Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

Abstract

Airway wall remodeling is a pathology occurring in chronic inflammatory lung diseases including asthma, chronic obstructive pulmonary disease, and fibrosis. In 2017, the American Thoracic Society released a research statement highlighting the gaps in knowledge and understanding of airway wall remodeling. The four major challenges addressed in this statement were: (i) the lack of consensus to define “airway wall remodeling” in different diseases, (ii) methodologic limitations and inappropriate models, (iii) the lack of anti-remodeling therapies, and (iv) the difficulty to define endpoints and outcomes in relevant studies. This review focuses on the importance of cell-cell interaction, especially the bronchial epithelium, in asthma-associated airway wall remodeling. The pathology of “airway wall remodeling” summarizes all structural changes of the airway wall without differentiating between different pheno- or endo-types of asthma. Indicators of airway wall remodeling have been reported in childhood asthma in the absence of any sign of inflammation; thus, the initiation event remains unknown. Recent studies have implied that the interaction between the epithelium with immune cells and sub-epithelial mesenchymal cells is modified in asthma by a yet unknown epigenetic mechanism during early childhood.

Application of Metabolomics in Obesity-Related Childhood Asthma Subtyping: A Narrative Scoping Review

“…More specifically, leptin triggers the expression of the intercellular adhesion molecule (ICAM-1) in bronchial epithelial cells and the proliferation and migration of airway epithelial cells. The different mechanisms that underlie airway remodeling in obese in vivo models of asthma may explain the endotypic heterogeneity [ 73 ]. Moreover, the adipose tissue from obese children is a source of proinflammatory mediators that may underlie chronic airway inflammation and airway remodeling [ 54 , 61 , 74 ].…”

Involvement of Transforming Growth Factor-β-Associated Kinase 1 in Fixed Airway Obstruction in Asthmatic Patients with Longer Disease Duration Independent on Airway Eosinophilia

“…3 In asthma, airway remodeling of the conducting airway walls leads to structural changes including loss of epithelial integrity, goblet cell and submucosal gland enlargement, basement membrane thickening, subepithelial fibrosis, increased smooth muscle mass, angiogenesis, and decreased cartilage integrity. [5][6][7] Airway remodeling features have been documented for all stages of asthma severity, are associated with the greater use of asthma medications, and result in fixed airflow obstruction (FAO). 3,8,9 Despite treatment with inhaled corticosteroids and long-acting bronchodilators, it has been shown longitudinally that they have no significant effects in improving fixed airflow obstruction over time if present in childhood.…”

“… 3 , 12 , 13 This is also supported by the evidence from a large cohort of adult asthmatics with active asthma or a history of asthma, that independent of asthma status and medication use, the extent of airway remodeling and fixed airflow obstruction did not alter over a 3-year time period. 14 All above data, in addition to the fact that none of the drugs used for asthma therapy provides any suppressive effects on airway wall remodeling, 5 suggest that there are additional mechanisms driving airway remodelling in chronic asthma. Intercepting these mechanisms may provide effective prevention and treatment of FAO and may enhance anti-remodeling effects of biologics in asthmatics.…”

Remodeling Phenotypes Take Center Stage in the Prediction of Preschool Wheeze Attacks

“…An increased density of blood vessels in the airways was also observed at this early stage and was associated with exacerbations at 1-year follow-up. Changes in vascularity may be due to both dilatation and congestion of existing vessels but also to the formation of new vessels (neoangiogenesis), possibly as a response to growth factors released from other injured airway structures, such as the epithelium or the smooth muscle ( 10 ). Because increased vascularity may then contribute to the amplification of airway inflammation, it is conceivable that vascular changes associate with an exacerbation-prone phenotype.…”