哮喘中的嗜酸性粒细胞炎症及有缺陷的上皮细胞的翻译控制
2020/02/11
摘要
哮喘中性粒细胞性炎症与白细胞介素(IL)-17A、糖皮质激素敏感性和支气管扩张剂诱导的1 s用力呼气容积可逆性(FEV1)有关。IL-17A与肿瘤坏死因子(TNF) -α在由主支气管上皮细胞(PBECs)产生中性粒细胞趋化因子CXCL-8 的产物过程中有协同作用。我们提出局部中性粒细胞炎症哮喘与IL-17A和TNF-α诱导的由哮喘患者的PBECs生产的CXCL-8 的产物有关的假设。大多数哮喘患者的PBECs对TNF-α和IL-17A,表现出一种夸大CXCL-8产物的反应，但对单独的TNF-α无此效应,并也对糖皮质激素不敏感。PBECs的高反应性与相应患者支气管肺泡灌洗液中CXCL-8水平和中性粒细胞数量密切相关，而与嗜酸性粒细胞无相关性。此外，这种高反应性也与支气管扩张剂诱导的FEV1%的可逆性相关。在分子水平上，翻译抑制因子t细胞内抗原-1相关蛋白(TiAR)无法转移到细胞质中以停止CXCL-8的产生，这与上皮细胞高反应性有关，TiAR敲除证实了这一点。这与也产生其他高水平的炎症介质的发现一致。哮喘患者的高敏的PBECs可能是嗜中性粒细胞和皮质类固醇不敏感的炎症和FEV1降低的基础，而与嗜酸性炎症无关。在嗜中性粒细胞、皮质激素不敏感型哮喘中，TiAR的胞质转位正常化是一个潜在的治疗靶点。
Neutrophilic inflammation in asthma and defective epithelial translational control.
Ravi A et al. Eur Respir J. 2019 Aug 15.
Abstract
Neutrophilic inflammation in asthma is associated with interleukin (IL)-17A, corticosteroid-insensitivity and bronchodilator-induced forced expiratory volume in 1 s (FEV1) reversibility. IL-17A synergises with tumour necrosis factor (TNF)-α in the production of the neutrophil chemokine CXCL-8 by primary bronchial epithelial cells (PBECs).We hypothesised that local neutrophilic inflammation in asthma correlates with IL-17A and TNF-α-induced CXCL-8 production by PBECs from asthma patients.PBECs from most asthma patients displayed an exaggerated CXCL-8 production in response to TNF-α and IL-17A, but not to TNF-α alone, and which was also insensitive to corticosteroids. This hyperresponsiveness of PBECs strongly correlated with CXCL-8 levels and neutrophil numbers in bronchoalveolar lavage from the corresponding patients, but not with that of eosinophils. In addition, this hyperresponsiveness also correlated with bronchodilator-induced FEV1 % reversibility. At the molecular level, epithelial hyperresponsiveness was associated with failure of the translational repressor T-cell internal antigen-1 related protein (TiAR) to translocate to the cytoplasm to halt CXCL-8 production, as confirmed by TiAR knockdown. This is in line with the finding that hyperresponsive PBECs also produced enhanced levels of other inflammatory mediators.Hyperresponsive PBECs in asthma patients may underlie neutrophilic and corticosteroid-insensitive inflammation and a reduced FEV1, irrespective of eosinophilic inflammation. Normalising cytoplasmic translocation of TiAR is a potential therapeutic target in neutrophilic, corticosteroid-insensitive asthma.
哮喘中性粒细胞性炎症与白细胞介素(IL)-17A、糖皮质激素敏感性和支气管扩张剂诱导的1 s用力呼气容积可逆性(FEV1)有关。IL-17A与肿瘤坏死因子(TNF) -α在由主支气管上皮细胞(PBECs)产生中性粒细胞趋化因子CXCL-8 的产物过程中有协同作用。我们提出局部中性粒细胞炎症哮喘与IL-17A和TNF-α诱导的由哮喘患者的PBECs生产的CXCL-8 的产物有关的假设。大多数哮喘患者的PBECs对TNF-α和IL-17A,表现出一种夸大CXCL-8产物的反应，但对单独的TNF-α无此效应,并也对糖皮质激素不敏感。PBECs的高反应性与相应患者支气管肺泡灌洗液中CXCL-8水平和中性粒细胞数量密切相关，而与嗜酸性粒细胞无相关性。此外，这种高反应性也与支气管扩张剂诱导的FEV1%的可逆性相关。在分子水平上，翻译抑制因子t细胞内抗原-1相关蛋白(TiAR)无法转移到细胞质中以停止CXCL-8的产生，这与上皮细胞高反应性有关，TiAR敲除证实了这一点。这与也产生其他高水平的炎症介质的发现一致。哮喘患者的高敏的PBECs可能是嗜中性粒细胞和皮质类固醇不敏感的炎症和FEV1降低的基础，而与嗜酸性炎症无关。在嗜中性粒细胞、皮质激素不敏感型哮喘中，TiAR的胞质转位正常化是一个潜在的治疗靶点。
（中国医科大学附属第一医院 李文扬 摘译 杨冬 审校）
（Ravi A et al. Eur Respir J. 2019 Aug 15.）
（Ravi A et al. Eur Respir J. 2019 Aug 15.）
Neutrophilic inflammation in asthma and defective epithelial translational control.
Ravi A et al. Eur Respir J. 2019 Aug 15.
Abstract
Neutrophilic inflammation in asthma is associated with interleukin (IL)-17A, corticosteroid-insensitivity and bronchodilator-induced forced expiratory volume in 1 s (FEV1) reversibility. IL-17A synergises with tumour necrosis factor (TNF)-α in the production of the neutrophil chemokine CXCL-8 by primary bronchial epithelial cells (PBECs).We hypothesised that local neutrophilic inflammation in asthma correlates with IL-17A and TNF-α-induced CXCL-8 production by PBECs from asthma patients.PBECs from most asthma patients displayed an exaggerated CXCL-8 production in response to TNF-α and IL-17A, but not to TNF-α alone, and which was also insensitive to corticosteroids. This hyperresponsiveness of PBECs strongly correlated with CXCL-8 levels and neutrophil numbers in bronchoalveolar lavage from the corresponding patients, but not with that of eosinophils. In addition, this hyperresponsiveness also correlated with bronchodilator-induced FEV1 % reversibility. At the molecular level, epithelial hyperresponsiveness was associated with failure of the translational repressor T-cell internal antigen-1 related protein (TiAR) to translocate to the cytoplasm to halt CXCL-8 production, as confirmed by TiAR knockdown. This is in line with the finding that hyperresponsive PBECs also produced enhanced levels of other inflammatory mediators.Hyperresponsive PBECs in asthma patients may underlie neutrophilic and corticosteroid-insensitive inflammation and a reduced FEV1, irrespective of eosinophilic inflammation. Normalising cytoplasmic translocation of TiAR is a potential therapeutic target in neutrophilic, corticosteroid-insensitive asthma.
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