Pregnancy Zone Protein Is Associated with Airway Infection, Neutrophil Extracellular Trap Formation, and Disease Severity in Bronchiectasis
Pregnancy Zone Protein Is Associated with Airway Infection, Neutrophil Extracellular Trap Formation, and Disease Severity in Bronchiectasis
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DOI：
10.1164/rccm.201812-2351oc
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发表时间：
2019-10-15
影响因子：
24.7
通讯作者：
Chalmers, James D.
中科院分区：
文献类型：
--
作者：
Finch, Simon;Shoemark, Amelia;Chalmers, James D.
原理：PZP（妊娠带蛋白）是一种广谱免疫抑制蛋白，被认为在怀孕期间抑制t细胞功能以防止胎儿排斥。以前在呼吸道中没有报道过。目的：探讨支气管扩张气道PZP的特征及其与疾病严重程度的关系。方法：采用无标记液相色谱/质谱法对高分辨率计算机断层扫描证实的支气管扩张患者进行痰蛋白谱分析。结果与未感染铜绿假单胞菌的患者进行了比较。经验证的ELISA法测定痰液和血清PZP。通过培养和16S核糖体RNA测序确定气道感染情况。采用免疫荧光法、ELISA法和电镜技术鉴定多种刺激处理的中性粒细胞中PZP的细胞来源。测量和主要结果：PZP升高与铜绿假单胞菌感染有关。在一项124例患者的验证性研究中，痰中PZP浓度与支气管扩张严重程度指数、恶化频率和症状显著相关，而血清中PZP浓度与此无关。变形菌如铜绿假单胞菌的气道感染与PZP浓度升高有关。痰液中PZP与气道细菌负荷有直接关系。在体外实验中，中性粒细胞被肉豆酸酯佛醇诱导形成中性粒细胞胞外陷阱（NETs），释放出高浓度的PZP，荧光显微镜证实NETs中存在PZP，而荧光显微镜和电镜则将PZP定位于中性粒细胞的细胞质和细胞核。有效的抗生素治疗可降低痰PZP。结论：PZP释放到NETs中。我们报告了慢性气道炎症期间支气管扩张的气道感染，NET形成和疾病严重程度之间的新联系。
Rationale: PZP (pregnancy zone protein) is a broad-spectrum immunosuppressive protein believed to suppress T-cell function during pregnancy to prevent fetal rejection. It has not previously been reported in the airway.Objectives: To characterize PZP in the bronchiectasis airway, including its relationship with disease severity.Methods: Label-free liquid chromatography/mass spectrometry was performed for sputum protein profiling of patients with bronchiectasis confirmed by high-resolution computed tomography. Results for patients with and without Pseudomonas aeruginosa infection were compared. Sputum and serum PZP was measured by validated ELISA. Airway infection status was established by culture and 16S ribosomal RNA sequencing. Immunofluorescence, ELISA, and electron microscopy were used to identify the cellular source of PZP in neutrophils treated with multiple stimuli.Measurements and Main Results: Elevated PZP was identified by label-free liquid chromatography/mass spectrometry as being associated with P. aeruginosa infection. In a validation study of 124 patients, sputum but not serum concentrations of PZP were significantly associated with the Bronchiectasis Severity Index, the frequency of exacerbations, and symptoms. Airway infection with Proteobacteria such as P. aeruginosa was associated with higher concentrations of PZP. PZP in sputum was directly related to airway bacterial load. Neutrophils induced to form neutrophil extracellular traps (NETs) with phorbol myristate acetate released high concentrations of PZP in vitro, and fluorescence microscopy confirmed the presence of PZP in NETs, whereas fluorescence and electron microscopy localized PZP to the cytoplasm and nuclei of neutrophils. Effective antibiotic therapy reduced sputum PZP.Conclusions: PZP is released into NETs. We report a novel link between airway infection, NET formation, and disease severity in bronchiectasis during chronic airway inflammation.