上皮细胞源性层粘连蛋白调节早期气道疾病的细胞外基质动力学研究
2026/02/02
背景：气道重塑是学龄前喘息（PSW）和学龄期哮喘（SA）的显著病理特征。尽管在PSW和SA中已阐述了肺功能异常、细胞外基质（ECM）变化与气道重塑之间的关联，但其潜在机制尚未明确。
目的：本研究旨在探究导致幼鼠（1-5岁）和儿童（6-16岁）气道细胞外基质（ECM）环境改变的机制，并追踪屋尘螨（HDM）暴露新生儿小鼠的ECM动态变化。
方法：本研究采用空间转录组学、共聚焦显微镜和SHG显微镜技术，对PSW和SA患者的支气管镜下活检样本（PSW）以及高剂量屋尘螨（HDM）暴露的新生小鼠肺标本进行分析，以揭示过敏性气道炎症过程中转录、表型和结构性细胞外基质（ECM）相关的改变。
结果：本研究对PSW和SA患儿气道进行空间转录组分析显示，两种疾病中富含成纤维细胞的区域均出现I、Ⅱ和Ⅲ型纤维胶原以及基膜胶原VI的基因表达上调。同样，在经屋尘螨（HDM）暴露的新生小鼠支气管周围区域也观察到Ⅲ型和Ⅵ型胶原沉积增加，同时伴有胶原纤维排列紊乱的加重。这种胶原紊乱现象在PSW和SA患儿的气道中同样明显，且伴随着支气管上皮细胞衍生的层粘连蛋白）生成增多，以及PSW、SA患儿和HDM暴露新生小鼠气道中层粘连蛋白的增加。层粘连蛋白直接改变原代健康气道成纤维细胞功能，促进其增殖和胶原生成。
结论：本研究证明了胶原蛋白相关表型和几何变化在早期气道重塑中的作用，并表明层粘连蛋白是PSW和SA中与胶原蛋白组织相关的关键重塑因素。
Epithelial cell derived lumican modulates extracellular matrix dynamics in early-life airways disease.
Puttur F, Traves WJ, Martin MG, Di Carmine S, Fercoq F, Gaboriau DCA, Entwistle LJ, Yates L, Joulia R, Patti S, Stölting H, Campbell C, Gore ML, Walker SA, Loewenthal LE, Molyneaux PL, Carlin LM, Saglani S, Lloyd CM.
Abstract
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.
目的：本研究旨在探究导致幼鼠（1-5岁）和儿童（6-16岁）气道细胞外基质（ECM）环境改变的机制，并追踪屋尘螨（HDM）暴露新生儿小鼠的ECM动态变化。
方法：本研究采用空间转录组学、共聚焦显微镜和SHG显微镜技术，对PSW和SA患者的支气管镜下活检样本（PSW）以及高剂量屋尘螨（HDM）暴露的新生小鼠肺标本进行分析，以揭示过敏性气道炎症过程中转录、表型和结构性细胞外基质（ECM）相关的改变。
结果：本研究对PSW和SA患儿气道进行空间转录组分析显示，两种疾病中富含成纤维细胞的区域均出现I、Ⅱ和Ⅲ型纤维胶原以及基膜胶原VI的基因表达上调。同样，在经屋尘螨（HDM）暴露的新生小鼠支气管周围区域也观察到Ⅲ型和Ⅵ型胶原沉积增加，同时伴有胶原纤维排列紊乱的加重。这种胶原紊乱现象在PSW和SA患儿的气道中同样明显，且伴随着支气管上皮细胞衍生的层粘连蛋白）生成增多，以及PSW、SA患儿和HDM暴露新生小鼠气道中层粘连蛋白的增加。层粘连蛋白直接改变原代健康气道成纤维细胞功能，促进其增殖和胶原生成。
结论：本研究证明了胶原蛋白相关表型和几何变化在早期气道重塑中的作用，并表明层粘连蛋白是PSW和SA中与胶原蛋白组织相关的关键重塑因素。
（中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校）
（J Allergy Clin Immunol. 2026 Jan;157(1):176-189. doi: 10.1016/j.jaci.2025.08.030.）
（J Allergy Clin Immunol. 2026 Jan;157(1):176-189. doi: 10.1016/j.jaci.2025.08.030.）
Epithelial cell derived lumican modulates extracellular matrix dynamics in early-life airways disease.
Puttur F, Traves WJ, Martin MG, Di Carmine S, Fercoq F, Gaboriau DCA, Entwistle LJ, Yates L, Joulia R, Patti S, Stölting H, Campbell C, Gore ML, Walker SA, Loewenthal LE, Molyneaux PL, Carlin LM, Saglani S, Lloyd CM.
Abstract
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.
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