混合型炎症哮喘小鼠模型中，中性粒细胞通过中性粒细胞弹性蛋白酶诱导的FGF-2促使平滑肌增生
2018/12/24
背景：支气管哮喘传统上以慢性过敏性炎症为特征，包括嗜酸粒细胞增多和Th2型细胞因子升高。 最近，IL-17衍生的中性粒细胞浸润显示与哮喘严重程度和气道重塑相关。
目的：研究IL-17衍生的中性粒细胞在慢性支气管哮喘气道重塑中的作用。
方法：我们利用屋尘螨抗原诱导哮喘小鼠模型。鼻内致敏和慢性抗原激发引起混合性过敏性炎症，包括嗜酸粒细胞和中性粒细胞（Mix-in组）。 我们中和了IL-17和成纤维细胞生长因子-2（fibroblast growth factor-2, FGF-2），并研究了Mix-in组气道重塑的机制。
结果：Mix-in组显示出肺组织中的中性粒细胞浸润和高水平的IL-17。 Mix-in组也表现出更多的支气管平滑肌增生。IL-17中和降低了Mix-in组中所有这些效应的幅度。抗体阵列显示Mix-in组中FGF-2相对于Eo-ip组增加，并且FGF-2升高与平滑肌肥大/增生相关。高浓度的中性粒细胞弹性蛋白酶增强支气管上皮细胞中的E-钙粘蛋白/β-连环蛋白信号传导。中性粒细胞弹性蛋白酶抑制剂治疗降低了FGF-2的产生和E-钙粘蛋白/β-连环蛋白信号传导，从而抑制了平滑肌增生。
结论：IL-17 /中性粒细胞轴可能通过促进混合性过敏性炎症中的平滑肌肥大/增生，从而在气道重塑中起重要作用，因此可作为治疗重症哮喘的潜在治疗靶点。
Neutrophils induce smooth muscle hyperplasia via neutrophil elastase-induced FGF-2 in a mouse model of asthma with mixed inflammation
Ogawa H; Azuma M; Tsunematsu T; Morimoto Y; Kondo M; Tezuka T; Nishioka Y; Tsuneyama K.
Clin Exp Allergy. 2018;1-11
Background: Bronchial asthma is traditionally characterized by chronic allergic inflammation, including eosinophilia and elevated Th2 cytokines. Recently, IL-17- derived neutrophil infiltration was shown to correlate with asthma severity and airway remodelling.
Objective: To investigate the role of IL-17-derived neutrophils in airway remodelling in chronic bronchial asthma.
Methods: We utilized house dust mite antigen-induced mouse models of asthma. Intranasal sensitization and chronic antigen challenge caused a mixed allergic inflammation that included eosinophils and neutrophils (Mix-in group). We neutralized IL-17 and fibroblast growth factor (FGF-2) and investigated the mechanism of airway remodelling in the Mix-in group.
Results: The Mix-in group displayed neutrophilic infiltration and high levels of IL-17 in lung tissue. The Mix-in group also exhibited more bronchial smooth muscle hyperplasia. IL-17 neutralization decreased the magnitude of all of these effects in the Mix-in group. Antibody arrays revealed an increase in FGF-2 in the Mix-in Group relative to the Eo-ip group, and FGF-2 elevation was associated with smooth muscle hypertrophy/hyperplasia. High concentrations of neutrophil elastase enhanced E-cadherin/β-catenin signalling in bronchial epithelial cells. Neutrophil elastase inhibitor treatment decreased FGF-2 production and E-cadherin/β-catenin signalling, which inhibited smooth muscle hyperplasia.
Conclusion: The IL-17/neutrophil axis may play an important role in airway remodelling by contributing to smooth muscle hypertrophy/hyperplasia in mixed allergic inflammation and accordingly represents an attractive therapeutic target for severe asthma.
目的：研究IL-17衍生的中性粒细胞在慢性支气管哮喘气道重塑中的作用。
方法：我们利用屋尘螨抗原诱导哮喘小鼠模型。鼻内致敏和慢性抗原激发引起混合性过敏性炎症，包括嗜酸粒细胞和中性粒细胞（Mix-in组）。 我们中和了IL-17和成纤维细胞生长因子-2（fibroblast growth factor-2, FGF-2），并研究了Mix-in组气道重塑的机制。
结果：Mix-in组显示出肺组织中的中性粒细胞浸润和高水平的IL-17。 Mix-in组也表现出更多的支气管平滑肌增生。IL-17中和降低了Mix-in组中所有这些效应的幅度。抗体阵列显示Mix-in组中FGF-2相对于Eo-ip组增加，并且FGF-2升高与平滑肌肥大/增生相关。高浓度的中性粒细胞弹性蛋白酶增强支气管上皮细胞中的E-钙粘蛋白/β-连环蛋白信号传导。中性粒细胞弹性蛋白酶抑制剂治疗降低了FGF-2的产生和E-钙粘蛋白/β-连环蛋白信号传导，从而抑制了平滑肌增生。
结论：IL-17 /中性粒细胞轴可能通过促进混合性过敏性炎症中的平滑肌肥大/增生，从而在气道重塑中起重要作用，因此可作为治疗重症哮喘的潜在治疗靶点。
(黄丹1 张红萍1 王刚2 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（Clin Exp Allergy. 2018;1-11）
（Clin Exp Allergy. 2018;1-11）
Neutrophils induce smooth muscle hyperplasia via neutrophil elastase-induced FGF-2 in a mouse model of asthma with mixed inflammation
Ogawa H; Azuma M; Tsunematsu T; Morimoto Y; Kondo M; Tezuka T; Nishioka Y; Tsuneyama K.
Clin Exp Allergy. 2018;1-11
Background: Bronchial asthma is traditionally characterized by chronic allergic inflammation, including eosinophilia and elevated Th2 cytokines. Recently, IL-17- derived neutrophil infiltration was shown to correlate with asthma severity and airway remodelling.
Objective: To investigate the role of IL-17-derived neutrophils in airway remodelling in chronic bronchial asthma.
Methods: We utilized house dust mite antigen-induced mouse models of asthma. Intranasal sensitization and chronic antigen challenge caused a mixed allergic inflammation that included eosinophils and neutrophils (Mix-in group). We neutralized IL-17 and fibroblast growth factor (FGF-2) and investigated the mechanism of airway remodelling in the Mix-in group.
Results: The Mix-in group displayed neutrophilic infiltration and high levels of IL-17 in lung tissue. The Mix-in group also exhibited more bronchial smooth muscle hyperplasia. IL-17 neutralization decreased the magnitude of all of these effects in the Mix-in group. Antibody arrays revealed an increase in FGF-2 in the Mix-in Group relative to the Eo-ip group, and FGF-2 elevation was associated with smooth muscle hypertrophy/hyperplasia. High concentrations of neutrophil elastase enhanced E-cadherin/β-catenin signalling in bronchial epithelial cells. Neutrophil elastase inhibitor treatment decreased FGF-2 production and E-cadherin/β-catenin signalling, which inhibited smooth muscle hyperplasia.
Conclusion: The IL-17/neutrophil axis may play an important role in airway remodelling by contributing to smooth muscle hypertrophy/hyperplasia in mixed allergic inflammation and accordingly represents an attractive therapeutic target for severe asthma.
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肠道微生物群与过敏致敏，湿疹和哮喘之间的关联：一项系统综述
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