哮喘黏液栓的细胞和分子特征提供了有关其形成和持续存在的线索
2025/07/15
摘要：
背景：黏液栓在急性哮喘中形成，在慢性病程中持续存在。尽管嗜酸性粒细胞参与黏液病理机制，但关于哮喘黏液栓形成和持续存在的许多机制细节尚不清楚。
方法：本研究利用组织学和空间单细胞蛋白质组学，我们对14例哮喘患者(致死性哮喘9例,非致死性哮喘5例)和对照组(慢性阻塞性肺疾病10例,无肺部疾病14例)的非移植供肺的黏液阻塞气道进行了特征分析。此外，我们利用气道上皮细胞-嗜酸性粒细胞(AEC-eosinophil)共培养模型探究AEC黏液对嗜酸性粒细胞脱颗粒的影响。
结果：哮喘黏液栓黏附于气道，表现为2型固有淋巴细胞浸润、平滑肌细胞和表达MUC5AC的杯状细胞增生。哮喘黏液栓中浸润的免疫细胞大多呈现嗜酸性粒细胞过氧化物酶(EPX)和中性粒细胞弹性蛋白酶双阳性，提示中性粒细胞从脱颗粒的嗜酸性粒细胞中内化EPX。事实上，暴露于IL-13激活的AECs黏液中的嗜酸性粒细胞，通过CD11b和聚糖依赖性途径发生细胞裂解脱颗粒。双阳性粒细胞在黏液栓中出现的比例不同。寡粒细胞型黏液栓富含MUC5AC，而粒细胞型黏液栓则混合了MUC5AC、MUC5B和细胞外DNA陷阱。寡粒细胞型黏液栓更常见于(急性)致死性哮喘；粒细胞型黏液栓则主要见于(慢性)非致死性哮喘。
结论：综上，我们的数据表明，在致死性哮喘中富含黏蛋白的黏液栓的形成源于重塑气道中的急性杯状细胞脱颗粒，而慢性哮喘中粒细胞型黏液栓的持续存在是由于上皮细胞-黏蛋白-粒细胞相互作用形成的微环境稳态。
Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence
Liegeois MA, Hsieh A, Al-Fouadi M, Charbit AR, Yang CX, Hackett TL, Fahy JV. Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence.
J Clin Invest. 2025 Mar 17;135(6):e186889. doi: 10.1172/JCI186889. PMID: 40091838; PMCID: PMC11910225.
Abstract:
BACKGROUND. Mucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.
METHODS. Using histology and spatial, single-cell proteomics, we characterized mucus-plugged airways from nontransplantable donor lungs of 14 patients with asthma (9 with fatal asthma and 5 with nonfatal asthma) and individuals acting as controls (10 with chronic obstructive pulmonary disease and 14 free of lung disease). Additionally, we used an airway epithelial cell-eosinophil (AEC-eosinophil) coculture model to explore how AEC mucus affects eosinophil degranulation.
RESULTS. Asthma mucus plugs were tethered to airways showing infiltration with innate lymphoid type 2 cells and hyperplasia of smooth muscle cells and MUC5AC-expressing goblet cells. Asthma mucus plugs were infiltrated with immune cells that were mostly dual positive for eosinophil peroxidase (EPX) and neutrophil elastase, suggesting that neutrophils internalize EPX from degranulating eosinophils. Indeed, eosinophils exposed to mucus from IL-13-activated AECs underwent CD11b- and glycan-dependent cytolytic degranulation. Dual-positive granulocytes varied in frequency in mucus plugs. Whereas paucigranulocytic plugs were MUC5AC rich, granulocytic plugs had a mix of MUC5AC, MUC5B, and extracellular DNA traps. Paucigranulocytic plugs occurred more frequently in (acute) fatal asthma and granulocytic plugs predominated in (chronic) nonfatal asthma.
CONCLUSION. Together, our data suggest that mucin-rich mucus plugs in fatal asthma form because of acute goblet cell degranulation in remodeled airways and that granulocytic mucus plugs in chronic asthma persist because of a sustaining niche characterized by epithelial cell-mucin-granulocyte cross-talk.
