在混合炎症性哮喘小鼠模型中，中性粒细胞可通过中性粒细胞弹性蛋白酶介导的FGF-2诱导平滑肌增生
2018/11/13
摘要
背景：支气管哮喘一般以慢性过敏性炎症为特征，包括嗜酸性粒细胞增多和Th2细胞因子升高。最近发现IL-17诱导的中性粒细胞浸润与哮喘严重程度和气道重塑有关。
目的：探讨IL-17诱导的中性粒细胞在慢性支气管哮喘气道重塑中的作用。
方法：我们利用室内尘螨抗原诱导小鼠哮喘模型。鼻内致敏和慢性抗原刺激导致混合过敏性炎症，包括嗜酸性粒细胞和中性粒细胞(混合组)。我们中和了IL-17和成纤维细胞生长因子(FGF-2)，并研究混合组气道重塑的机制。
结果：混合组肺组织中出现中性粒细胞浸润且IL-17水平升高。混合组同时还出现支气管平滑肌增生。IL-17中和抗体降低了混合组中所有这些效应的强度。抗体芯片分析显示混合组FGF-2较Eo-ip组相对增加，FGF-2升高与平滑肌肥大/增生有关。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钙粘蛋白/β-catenin信号。中性粒细胞弹性蛋白酶抑制剂治疗减少FGF-2生产并抑制钙粘蛋白/β-catenin信号通路从而抑制平滑肌增生。
结论：在混合性过敏性炎症中IL-17/中性粒细胞轴通过促进平滑肌肥大/增生可能在气道重塑中发挥重要作用，并因此成为一个有吸引力的重症哮喘治疗靶点。这篇文章受版权保护。保留所有权利。
Neutrophils induce smooth muscle hyperplasia via neutrophil elastase-induced FGF-2 in a mouse model of asthma with mixed inflammation.
Ogawa H et al. Clin Exp Allergy. 2018 Sep 1.
Abstract
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 remodeling.
OBJECTIVE: To investigate the role of IL-17-derived neutrophils in airway remodeling 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 remodeling 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 signaling in bronchial epithelial cells. Neutrophil elastase inhibitor treatment decreased FGF-2 production and E-cadherin/β-catenin signaling, which inhibited smooth muscle hyperplasia.
CONCLUSION: The IL-17/neutrophil axis may play an important role in airway remodeling by contributing to smooth muscle hypertrophy/hyperplasia in mixed allergic inflammation, and accordingly represents an attractive therapeutic target for severe asthma. This article is protected by copyright. All rights reserved.
背景：支气管哮喘一般以慢性过敏性炎症为特征，包括嗜酸性粒细胞增多和Th2细胞因子升高。最近发现IL-17诱导的中性粒细胞浸润与哮喘严重程度和气道重塑有关。
目的：探讨IL-17诱导的中性粒细胞在慢性支气管哮喘气道重塑中的作用。
方法：我们利用室内尘螨抗原诱导小鼠哮喘模型。鼻内致敏和慢性抗原刺激导致混合过敏性炎症，包括嗜酸性粒细胞和中性粒细胞(混合组)。我们中和了IL-17和成纤维细胞生长因子(FGF-2)，并研究混合组气道重塑的机制。
结果：混合组肺组织中出现中性粒细胞浸润且IL-17水平升高。混合组同时还出现支气管平滑肌增生。IL-17中和抗体降低了混合组中所有这些效应的强度。抗体芯片分析显示混合组FGF-2较Eo-ip组相对增加，FGF-2升高与平滑肌肥大/增生有关。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钙粘蛋白/β-catenin信号。中性粒细胞弹性蛋白酶抑制剂治疗减少FGF-2生产并抑制钙粘蛋白/β-catenin信号通路从而抑制平滑肌增生。
结论：在混合性过敏性炎症中IL-17/中性粒细胞轴通过促进平滑肌肥大/增生可能在气道重塑中发挥重要作用，并因此成为一个有吸引力的重症哮喘治疗靶点。这篇文章受版权保护。保留所有权利。
（复旦大学附属中山医院呼吸与危重症医学科 魏婷婷 摘译 毕晶 审校）
（Clin Exp Allergy. 2018 Sep 1.）
（Clin Exp Allergy. 2018 Sep 1.）
Neutrophils induce smooth muscle hyperplasia via neutrophil elastase-induced FGF-2 in a mouse model of asthma with mixed inflammation.
Ogawa H et al. Clin Exp Allergy. 2018 Sep 1.
Abstract
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 remodeling.
OBJECTIVE: To investigate the role of IL-17-derived neutrophils in airway remodeling 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 remodeling 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 signaling in bronchial epithelial cells. Neutrophil elastase inhibitor treatment decreased FGF-2 production and E-cadherin/β-catenin signaling, which inhibited smooth muscle hyperplasia.
CONCLUSION: The IL-17/neutrophil axis may play an important role in airway remodeling by contributing to smooth muscle hypertrophy/hyperplasia in mixed allergic inflammation, and accordingly represents an attractive therapeutic target for severe asthma. This article is protected by copyright. All rights reserved.
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妊娠期香烟烟雾的暴露与跨代效应：一项关于哮喘动物的综述
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年轻人与老年支气管哮喘个体的上呼吸道微生物群及其功能基因差异
