Bronchoconstriction damages airway epithelia by crowding-induced excess cell extrusion

• 成果类型: Article
• 署名作者: Bagley, Dustin C.; Russell, Tobias; Ortiz-Zapater, Elena; Stinson, Sally; Fox, Kristina; Redd, Polly F.; Joseph, Merry; Deering-Rice, Cassandra; Reilly, Christopher; Parsons, Maddy; Brightling, Christopher; Rosenblatt, Jody
• 署名单位: University of London; King's College London; University of Valencia; University of Leicester; Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; University of London; King's College London
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13663
• DOI: 10.1126/science.adk2758
• 发表日期: 2024-04-05
• 页码: 66-73
• 关键词: receptor potential ankyrin-1; inflammation; leukotrienes; pathogenesis; eosinophilia; activation; prevention; MODEL

摘要

Asthma is deemed an inflammatory disease, yet the defining diagnostic feature is mechanical bronchoconstriction. We previously discovered a conserved process called cell extrusion that drives homeostatic epithelial cell death when cells become too crowded. In this work, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion in both mice and humans. Although relaxing the airways with the rescue treatment albuterol did not affect these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these features. Our findings show that bronchoconstriction causes epithelial damage and inflammation by excess crowding-induced cell extrusion and suggest that blocking epithelial extrusion, instead of the ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle.