Airway G-CSF identifies neutrophilic inflammation and contributes to asthma progression
Airway G-CSF identifies neutrophilic inflammation and contributes to asthma progression
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DOI：
10.1183/13993003.00827-2019
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发表时间：
2020-02-01
影响因子：
24.3
通讯作者：
Lee, Seung-Woo
中科院分区：
文献类型：
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作者：
Kim, Young-Min;Kim, Hyekang;Lee, Seung-Woo
基于相关生物标志物的哮喘患者分层能够预测哮喘患者对免疫靶向治疗的反应性。嗜酸性粒细胞性哮喘患者的个体化治疗已改善了临床结局;嗜酸性粒细胞性哮喘患者的类似治疗方法尚未开发。我们确定了气道中的集落刺激因子（CSF）是否反映了哮喘的炎症表型，并有助于嗜酸性asthma.We分析了三种不同的哮喘小鼠模型，并评估了根据炎症表型分层的人类哮喘患者痰液中的细胞因子谱。此外，我们评估了各种细胞因子阻断剂在小鼠嗜中性粒细胞哮喘模型中的治疗效果。在CSF中，气道粒细胞CSF（G-CSF）通过促进骨髓中中性粒细胞的发育而促进气道嗜中性粒细胞的形成，从而在小鼠哮喘模型中区分嗜酸性粒细胞炎症和嗜酸性粒细胞炎症。G-CSF是通过用白细胞介素（IL）-17 A和肿瘤坏死因子（TNF）-α同时刺激肺上皮细胞产生的;因此，在IL-17 AxTNF-α双敲除小鼠中使用单克隆抗体或细胞因子遗传缺陷双重阻断上游刺激可降低G-CSF的血清水平，从而减轻气道中的嗜酸性炎症。在人类中，痰液中G-CSF水平可用于对嗜中性粒细胞为主炎症的哮喘患者进行分层，我们的研究结果表明，促骨髓生成的G-CSF和细胞因子作为上游诱导因子是嗜中性粒细胞哮喘患者潜在的诊断和治疗靶点。
Stratification of asthmatic patients based on relevant biomarkers enables the prediction of responsiveness against immune-targeted therapies in patients with asthma. Individualised therapy in patients with eosinophilic asthma has yielded improved clinical outcomes; similar approaches in patients with neutrophilic asthma have yet to be developed. We determined whether colony-stimulating factors (CSFs) in the airway reflect the inflammatory phenotypes of asthma and contribute to disease progression of neutrophilic asthma.We analysed three different mouse models of asthma and assessed cytokine profiles in sputum from human patients with asthma stratified according to inflammatory phenotype. In addition, we evaluated the therapeutic efficacy of various cytokine blockades in a mouse model of neutrophilic asthma.Among the CSFs, airway granulocyte CSF (G-CSF) contributes to airway neutrophilia by promoting neutrophil development in bone marrow and thereby distinguishes neutrophilic inflammation from eosinophilic inflammation in mouse models of asthma. G-CSF is produced by concurrent stimulation of the lung epithelium with interleukin (IL)-17A and tumour necrosis factor (TNF)-alpha; therefore, dual blockade of upstream stimuli using monoclonal antibodies or genetic deficiency of the cytokines in IL-17AxTNF-alpha double-knockout mice reduced the serum level of G-CSF, leading to alleviation of neutrophilic inflammation in the airway. In humans, the sputum level of G-CSF can be used to stratify patients with asthma with neutrophil-dominated inflammation.Our results indicated that myelopoiesis-promoting G-CSF and cytokines as the upstream inducing factors are potential diagnostic and therapeutic targets in patients with neutrophilic asthma.