Background: Airway remodeling is a prominent pathologic feature in preschool wheeze (PSW) and school-age asthma (SA). Although the relationships between altered lung function, extracellular matrix (ECM) changes, and airway remodeling are described in PSW and SA, the underlying mechanisms remain undefined.
Objective: We sought to investigate mechanisms resulting in altered airway ECM landscape in PSW (1-5 years of age) and SA (6-16 years of age) and track ECM dynamics in house dust mite (HDM)-exposed neonatal mice.
Methods: We applied spatial transcriptomics, confocal microscopy, and SHG microscopy in PSW and SA endobronchial biopsy specimens and in HDM-exposed neonatal mice lung specimens to reveal transcriptional, phenotypic, and structural ECM-associated changes during allergic airway inflammation.
Results: Spatial transcriptomic analysis of the airways of children with PSW and SA revealed increased gene expression for fibrillar collagens I, II, and III and basement membrane collagen VI in fibroblast-rich regions in both diseases. Similarly, increased collagen III and collagen VI deposition with exaggerated collagen fibril disorganization was observed in the peribronchial regions of HDM-exposed neonatal mice. Collagen disorganization was also evident in the airways of children with PSW and SA and was accompanied by increased production of bronchial epithelial cell-derived lumican and increased airway lumican in children with PSW, children with SA, and HDM-exposed neonatal mice. Lumican directly altered primary healthy airway fibroblast function, increasing proliferation and collagen production.
Conclusions: We demonstrate a previously uncharacterized role of collagen-associated phenotypic and geometric changes in early-life airway remodeling and show lumican as a crucial remodeling factor associated with collagen organization in PSW and SA.
Keywords: Preschool wheeze; early life immunity; extracellular matrix; school-age asthma.
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