DEL-1作为一种抗中性粒细胞跨上皮迁移分子，可抑制哮喘患者的气道中性粒细胞炎症
2023/09/21
摘要
背景：中性粒细胞迁移到气道是中性粒细胞哮喘的关键过程。发育性内皮细胞-1（DEL-1）是一种细胞外基质蛋白，是一种中性粒细胞粘附抑制剂，可减轻中性粒细胞炎症。
方法：采用ELISA法测定哮喘患者呼出气冷凝液（EBC）和血清中DEL-1的含量。在体外共培养模型中检测DEL-1对中性粒细胞粘附和跨上皮迁移的调节。在小鼠体内研究了DEL-1腺病毒载体介导的过表达对卵清蛋白/脂多糖（OVA/LPS）诱导的中性粒细胞哮喘的影响。
结果：DEL-1主要在人支气管上皮细胞中表达，在哮喘患者中表达减少。与正常受试者相比，重症哮喘患者的血清DEL-1浓度降低（567.1±75.3 vs.276.8±29.36 pg/mL，p<.001），并且与血液中性粒细胞（r=-0.2881，p=.0384）和中性粒细胞与淋巴细胞比率（NLR）呈负相关（r=-0.5469，p<.0001）。重症哮喘患者EBC中的DEL-1浓度（113.2±8.09 pg/mL）也低于正常受试者（193.0±7.61 pg/mL，p<.001），与哮喘患者的哮喘控制试验（ACT）评分呈正相关（r=0.3678，p=.0035），与EBC IL-17（r=-0.3756，p=.0131）、髓过氧化物酶（MPO）（r=-0.5967，p=.0055）和中性粒细胞弹性蛋白酶（NE）（r=-0.5488，p=.0009）表达呈负相关。哮喘患者的中性粒细胞粘附和跨上皮迁移与LFA-1与ICAM-1的结合有关，并被DEL-1抑制。DEL-1 mRNA和人支气管上皮细胞中DEL-1mRNA和蛋白的表达受IL-17的调节。外源性DEL-1抑制IL-17增强的中性粒细胞粘附和迁移。中性粒细胞哮喘小鼠模型的气道中DEL-1表达降低，而中性粒细胞浸润增加。这是通过DEL-1过表达来阻止的。
结论：DEL-1下调导致中性粒细胞在支气管上皮细胞中迁移增加，并与哮喘中性粒细胞气道炎症有关。
DEL-1, as an anti-neutrophil transepithelial migration molecule, inhibits airway neutrophilic inflammation in asthma
Man Jia, Heng Fu, Xinyu Jiang, Lina Wang, Jiayan Xu, Peter J Barnes, Ian M Adcock, Yi Liu, Shujuan He, Fan Zhang, Lei Yao, Peng Sun, Xin Yao
Abstract
Background: Neutrophil migration into the airways is a key process in neutrophilic asthma. Developmental endothelial locus-1 (DEL-1), an extracellular matrix protein, is a neutrophil adhesion inhibitor that attenuates neutrophilic inflammation.
Methods: Levels of DEL-1 were measured in exhaled breath condensate (EBC) and serum in asthma patients by ELISA. DEL-1 modulation of neutrophil adhesion and transepithelial migration was examined in a co-culture model in vitro. The effects of DEL-1-adenoviral vector-mediated overexpression on ovalbumin/lipopolysaccharide (OVA/LPS)-induced neutrophilic asthma were studied in mice in vivo.
Results: DEL-1 was primarily expressed in human bronchial epithelial cells and was decreased in asthma patients. Serum DEL-1 concentrations were reduced in patients with severe asthma compared with normal subjects (567.1 ± 75.3 vs. 276.8 ± 29.36 pg/mL, p < .001) and were negatively correlated to blood neutrophils (r = -0.2881, p = .0384) and neutrophil-to-lymphocyte ratio (NLR) (r = -0.5469, p < .0001). DEL-1 concentrations in the EBC of severe asthmatic patients (113.2 ± 8.09 pg/mL) were also lower than normal subjects (193.0 ± 7.61 pg/mL, p < .001) and were positively correlated with the asthma control test (ACT) score (r = 0.3678, p = .0035) and negatively related to EBC IL-17 (r = -0.3756, p = .0131), myeloperoxidase (MPO) (r = -0.5967, p = .0055), and neutrophil elastase (NE) (r = -0.5488, p = .0009) expression in asthma patients. Neutrophil adhesion and transepithelial migration in asthma patients were associated with LFA-1 binding to ICAM-1 and inhibited by DEL-1. DEL-1 mRNA and protein expression in human bronchial epithelial cells were regulated by IL-17. Exogenous DEL-1 inhibited IL-17-enhanced neutrophil adhesion and migration. DEL-1 expression was decreased while neutrophil infiltration was increased in the airway of a murine model of neutrophilic asthma. This was prevented by DEL-1 overexpression.
Conclusions: DEL-1 down-regulation leads to increased neutrophil migration across bronchial epithelial cells and is associated with neutrophilic airway inflammation in asthma.