背景：黏液栓在急性哮喘中形成，在慢性病程中持续存在。尽管嗜酸性粒细胞参与黏液病理机制，但关于哮喘黏液栓形成和持续存在的许多机制细节尚不清楚。
方法：本研究利用组织学和空间单细胞蛋白质组学，我们对14例哮喘患者(致死性哮喘9例,非致死性哮喘5例)和对照组(慢性阻塞性肺疾病10例,无肺部疾病14例)的非移植供肺的黏液阻塞气道进行了特征分析。此外，我们利用气道上皮细胞-嗜酸性粒细胞(AEC-eosinophil)共培养模型探究AEC黏液对嗜酸性粒细胞脱颗粒的影响。
结果：哮喘黏液栓黏附于气道，表现为2型固有淋巴细胞浸润、平滑肌细胞和表达MUC5AC的杯状细胞增生。哮喘黏液栓中浸润的免疫细胞大多呈现嗜酸性粒细胞过氧化物酶(EPX)和中性粒细胞弹性蛋白酶双阳性，提示中性粒细胞从脱颗粒的嗜酸性粒细胞中内化EPX。事实上，暴露于IL-13激活的AECs黏液中的嗜酸性粒细胞，通过CD11b和聚糖依赖性途径发生细胞裂解脱颗粒。双阳性粒细胞在黏液栓中出现的比例不同。寡粒细胞型黏液栓富含MUC5AC，而粒细胞型黏液栓则混合了MUC5AC、MUC5B和细胞外DNA陷阱。寡粒细胞型黏液栓更常见于(急性)致死性哮喘；粒细胞型黏液栓则主要见于(慢性)非致死性哮喘。
结论：综上，我们的数据表明，在致死性哮喘中富含黏蛋白的黏液栓的形成源于重塑气道中的急性杯状细胞脱颗粒，而慢性哮喘中粒细胞型黏液栓的持续存在是由于上皮细胞-黏蛋白-粒细胞相互作用形成的微环境稳态。
（四川大学华西医院呼吸与危重症医学科 杨倩1 王霁1 王刚1 译）
（J Clin Invest. 2025 Mar 17;135(6):e186889. doi: 10.1172/JCI186889. PMID: 40091838; PMCID: PMC11910225.）
（J Clin Invest. 2025 Mar 17;135(6):e186889. doi: 10.1172/JCI186889. PMID: 40091838; PMCID: PMC11910225.）
Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence
Liegeois MA, Hsieh A, Al-Fouadi M, Charbit AR, Yang CX, Hackett TL, Fahy JV. Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence.
J Clin Invest. 2025 Mar 17;135(6):e186889. doi: 10.1172/JCI186889. PMID: 40091838; PMCID: PMC11910225.
Abstract:
BACKGROUND. Mucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.
METHODS. Using histology and spatial, single-cell proteomics, we characterized mucus-plugged airways from nontransplantable donor lungs of 14 patients with asthma (9 with fatal asthma and 5 with nonfatal asthma) and individuals acting as controls (10 with chronic obstructive pulmonary disease and 14 free of lung disease). Additionally, we used an airway epithelial cell-eosinophil (AEC-eosinophil) coculture model to explore how AEC mucus affects eosinophil degranulation.
RESULTS. Asthma mucus plugs were tethered to airways showing infiltration with innate lymphoid type 2 cells and hyperplasia of smooth muscle cells and MUC5AC-expressing goblet cells. Asthma mucus plugs were infiltrated with immune cells that were mostly dual positive for eosinophil peroxidase (EPX) and neutrophil elastase, suggesting that neutrophils internalize EPX from degranulating eosinophils. Indeed, eosinophils exposed to mucus from IL-13-activated AECs underwent CD11b- and glycan-dependent cytolytic degranulation. Dual-positive granulocytes varied in frequency in mucus plugs. Whereas paucigranulocytic plugs were MUC5AC rich, granulocytic plugs had a mix of MUC5AC, MUC5B, and extracellular DNA traps. Paucigranulocytic plugs occurred more frequently in (acute) fatal asthma and granulocytic plugs predominated in (chronic) nonfatal asthma.
CONCLUSION. Together, our data suggest that mucin-rich mucus plugs in fatal asthma form because of acute goblet cell degranulation in remodeled airways and that granulocytic mucus plugs in chronic asthma persist because of a sustaining niche characterized by epithelial cell-mucin-granulocyte cross-talk.
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