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.

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.

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.

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.

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.