Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.

Autor:	Ali MK; Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA, USA.; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia., Kim RY; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, 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; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, 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.; Respiratory Pharmacology and Toxicology Group, National Heart and Lung Institute, Imperial College London, London, UK., Liu G; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, Australia., Martin KL; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia., Starkey MR; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.; Dept of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Australia., 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; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, Australia., Pathinayake PS; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Medicine and Public Health, 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; Medical School, Harry Perkins Medical Research Institute, University of Western Australia, Fiona Stanley Hospital, Perth, 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; Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK., Kermani NZ; Data Science Institute, Dept of Computing, Imperial College London, London, UK., Guo YK; Data Science Institute, Dept of Computing, Imperial College London, London, UK., Aryal R; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia., Mumby S; Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK., Pavlidis S; Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK., Adcock IM; Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK., Weaver J; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia., Xenaki D; Woolcock Institute of Medical Research, University of Sydney and School of Life Sciences, University of Technology Sydney, Sydney, Australia., Oliver BG; Woolcock Institute of Medical Research, University of Sydney and School of Life Sciences, University of Technology Sydney, Sydney, Australia., Holliday EG; Hunter Medical Research Institute, New Lambton, Australia.; School of Medicine and Public Health, University of Newcastle, Callaghan, Australia., Foster PS; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia., Wark PA; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.; Dept of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, Australia., Johnstone DM; Discipline of Physiology and Bosch Institute, University of Sydney, Sydney, Australia., Milward EA; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia., Hansbro PM; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, Australia.; These authors contributed equally., Horvat JC; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.; These authors contributed equally.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2020 Apr 23; Vol. 55 (4). Date of Electronic Publication: 2020 Apr 23 (Print Publication: 2020).
DOI:	10.1183/13993003.01340-2019
Abstrakt:	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 (FEV 1 ). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV 1 /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. Competing Interests: Conflict of interest: M.K. Ali has nothing to disclose. Conflict of interest: R.Y. Kim has nothing to disclose. Conflict of interest: A.C. Brown has nothing to disclose. Conflict of interest: J.R. Mayall has nothing to disclose. Conflict of interest: R. Karim has nothing to disclose. Conflict of interest: J.W. Pinkerton has nothing to disclose. Conflict of interest: G. Liu has nothing to disclose. Conflict of interest: K.L. Martin has nothing to disclose. Conflict of interest: M.R. Starkey has nothing to disclose. Conflict of interest: A.L. Pillar has nothing to disclose. Conflict of interest: C. Donovan has nothing to disclose. Conflict of interest: P.S. Pathinayake has nothing to disclose. Conflict of interest: O.R. Carroll has nothing to disclose. Conflict of interest: D. Trinder has nothing to disclose. Conflict of interest: H.L. Tay has nothing to disclose. Conflict of interest: Y.E. Badi has nothing to disclose. Conflict of interest: N.Z. Kermani has nothing to disclose. Conflict of interest: Y-K. Guo has nothing to disclose. Conflict of interest: R. Aryal has nothing to disclose. Conflict of interest: S. Mumby has nothing to disclose. Conflict of interest: S. Pavlidis has nothing to disclose. Conflict of interest: I.M. Adcock reports grants from EU-IMI, during the conduct of the study. Conflict of interest: J. Weaver has nothing to disclose. Conflict of interest: D. Xenaki has nothing to disclose. Conflict of interest: B.G. Oliver has nothing to disclose. Conflict of interest: E.G. Holliday has nothing to disclose. Conflict of interest: P.S. Foster has nothing to disclose. Conflict of interest: P.A. Wark has nothing to disclose. Conflict of interest: D.M. Johnstone has nothing to disclose. Conflict of interest: E.A. Milward has nothing to disclose. Conflict of interest: P.M. Hansbro has nothing to disclose. Conflict of interest: J.C. Horvat has nothing to disclose. (Copyright ©ERS 2020.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu