BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION 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. TRIAL REGISTRATION Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915. FUNDING 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.

中文翻译：

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哮喘患者的粘液堵塞与嗜酸性粒细胞增多和气流阻塞有关。

背景技术在慢性重症哮喘中，尚未确定粘液塞与气流阻塞之间的联系，并且嗜酸性粒细胞及其产物在粘液塞形成中的作用尚不清楚。方法在临床研究中，我们开发并应用了基于支气管肺段的评分系统，以对来自146名哮喘患者和22名对照的多探测器计算机断层扫描（MDCT）肺部扫描进行定量粘液栓塞，并分析了粘液栓塞评分，强制性呼气量之间的关系。 1秒（FEV1），以及气道嗜酸性粒细胞。此外，我们使用气道粘液凝胶模型来研究嗜酸性粒细胞过氧化物酶（EPO）产生的氧化剂是否氧化半胱氨酸硫醇基团以促进粘液塞形成。结果在58％的哮喘患者和4.5％的对照组中，粘液栓塞至少出现在20个肺段中的1个，并且哮喘患者的堵塞物在同一部位持续了多年。FEV1小于预期量的60％的哮喘患者中有67％的患者有较高的粘液评分（栓塞≥4个部分），FEV1的60％-80％的患者为19％，FEV1的80％的患者为6％ （P <0.001），并与痰中嗜酸性粒细胞和EPO显着增加有关。EPO催化H2O2氧化硫氰酸盐和溴化物，生成使半胱氨酸硫醇基交联并使硫醇化水凝胶变硬的氧化剂。结论粘液塞是严重哮喘中慢性气流阻塞的合理机制，EPO产生的氧化剂可能介导粘液塞的形成。我们提出了一种使用MDCT肺部扫描量化气道粘液堵塞的方法，并建议治疗粘液堵塞可改善慢性重症哮喘的气流。试验注册Clinicaltrials.gov NCT01718197，NCT01606826，NCT01750411，NCT01761058，NCT01761630，NCT01759186，NCT01716494和NCT01760915。NIH资助P01 HL107201，R01 HL080414，U10 HL109146，U10 HL109164，U10 HL109172，U10 HL109086，U10 HL109250，U10 HL109168，U10 HL109257，U10 HL109152和P01 HL107202以及ULTRTR000000000和NationalTROFTR12000的国家中心。