Division of Pulmonary and Critical Care Medicine, Department of Medicine and Cardiovascular Research Institute, and.
Department of Radiology and Biomedical Imaging, UCSF, San Francisco, California, USA.
J Clin Invest. 2018 Mar 1;128(3):997-1009. doi: 10.1172/JCI95693. Epub 2018 Feb 5.
The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown.
In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation.
Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%-80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels.
Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma.
Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915.
NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.
在慢性重度哮喘中，黏液栓与气流阻塞之间的联系尚未建立，而嗜酸性粒细胞及其产物在黏液栓形成中的作用尚不清楚。
在临床研究中，我们开发并应用了一种基于支气管-肺段的评分系统，对 146 例哮喘患者和 22 例对照者的多排 CT（MDCT）肺部扫描中的黏液栓进行定量，并分析了黏液栓评分、第 1 秒用力呼气量（FEV1）和气道嗜酸性粒细胞之间的关系。此外，我们还使用气道黏液凝胶模型来探讨嗜酸性粒细胞过氧化物酶（EPO）产生的氧化剂是否可以氧化半胱氨酸巯基基团以促进黏液栓形成。
在 58%的哮喘患者中至少有 1 个肺段存在黏液栓，而在对照组中只有 4.5%存在，且哮喘患者的黏液栓在同一肺段中持续存在多年。高黏液评分（≥ 4 个肺段有黏液栓）发生在 67%的 FEV1 低于预计值 60%的哮喘患者、19%的 FEV1 为 60%-80%的患者和 6%的 FEV1 大于 80%的患者（P < 0.001），并且与痰中嗜酸性粒细胞和 EPO 的显著增加相关。EPO 催化 H2O2 对硫氰酸盐和溴化物的氧化，生成可交联半胱氨酸巯基基团并使巯基化水凝胶变硬的氧化剂。
黏液栓可能是慢性重度哮喘中慢性气流阻塞的一种合理机制，EPO 产生的氧化剂可能介导黏液栓的形成。我们提出了一种使用 MDCT 肺部扫描定量气道黏液栓的方法，并建议治疗黏液栓可能改善慢性重度哮喘的气流。
NCT01718197、NCT01606826、NCT01750411、NCT01761058、NCT01761630、NCT01759186、NCT01716494 和 NCT01760915。
美国国立卫生研究院 P01 HL107201、R01 HL080414、U10 HL109146、U10 HL109164、U10 HL109172、U10 HL109086、U10 HL109250、U10 HL109150、U10 HL109257、U10 HL109152 和 P01 HL107202 以及美国国立转化医学科学中心 UL1TR0000427、UL1TR000448 和 KL2TR000428 资助。
