Airway remodelling is a prominent pathological feature in pre-school wheeze (PSW) and school-age asthma (SA). Although the relationships between altered lung function, extracellular matrix (ECM) changes and airway remodelling are described in PSW and SA, the underlying mechanisms remain undefined. To investigate mechanisms resulting in altered airway ECM-landscape in PSW (1-5 years) and SA (6-16 years) and track ECM-dynamics in house dust mite (HDM) exposed neonatal mice. We applied spatial transcriptomics, confocal and second harmonic generation microscopy, in PSW and SA endobronchial biopsies and in HDM-exposed neonatal mice lungs 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, -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 disorganisation were observed in the peribronchial regions of HDM-exposed neonatal mice. Collagen disorganisation 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 PSW, SA, and HDM-exposed neonatal mice. Lumican directly altered primary healthy airway fibroblast function, increasing proliferation and collagen production. We demonstrate a previously uncharacterised role of collagen-associated phenotypic and geometric changes in early-life airway remodelling and show lumican as a crucial remodelling factor associated with collagen organisation in PSW and SA.
Puttur et al. (Mon,) studied this question.