Scottish Centre for Respiratory Research, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Institut d'Invesitgacio Biomedica (IIB) Sant Pau, Barcelona, Spain.
J Allergy Clin Immunol. 2018 Jan;141(1):117-127. doi: 10.1016/j.jaci.2017.04.022. Epub 2017 May 13.
Neutrophil extracellular traps (NETs) have been observed in the airway in patients with chronic obstructive pulmonary disease (COPD), but their clinical and pathophysiologic implications have not been defined.
We sought to determine whether NETs are associated with disease severity in patients with COPD and how they are associated with microbiota composition and airway neutrophil function.
NET protein complexes (DNA-elastase and histone-elastase complexes), cell-free DNA, and neutrophil biomarkers were quantified in soluble sputum and serum from patients with COPD during periods of disease stability and during exacerbations and compared with clinical measures of disease severity and the sputum microbiome. Peripheral blood and airway neutrophil function were evaluated by means of flow cytometry ex vivo and experimentally after stimulation of NET formation.
Sputum NET complexes were associated with the severity of COPD evaluated by using the composite Global Initiative for Obstructive Lung Disease scale (P < .0001). This relationship was due to modest correlations between NET complexes and FEV, symptoms evaluated by using the COPD assessment test, and higher levels of NET complexes in patients with frequent exacerbations (P = .002). Microbiota composition was heterogeneous, but there was a correlation between NET complexes and both microbiota diversity (P = .009) and dominance of Haemophilus species operational taxonomic units (P = .01). Ex vivo airway neutrophil phagocytosis of bacteria was reduced in patients with increased sputum NET complexes. Consistent results were observed regardless of the method of quantifying sputum NETs. Failure of phagocytosis could be induced experimentally by incubating healthy control neutrophils with soluble sputum from patients with COPD.
NET formation is increased in patients with severe COPD and associated with more frequent exacerbations and a loss of microbiota diversity.
在慢性阻塞性肺疾病（COPD）患者的气道中观察到中性粒细胞胞外陷阱（NETs），但其临床和病理生理意义尚未确定。
我们旨在确定 NET 是否与 COPD 患者的疾病严重程度相关，以及它们与微生物群组成和气道中性粒细胞功能的关系。
在 COPD 患者疾病稳定期和加重期测量可溶性痰和血清中的 NET 蛋白复合物（DNA-弹性蛋白酶和组蛋白-弹性蛋白酶复合物）、无细胞 DNA 和中性粒细胞生物标志物，并与疾病严重程度的临床指标和痰微生物组进行比较。通过体外流式细胞术和 NET 形成刺激后的实验评估外周血和气道中性粒细胞功能。
痰 NET 复合物与使用综合全球倡议阻塞性肺病量表评估的 COPD 严重程度相关（P<0.0001）。这种关系归因于 NET 复合物与 FEV、COPD 评估测试评估的症状之间的适度相关性，以及频繁加重的患者 NET 复合物水平较高（P=0.002）。微生物群组成存在异质性，但 NET 复合物与微生物群多样性（P=0.009）和 Haemophilus 种操作分类单位的优势（P=0.01）之间存在相关性。在痰 NET 复合物增加的患者中，气道中性粒细胞对细菌的吞噬作用降低。无论采用何种方法定量痰 NET，都观察到一致的结果。通过用 COPD 患者的可溶性痰孵育健康对照中性粒细胞，可在实验中诱导吞噬作用失败。
严重 COPD 患者的 NET 形成增加，与更频繁的加重和微生物群多样性丧失有关。
