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Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.
Ali, Md Khadem; Kim, Richard Y; Brown, Alexandra C; Mayall, Jemma R; Karim, Rafia; Pinkerton, James W; Liu, Gang; Martin, Kristy L; Starkey, Malcolm R; Pillar, Amber L; Donovan, Chantal; Pathinayake, Prabuddha S; Carroll, Olivia R; Trinder, Debbie; Tay, Hock L; Badi, Yusef E; Kermani, Nazanin Z; Guo, Yi-Ke; Aryal, Ritambhara; Mumby, Sharon; Pavlidis, Stelios; Adcock, Ian M; Weaver, Jessica; Xenaki, Dikaia; Oliver, Brian G; Holliday, Elizabeth G; Foster, Paul S; Wark, Peter A; Johnstone, Daniel M; Milward, Elizabeth A; Hansbro, Philip M; Horvat, Jay C.
Afiliação
  • Ali MK; Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA, USA.
  • Kim RY; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Brown AC; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Mayall JR; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, Australia.
  • Karim R; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Pinkerton JW; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Liu G; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Martin KL; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Starkey MR; Respiratory Pharmacology and Toxicology Group, National Heart and Lung Institute, Imperial College London, London, UK.
  • Pillar AL; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Donovan C; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, Australia.
  • Pathinayake PS; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Carroll OR; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Trinder D; Dept of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Australia.
  • Tay HL; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Badi YE; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Kermani NZ; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, Australia.
  • Guo YK; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.
  • Aryal R; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Mumby S; Medical School, Harry Perkins Medical Research Institute, University of Western Australia, Fiona Stanley Hospital, Perth, Australia.
  • Pavlidis S; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Adcock IM; Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
  • Weaver J; Data Science Institute, Dept of Computing, Imperial College London, London, UK.
  • Xenaki D; Data Science Institute, Dept of Computing, Imperial College London, London, UK.
  • Oliver BG; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Holliday EG; Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
  • Foster PS; Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
  • Wark PA; Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
  • Johnstone DM; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
  • Milward EA; Woolcock Institute of Medical Research, University of Sydney and School of Life Sciences, University of Technology Sydney, Sydney, Australia.
  • Hansbro PM; Woolcock Institute of Medical Research, University of Sydney and School of Life Sciences, University of Technology Sydney, Sydney, Australia.
  • Horvat JC; Hunter Medical Research Institute, New Lambton, Australia.
Eur Respir J ; 55(4)2020 04.
Article em En | MEDLINE | ID: mdl-32184317
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 (FVC) ratio. 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 in vivo, including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses.Together 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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Asma Tipo de estudo: Etiology_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Asma Tipo de estudo: Etiology_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article