肺铁水平和调节在哮喘的发病机制和严重程度中的关键作用
2020/04/07
摘要
越来越多的证据强调了铁调节与呼吸系统疾病之间的关系。因此我们评估了临床和实验哮喘中铁水平与调节反应之间的关系。结果显示重度或轻中度哮喘患者的支气管肺泡灌洗（BAL）上清液中的无铁细胞水平降低，并且与较低的一秒用力肺活量相关（FEV1）。相反，这些患者的BAL中载铁细胞数量增加并且与较低的FEV1 /用力肺活量（FEV1 / FVC）相关。在哮喘中，铁螯合分子二价金属转运蛋白1（DMT1）和转铁蛋白受体1（TFR1）的气道组织表达增加，其中TFR1表达与肺功能降低和气道中2型（T2）炎症反应增加有关。此外，与人类疾病类似，在屋尘螨（HDM）诱导的实验性哮喘模型中，肺铁水平升高与气道组织中Tfr1表达增加有关。我们发现巨噬细胞是增加Tfr1的主要来源，Tfr1+巨噬细胞增加了Il13的表达。我们还发现铁水平升高会导致离体人气道平滑肌（ASM）细胞和成纤维细胞中促炎性细胞因子和/或细胞外基质（ECM）反应增加，并诱发哮喘的关键特征，包括气道高反应性和纤维化以及体内T2炎症反应。这些相互补充的临床和实验数据共同强调了改变肺铁水平和调节在哮喘中的重要性，以及需要更多地关注铁在疾病发病机制和严重程度中的作用和潜在的治疗靶点。
Crucial Role for Lung Iron Level and Regulation in the Pathogenesis and Severity of Asthma.
Md Khadem Ali, Richard Y Kim, Alexandra C Brown, Jemma R Mayall, Rafia Karim, James W Pinkerton, Gang Liu, Kristy L Martin, Malcolm R Starkey, Amber Pillar, Chantal Donovan, Prabuddha S Pathinayake, Olivia R Carroll, Debbie Trinder, Hock L Tay, Yusef E Badi, Nazanin Z Kermani, Yi-Ke Guo, Ritambhara Aryal, Sharon Mumby, Stelios Pavlidis, Ian M Adcock, Jessica Weaver, Dikaia Xenaki, Brian G Oliver, Elizabeth G Holliday, Paul S Foster, Peter A Wark, Daniel M Johnstone, Elizabeth A Milward, Philip M Hansbro, Jay C Horvat.
Abstract
Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FEV1/FVC). The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma with TFR1 expression correlating with reduced lung function and increased type 2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma, including airway hyper-responsiveness and fibrosis and T2 inflammatory responses, in vivoTogether these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.
越来越多的证据强调了铁调节与呼吸系统疾病之间的关系。因此我们评估了临床和实验哮喘中铁水平与调节反应之间的关系。结果显示重度或轻中度哮喘患者的支气管肺泡灌洗（BAL）上清液中的无铁细胞水平降低，并且与较低的一秒用力肺活量相关（FEV1）。相反，这些患者的BAL中载铁细胞数量增加并且与较低的FEV1 /用力肺活量（FEV1 / FVC）相关。在哮喘中，铁螯合分子二价金属转运蛋白1（DMT1）和转铁蛋白受体1（TFR1）的气道组织表达增加，其中TFR1表达与肺功能降低和气道中2型（T2）炎症反应增加有关。此外，与人类疾病类似，在屋尘螨（HDM）诱导的实验性哮喘模型中，肺铁水平升高与气道组织中Tfr1表达增加有关。我们发现巨噬细胞是增加Tfr1的主要来源，Tfr1+巨噬细胞增加了Il13的表达。我们还发现铁水平升高会导致离体人气道平滑肌（ASM）细胞和成纤维细胞中促炎性细胞因子和/或细胞外基质（ECM）反应增加，并诱发哮喘的关键特征，包括气道高反应性和纤维化以及体内T2炎症反应。这些相互补充的临床和实验数据共同强调了改变肺铁水平和调节在哮喘中的重要性，以及需要更多地关注铁在疾病发病机制和严重程度中的作用和潜在的治疗靶点。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校 )
(Eur Respir J (IF: 11.807)2020 Mar 17. PMID: 32184317 DOI: 10.1183/13993003.01340-2019.)
(Eur Respir J (IF: 11.807)2020 Mar 17. PMID: 32184317 DOI: 10.1183/13993003.01340-2019.)
Crucial Role for Lung Iron Level and Regulation in the Pathogenesis and Severity of Asthma.
Md Khadem Ali, Richard Y Kim, Alexandra C Brown, Jemma R Mayall, Rafia Karim, James W Pinkerton, Gang Liu, Kristy L Martin, Malcolm R Starkey, Amber Pillar, Chantal Donovan, Prabuddha S Pathinayake, Olivia R Carroll, Debbie Trinder, Hock L Tay, Yusef E Badi, Nazanin Z Kermani, Yi-Ke Guo, Ritambhara Aryal, Sharon Mumby, Stelios Pavlidis, Ian M Adcock, Jessica Weaver, Dikaia Xenaki, Brian G Oliver, Elizabeth G Holliday, Paul S Foster, Peter A Wark, Daniel M Johnstone, Elizabeth A Milward, Philip M Hansbro, Jay C Horvat.
Abstract
Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FEV1/FVC). The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma with TFR1 expression correlating with reduced lung function and increased type 2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma, including airway hyper-responsiveness and fibrosis and T2 inflammatory responses, in vivoTogether these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.
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过敏性气道反应时肺部造血细胞外RNAs和囊泡的增加
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减少抗生素使用、肠道微生物群和儿童哮喘发病率的关系：基于人群和前瞻性队列研究的证据
