哮喘患者的黏液栓塞与嗜酸性粒细胞增多和气流阻塞有关
2018/05/30
摘要
背景：慢性重症哮喘中黏液栓与气流阻塞之间的联系尚未证实，嗜酸性粒细胞及其分泌物在黏液栓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，对来自146位哮喘患者和22位对照患者的肺部多排螺旋CT（MDCT）扫描结果进行黏液栓定量分析，并分析黏液栓塞评分、第1秒用力呼气量（FEV1）和气道嗜酸性粒细胞间的关系。此外，我们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）产生的氧化剂是否氧化半胱氨酸硫醇基团以促进粘液栓形成。
结果：在58％的哮喘患者中，至少1/20的肺段出现黏液栓，对照组的比例仅有4.5％，并且哮喘患者的栓塞常年存于同一肺段。 FEV1 <60％的哮喘患者中有67％为高黏液评分（黏液栓存在于≥4个肺段），FEV1为60％-80％的患者为19％，FEV1> 80％的患者为6％ （P <0.001），高黏液评分与显著增加的痰嗜酸性粒细胞和EPO相关。EPO催化H2O2氧化硫氰酸盐和溴化物生成氧化剂，交联半胱氨酸巯基基团并使硫醇盐水凝胶变硬。
结论：黏液栓塞可能是重症哮喘慢性气流阻塞的机制，EPO产生的氧化剂可能介导黏液栓形成。 我们提出了一种使用MDCT肺部扫描量化气道黏液堵塞的方法，并且认为治疗黏液栓塞可以改善慢性重症哮喘中的气流。
Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction.
Dunican EM, Elicker BM, Gierada DS, Nagle SK, Schiebler ML, Newell JD, Raymond WW, Lachowicz-Scroggins ME, Di Maio S, Hoffman EA, Castro M, Fain SB, Jarjour NN, Israel E, Levy BD, Erzurum SC, Wenzel SE, Meyers DA, Bleecker ER, Phillips BR, Mauger DT, Gordon ED, Woodruff PG, Peters MC, Fahy JV; National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP).
Abstract
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.
CONCLUSIONS: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.
背景：慢性重症哮喘中黏液栓与气流阻塞之间的联系尚未证实，嗜酸性粒细胞及其分泌物在黏液栓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，对来自146位哮喘患者和22位对照患者的肺部多排螺旋CT（MDCT）扫描结果进行黏液栓定量分析，并分析黏液栓塞评分、第1秒用力呼气量（FEV1）和气道嗜酸性粒细胞间的关系。此外，我们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）产生的氧化剂是否氧化半胱氨酸硫醇基团以促进粘液栓形成。
结果：在58％的哮喘患者中，至少1/20的肺段出现黏液栓，对照组的比例仅有4.5％，并且哮喘患者的栓塞常年存于同一肺段。 FEV1 <60％的哮喘患者中有67％为高黏液评分（黏液栓存在于≥4个肺段），FEV1为60％-80％的患者为19％，FEV1> 80％的患者为6％ （P <0.001），高黏液评分与显著增加的痰嗜酸性粒细胞和EPO相关。EPO催化H2O2氧化硫氰酸盐和溴化物生成氧化剂，交联半胱氨酸巯基基团并使硫醇盐水凝胶变硬。
结论：黏液栓塞可能是重症哮喘慢性气流阻塞的机制，EPO产生的氧化剂可能介导黏液栓形成。 我们提出了一种使用MDCT肺部扫描量化气道黏液堵塞的方法，并且认为治疗黏液栓塞可以改善慢性重症哮喘中的气流。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Clin Invest. 2018 Feb 5. pii: 95693.)
(J Clin Invest. 2018 Feb 5. pii: 95693.)
Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction.
Dunican EM, Elicker BM, Gierada DS, Nagle SK, Schiebler ML, Newell JD, Raymond WW, Lachowicz-Scroggins ME, Di Maio S, Hoffman EA, Castro M, Fain SB, Jarjour NN, Israel E, Levy BD, Erzurum SC, Wenzel SE, Meyers DA, Bleecker ER, Phillips BR, Mauger DT, Gordon ED, Woodruff PG, Peters MC, Fahy JV; National Heart Lung and Blood Institute (NHLBI) Severe Asthma Research Program (SARP).
Abstract
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.
CONCLUSIONS: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.
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海拔1500米以上，是 哮喘发病率的主要决定因素，一项生态学研究
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怀孕前，孕期中和产后哮喘患者的治疗：一项基于人群的队列研究