背景：中性粒细胞迁移到气道是中性粒细胞哮喘的关键过程。发育性内皮细胞-1（DEL-1）是一种细胞外基质蛋白，是一种中性粒细胞粘附抑制剂，可减轻中性粒细胞炎症。
方法：采用ELISA法测定哮喘患者呼出气冷凝液（EBC）和血清中DEL-1的含量。在体外共培养模型中检测DEL-1对中性粒细胞粘附和跨上皮迁移的调节。在小鼠体内研究了DEL-1腺病毒载体介导的过表达对卵清蛋白/脂多糖（OVA/LPS）诱导的中性粒细胞哮喘的影响。
结果：DEL-1主要在人支气管上皮细胞中表达，在哮喘患者中表达减少。与正常受试者相比，重症哮喘患者的血清DEL-1浓度降低（567.1±75.3 vs.276.8±29.36 pg/mL，p<.001），并且与血液中性粒细胞（r=-0.2881，p=.0384）和中性粒细胞与淋巴细胞比率（NLR）呈负相关（r=-0.5469，p<.0001）。重症哮喘患者EBC中的DEL-1浓度（113.2±8.09 pg/mL）也低于正常受试者（193.0±7.61 pg/mL，p<.001），与哮喘患者的哮喘控制试验（ACT）评分呈正相关（r=0.3678，p=.0035），与EBC IL-17（r=-0.3756，p=.0131）、髓过氧化物酶（MPO）（r=-0.5967，p=.0055）和中性粒细胞弹性蛋白酶（NE）（r=-0.5488，p=.0009）表达呈负相关。哮喘患者的中性粒细胞粘附和跨上皮迁移与LFA-1与ICAM-1的结合有关，并被DEL-1抑制。DEL-1 mRNA和人支气管上皮细胞中DEL-1mRNA和蛋白的表达受IL-17的调节。外源性DEL-1抑制IL-17增强的中性粒细胞粘附和迁移。中性粒细胞哮喘小鼠模型的气道中DEL-1表达降低，而中性粒细胞浸润增加。这是通过DEL-1过表达来阻止的。
结论：DEL-1下调导致中性粒细胞在支气管上皮细胞中迁移增加，并与哮喘中性粒细胞气道炎症有关。
(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)
(Allergy 2023 Sep 8. doi: 10.1111/all.15882.)
(Allergy 2023 Sep 8. doi: 10.1111/all.15882.)
DEL-1, as an anti-neutrophil transepithelial migration molecule, inhibits airway neutrophilic inflammation in asthma
Man Jia, Heng Fu, Xinyu Jiang, Lina Wang, Jiayan Xu, Peter J Barnes, Ian M Adcock, Yi Liu, Shujuan He, Fan Zhang, Lei Yao, Peng Sun, Xin Yao
Abstract
Background: Neutrophil migration into the airways is a key process in neutrophilic asthma. Developmental endothelial locus-1 (DEL-1), an extracellular matrix protein, is a neutrophil adhesion inhibitor that attenuates neutrophilic inflammation.
Methods: Levels of DEL-1 were measured in exhaled breath condensate (EBC) and serum in asthma patients by ELISA. DEL-1 modulation of neutrophil adhesion and transepithelial migration was examined in a co-culture model in vitro. The effects of DEL-1-adenoviral vector-mediated overexpression on ovalbumin/lipopolysaccharide (OVA/LPS)-induced neutrophilic asthma were studied in mice in vivo.
Results: DEL-1 was primarily expressed in human bronchial epithelial cells and was decreased in asthma patients. Serum DEL-1 concentrations were reduced in patients with severe asthma compared with normal subjects (567.1 ± 75.3 vs. 276.8 ± 29.36 pg/mL, p < .001) and were negatively correlated to blood neutrophils (r = -0.2881, p = .0384) and neutrophil-to-lymphocyte ratio (NLR) (r = -0.5469, p < .0001). DEL-1 concentrations in the EBC of severe asthmatic patients (113.2 ± 8.09 pg/mL) were also lower than normal subjects (193.0 ± 7.61 pg/mL, p < .001) and were positively correlated with the asthma control test (ACT) score (r = 0.3678, p = .0035) and negatively related to EBC IL-17 (r = -0.3756, p = .0131), myeloperoxidase (MPO) (r = -0.5967, p = .0055), and neutrophil elastase (NE) (r = -0.5488, p = .0009) expression in asthma patients. Neutrophil adhesion and transepithelial migration in asthma patients were associated with LFA-1 binding to ICAM-1 and inhibited by DEL-1. DEL-1 mRNA and protein expression in human bronchial epithelial cells were regulated by IL-17. Exogenous DEL-1 inhibited IL-17-enhanced neutrophil adhesion and migration. DEL-1 expression was decreased while neutrophil infiltration was increased in the airway of a murine model of neutrophilic asthma. This was prevented by DEL-1 overexpression.
Conclusions: DEL-1 down-regulation leads to increased neutrophil migration across bronchial epithelial cells and is associated with neutrophilic airway inflammation in asthma.
上一篇：
B细胞衍生的IL-10促进Bcl-3调节的哮喘过敏性增敏
下一篇：
循环CC16与支气管哮喘：一项从童年早期到成人期间基于人群、多中心研究
