Airway remodeling heterogeneity in asthma and its relationship to disease outcomes

Aileen Hsieh et al. Front Physiol. .

Abstract

Asthma affects an estimated 262 million people worldwide and caused over 461,000 deaths in 2019. The disease is characterized by chronic airway inflammation, reversible bronchoconstriction, and airway remodeling. Longitudinal studies have shown that current treatments for asthma (inhaled bronchodilators and corticosteroids) can reduce the frequency of exacerbations, but do not modify disease outcomes over time. Further, longitudinal studies in children to adulthood have shown that these treatments do not improve asthma severity or fixed airflow obstruction over time. In asthma, fixed airflow obstruction is caused by remodeling of the airway wall, but such airway remodeling also significantly contributes to airway closure during bronchoconstriction in acute asthmatic episodes. The goal of the current review is to understand what is known about the heterogeneity of airway remodeling in asthma and how this contributes to the disease process. We provide an overview of the existing knowledge on airway remodeling features observed in asthma, including loss of epithelial integrity, mucous cell metaplasia, extracellular matrix remodeling in both the airways and vessels, angiogenesis, and increased smooth muscle mass. While such studies have provided extensive knowledge on different aspects of airway remodeling, they have relied on biopsy sampling or pathological assessment of lungs from fatal asthma patients, which have limitations for understanding airway heterogeneity and the entire asthma syndrome. To further understand the heterogeneity of airway remodeling in asthma, we highlight the potential of in vivo imaging tools such as computed tomography and magnetic resonance imaging. Such volumetric imaging tools provide the opportunity to assess the heterogeneity of airway remodeling within the whole lung and have led to the novel identification of heterogenous gas trapping and mucus plugging as important predictors of patient outcomes. Lastly, we summarize the current knowledge of modification of airway remodeling with available asthma therapeutics to highlight the need for future studies that use in vivo imaging tools to assess airway remodeling outcomes.

Keywords: airway heterogeneity; airway remodeling; asthma; asthma therapeutics; computed tomgraphy (CT); magnetic resonance imaging (MRI); mucus plug.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Features of airway remodeling in asthma. Lung tissue was formalin-fixed paraffin-embedded (FFPE) and stained with Hematoxylin and Eosin stains. The left image in the panel demonstrates a conducting airway from a non-asthmatic individual (11 years) with no history of respiratory disease. The right image demonstrates a conducting airway of a fatal asthmatic individual (15 years) showing features of airway remodeling including: an altered epithelial barrier with goblet cell hyperplasia, angiogenesis, increased smooth muscle mass, thickened reticular basement membrane, sub-epithelial fibrosis, and mucus plugging of the airway lumen.
FIGURE 2
FIGURE 2
In vivo imaging of mucus plugging and ventilation defects in CT and MRI. (A) Lung computed tomography (CT) scans from three different asthma patients (A1, A2, and A3), which demonstrate the persistence of mucus plugs (Yellow arrowheads) in the same airway at baseline (2013) and 3 years later (2016). Orange arrowheads indicate blood vessels. This figure was adapted with permission from Figure 1 by Tang M et al. published in the American Journal of Respiratory and Critical Care Medicine 2022. (B) 129Xe magnetic resonance imaging (MRI) ventilation (teal) and computed tomography (CT) airway tree (yellow) for representative participants from four different asthma clusters. Cluster 1 has moderate heterogeneity as seen on MRI, moderate wall thickening and minimal luminal narrowing on CT. Clinically, cluster 1 has normal obstruction and no gas trapping. Cluster 2 has moderate MRI heterogeneity, significant wall thickening and minimal luminal narrowing. Clinically, this cluster pattern appears in females only, with moderate obstruction and gas trapping. Cluster 3 has moderate MRI heterogeneity with moderate wall thickening and significant luminal narrowing. Clinically, they tend to have more severe asthma and moderate obstruction with minimal gas trapping. Cluster 4 has significant MRI heterogeneity and moderate wall thickening with significant luminal narrowing. Clinically, cluster 4 patterning is male dominant with severe gas trapping and obstruction. Cluster analysis of asthma using MRI in combination with CT imaging may provide useful insight for asthma phenotyping and treatment decisions. This figure is adapted with permission from Figure 3B by Eddy R et al. published in Journal of Magnetic Resonance Imaging 2022. Copyright from RightsLink/John Wiley and Sons.
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Grants and funding

This study was funded by a Canadian Institutes of Health Research (CIHR) operating grant MOP 130504. AH is supported by a CIHR Canadian Graduate Scholarship-Master’s Program. T-LH is supported by a Tier I Canada Research Chair in Asthma and COPD Lung Pathobiology and Therapeutics.

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