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

Ali, MK; Kim, RY; Brown, AC; Mayall, JR; Karim, R; Pinkerton, JW; Liu, G; Martin, KL; Starkey, MR; Pillar, AL; Donovan, C; Pathinayake, PS; Carroll, OR; Trinder, D; Tay, HL; Badi, YE; Kermani, NZ; Guo, Y-K; Aryal, R; Mumby, S; Pavlidis, S; Adcock, IM; Weaver, J; Xenaki, D; Oliver, BG; Holliday, EG; Foster, PS; Wark, PA; Johnstone, DM; Milward, EA; Hansbro, PM; Horvat, JC

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

Ali, MK Kim, RY Brown, AC Mayall, JR Karim, R Pinkerton, JW Liu, G

Martin, KL Starkey, MR Pillar, AL Donovan, C

Pathinayake, PS Carroll, OR Trinder, D Tay, HL Badi, YE Kermani, NZ Guo, Y-K Aryal, R Mumby, S Pavlidis, S Adcock, IM Weaver, J Xenaki, D Oliver, BG Holliday, EG Foster, PS Wark, PA Johnstone, DM Milward, EA Hansbro, PM Horvat, JC

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Publisher:: EUROPEAN RESPIRATORY SOC JOURNALS LTD
Publication Type:: Journal Article
Citation:: The European respiratory journal, 2020, 55, (4)
Issue Date:: 2020-04-23

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Field	Value	Language
dc.contributor.author	Ali, MK
dc.contributor.author	Kim, RY
dc.contributor.author	Brown, AC
dc.contributor.author	Mayall, JR
dc.contributor.author	Karim, R
dc.contributor.author	Pinkerton, JW
dc.contributor.author	Liu, G https://orcid.org/0000-0002-0489-2638
dc.contributor.author	Martin, KL
dc.contributor.author	Starkey, MR
dc.contributor.author	Pillar, AL
dc.contributor.author	Donovan, C https://orcid.org/0000-0003-4558-329X
dc.contributor.author	Pathinayake, PS
dc.contributor.author	Carroll, OR
dc.contributor.author	Trinder, D
dc.contributor.author	Tay, HL
dc.contributor.author	Badi, YE
dc.contributor.author	Kermani, NZ
dc.contributor.author	Guo, Y-K
dc.contributor.author	Aryal, R
dc.contributor.author	Mumby, S
dc.contributor.author	Pavlidis, S
dc.contributor.author	Adcock, IM
dc.contributor.author	Weaver, J
dc.contributor.author	Xenaki, D
dc.contributor.author	Oliver, BG
dc.contributor.author	Holliday, EG
dc.contributor.author	Foster, PS
dc.contributor.author	Wark, PA
dc.contributor.author	Johnstone, DM
dc.contributor.author	Milward, EA
dc.contributor.author	Hansbro, PM
dc.contributor.author	Horvat, JC
dc.date.accessioned	2020-12-22T23:34:48Z
dc.date.available	2020-01-28
dc.date.available	2020-12-22T23:34:48Z
dc.date.issued	2020-04-23
dc.identifier.citation	The European respiratory journal, 2020, 55, (4)
dc.identifier.issn	0903-1936
dc.identifier.issn	1399-3003
dc.identifier.uri	http://hdl.handle.net/10453/144928
dc.description.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 (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.
dc.format	Electronic-Print
dc.language	eng
dc.publisher	EUROPEAN RESPIRATORY SOC JOURNALS LTD
dc.relation.ispartof	The European respiratory journal
dc.relation.isbasedon	10.1183/13993003.01340-2019
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	11 Medical and Health Sciences, 1116 Medical Physiology
dc.subject.classification	Respiratory System
dc.title	Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.
dc.type	Journal Article
utslib.citation.volume	55
utslib.location.activity	England
utslib.for	11 Medical and Health Sciences
utslib.for	1116 Medical Physiology
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access	*
dc.date.updated	2020-12-22T23:34:33Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	55
utslib.citation.issue	4

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 (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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/144928