Airway epithelial heterogeneity and mucus plugging in asthmatic bronchioles

作者：Stephen A. Schworer, Hiroaki Murano, Hong Dang, Matthew R. Markovetz, Minako Saito, Takafumi Kato, Takanori Asakura, Gang Chen, Rodney C. Gilmore, L. Morton, Catharina van Heusden, Michael Chua, E.R. Strickler, Zoey Y Wisniewski, Gillian Crisp, Elodie Mitchell, Kayleigh A. Doherty, Shania Mastan, Humberto E. Trejo Bittar, B. Cody, John B. Trudeau, Gabriela De la Cruz, Lauren M. Ralph, Frederic B. Askin, Reynold A. Panettieri, Cynthia Koziol‐White, Kevin M. Byrd, Alessandra Livraghi-Butrico, Wanda K. O’Neal, Scott H. Randell, Sally E. Wenzel, Kenichi Okuda, Richard C. Boucher · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2025 · DOI：10.1164/rccm.202409-1849oc · 被引用次数：10 · 研究领域：Asthma and respiratory diseases、Cancer Cells and Metastasis、Neonatal Respiratory Health Research

RATIONALE: Bronchiolar dysfunction is associated with asthma exacerbations and poor symptom control. However, the molecular pathophysiology of asthmatic bronchiolar disease is poorly defined. OBJECTIVES: Test the hypothesis that asthmatic bronchioles exhibit disturbances in epithelial biology that produce MUC5AC-dominated mucus plugs. METHODS: Peripheral lung tissues from severe asthmatics, fatal asthmatics (FA), and controls were evaluated with histology, RNA in situ hybridization, and immunohistochemistry. Isolated bronchiolar and bronchial basal cell responses to IL13 were compared in culture. Spatial transcriptomics and multiplex immunophenotyping were performed on excised tissue sections. MEASUREMENTS AND MAIN RESULTS: In excised tissues, severe and FA bronchiolar epithelia, depleted of distal airway secretory cells (DASCs) and enriched in MUC5AC goblet cells, circumscribed MUC5AC-dominated mucus plugs. In cultured bronchiolar basal cells, IL13 suppressed FOXA2 and DASC gene signatures and upregulated MUC5AC expression. Additional studies in severe and FA-excised tissues demonstrated that bronchiolar epithelia were populated by MUC5AC-expressing goblet cell niches heterogeneously distributed within single segments and, indeed, individual bronchioles. Spatial transcriptomics and immuno-proteomics of these MUC5AC-expressing bronchiolar niches identified increased goblet, suprabasal (SERPINB3), and basal cells, juxtaposed to a loss of DASC gene signatures. MUC5AC-high niche...