气道G-CSF可识别中性粒细胞炎症并促进哮喘进展
2019/12/09
摘要
根据相关生物标记物对哮喘患者进行分层，可以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经取得了良好的临床效果，而嗜中性粒细胞性哮喘患者的类似治疗方法尚未开发出来。我们检测了气道中的集落刺激因子（CSFs）是否能反映哮喘的炎症表型，是否促进中性粒细胞性哮喘病情进展。我们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哮喘患者痰中的细胞因子谱，此外，我们还评估了各种细胞因子阻滞剂对中性粒细胞哮喘小鼠模型的治疗效果。在CSFs中，气道粒细胞CSF（G-CSF）通过促进骨髓中中性粒细胞的发育进而促进气道中性粒细胞的增多，从而区分哮喘小鼠模型中的嗜中性粒细胞炎症和嗜酸性粒细胞炎症。G-CSF是由IL-17A和TNF-α同时刺激肺上皮产生的，因此，用单克隆抗体双重阻断上游刺激或用IL-17A×TNF-α双基因敲除（DKO）小鼠的遗传缺陷可降低血清G-CSF水平，导致气道中性粒细胞炎症减轻。痰中G-CSF水平可用于筛选中性粒细胞炎症为主的哮喘患者。本研究结果提示，骨髓生成促进的G-CSF和细胞因子等作为上游诱导因子，是中性粒细胞哮喘患者潜在的诊断和治疗靶点。
Airway G-CSF identifies neutrophilic inflammation and contributes to asthma progression.
Kim YM, Kim H, Lee S, Kim S, Lee JU, Choi Y, Park HW, You G, Kang H, Lee S, Park JS, Park Y, Park HS, Park CS, Lee SW.
Abstract
Stratification of asthmatics based on relevant biomarkers enables it to predict the responsiveness against immune-targeted therapies in patients with asthma. Individualised therapy in patients with eosinophilic asthma has yielded improved clinical outcomes, and similar approaches in those with neutrophilic asthma have yet to be developed. We determined whether the 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 the 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 the bone marrow (BM), 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 IL-17A and TNF-α; therefore, dual blockade of upstream stimuli using monoclonal antibodies or genetic deficiency of the cytokines in IL-17A × TNF-α double knockout (DKO) 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.
根据相关生物标记物对哮喘患者进行分层，可以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经取得了良好的临床效果，而嗜中性粒细胞性哮喘患者的类似治疗方法尚未开发出来。我们检测了气道中的集落刺激因子（CSFs）是否能反映哮喘的炎症表型，是否促进中性粒细胞性哮喘病情进展。我们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哮喘患者痰中的细胞因子谱，此外，我们还评估了各种细胞因子阻滞剂对中性粒细胞哮喘小鼠模型的治疗效果。在CSFs中，气道粒细胞CSF（G-CSF）通过促进骨髓中中性粒细胞的发育进而促进气道中性粒细胞的增多，从而区分哮喘小鼠模型中的嗜中性粒细胞炎症和嗜酸性粒细胞炎症。G-CSF是由IL-17A和TNF-α同时刺激肺上皮产生的，因此，用单克隆抗体双重阻断上游刺激或用IL-17A×TNF-α双基因敲除（DKO）小鼠的遗传缺陷可降低血清G-CSF水平，导致气道中性粒细胞炎症减轻。痰中G-CSF水平可用于筛选中性粒细胞炎症为主的哮喘患者。本研究结果提示，骨髓生成促进的G-CSF和细胞因子等作为上游诱导因子，是中性粒细胞哮喘患者潜在的诊断和治疗靶点。
(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)
(Eur Respir J. 2019 Nov 19. pii: 1900827. doi: 10.1183/13993003.00827-2019.)
(Eur Respir J. 2019 Nov 19. pii: 1900827. doi: 10.1183/13993003.00827-2019.)
Airway G-CSF identifies neutrophilic inflammation and contributes to asthma progression.
Kim YM, Kim H, Lee S, Kim S, Lee JU, Choi Y, Park HW, You G, Kang H, Lee S, Park JS, Park Y, Park HS, Park CS, Lee SW.
Abstract
Stratification of asthmatics based on relevant biomarkers enables it to predict the responsiveness against immune-targeted therapies in patients with asthma. Individualised therapy in patients with eosinophilic asthma has yielded improved clinical outcomes, and similar approaches in those with neutrophilic asthma have yet to be developed. We determined whether the 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 the 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 the bone marrow (BM), 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 IL-17A and TNF-α; therefore, dual blockade of upstream stimuli using monoclonal antibodies or genetic deficiency of the cytokines in IL-17A × TNF-α double knockout (DKO) 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.
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高温和低温加重哮喘的气道炎症：来自小鼠模型中的证据
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激素戒断引起轻中度哮喘控制不佳独立于经典中性粒激活途径
