Critical role for iron accumulation in the pathogenesis of fibrotic lung disease.

Ali, MK; Kim, RY; Brown, AC; Donovan, C; Vanka, KS; Mayall, JR; Liu, G; Pillar, AL; Jones-Freeman, B; Xenaki, D; Borghuis, T; Karim, R; Pinkerton, JW; Aryal, R; Heidari, M; Martin, KL; Burgess, JK; Oliver, BG; Trinder, D; Johnstone, DM; Milward, EA; Hansbro, PM; Horvat, JC

Critical role for iron accumulation in the pathogenesis of fibrotic lung disease.

Ali, MK Kim, RY Brown, AC Donovan, C

Vanka, KS Mayall, JR Liu, G

Pillar, AL Jones-Freeman, B Xenaki, D Borghuis, T Karim, R Pinkerton, JW Aryal, R Heidari, M Martin, KL Burgess, JK Oliver, BG Trinder, D Johnstone, DM Milward, EA Hansbro, PM Horvat, JC

Permalink

Publisher:: WILEY
Publication Type:: Journal Article
Citation:: The Journal of pathology, 2020, 251, (1), pp. 49-62
Issue Date:: 2020-05

Closed Access

	Filename	Description	Size
	path.5401.pdf	Published version	24.33 MB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Ali, MK
dc.contributor.author	Kim, RY
dc.contributor.author	Brown, AC
dc.contributor.author	Donovan, C https://orcid.org/0000-0003-4558-329X
dc.contributor.author	Vanka, KS
dc.contributor.author	Mayall, JR
dc.contributor.author	Liu, G https://orcid.org/0000-0002-0489-2638
dc.contributor.author	Pillar, AL
dc.contributor.author	Jones-Freeman, B
dc.contributor.author	Xenaki, D
dc.contributor.author	Borghuis, T
dc.contributor.author	Karim, R
dc.contributor.author	Pinkerton, JW
dc.contributor.author	Aryal, R
dc.contributor.author	Heidari, M
dc.contributor.author	Martin, KL
dc.contributor.author	Burgess, JK
dc.contributor.author	Oliver, BG
dc.contributor.author	Trinder, D
dc.contributor.author	Johnstone, DM
dc.contributor.author	Milward, EA
dc.contributor.author	Hansbro, PM
dc.contributor.author	Horvat, JC
dc.date.accessioned	2020-11-16T04:09:49Z
dc.date.available	2020-02-13
dc.date.available	2020-11-16T04:09:49Z
dc.date.issued	2020-05
dc.identifier.citation	The Journal of pathology, 2020, 251, (1), pp. 49-62
dc.identifier.issn	0022-3417
dc.identifier.issn	1096-9896
dc.identifier.uri	http://hdl.handle.net/10453/144052
dc.description.abstract	Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1+ macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	WILEY
dc.relation	http://purl.org/au-research/grants/nhmrc/APP1026880
dc.relation	http://purl.org/au-research/grants/nhmrc/APP1110368
dc.relation	http://purl.org/au-research/grants/nhmrc/1026880
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1110368
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1079187
dc.relation.ispartof	The Journal of pathology
dc.relation.isbasedon	10.1002/path.5401
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject	1103 Clinical Sciences
dc.subject.classification	Pathology
dc.subject.mesh	Lung
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Extracellular Matrix
dc.subject.mesh	Fibroblasts
dc.subject.mesh	Macrophages
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Humans
dc.subject.mesh	Iron
dc.subject.mesh	Bleomycin
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Idiopathic Pulmonary Fibrosis
dc.subject.mesh	Airway Remodeling
dc.subject.mesh	Lung
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Extracellular Matrix
dc.subject.mesh	Fibroblasts
dc.subject.mesh	Macrophages
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Humans
dc.subject.mesh	Iron
dc.subject.mesh	Bleomycin
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Idiopathic Pulmonary Fibrosis
dc.subject.mesh	Airway Remodeling
dc.subject.mesh	Airway Remodeling
dc.subject.mesh	Animals
dc.subject.mesh	Bleomycin
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Extracellular Matrix
dc.subject.mesh	Fibroblasts
dc.subject.mesh	Humans
dc.subject.mesh	Idiopathic Pulmonary Fibrosis
dc.subject.mesh	Iron
dc.subject.mesh	Lung
dc.subject.mesh	Macrophages
dc.subject.mesh	Mice, Knockout
dc.title	Critical role for iron accumulation in the pathogenesis of fibrotic lung disease.
dc.type	Journal Article
utslib.citation.volume	251
utslib.location.activity	England
utslib.for	1103 Clinical Sciences
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2020-11-16T04:09:30Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	251
utslib.citation.issue	1

Abstract:

Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1+ macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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

http://hdl.handle.net/10453/144052