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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1002/path.5401
Journal or Publication Title: The Journal of Pathology
Volume: 251
Number: 1
Page Range: pp. 49-62
Date: 2020
Divisions: UTS Centre for Inflammation
Depositing User: General Admin
Identification Number: 10.1002/path.5401
ISSN: 0022-3417
Date Deposited: 04 Jan 2021 04:03
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.

Creators:
Creators
Email
Ali, Md Khadem
UNSPECIFIED
Kim, Richard Y
UNSPECIFIED
Brown, Alexandra C
UNSPECIFIED
Donovan, Chantal
UNSPECIFIED
Vanka, Kanth S
UNSPECIFIED
Mayall, Jemma R
UNSPECIFIED
Liu, Gang
UNSPECIFIED
Pillar, Amber L
UNSPECIFIED
Jones‐Freeman, Bernadette
UNSPECIFIED
Xenaki, Dikaia
UNSPECIFIED
Borghuis, Theo
UNSPECIFIED
Karim, Rafia
UNSPECIFIED
Pinkerton, James W
UNSPECIFIED
Aryal, Ritambhara
UNSPECIFIED
Heidari, Moones
UNSPECIFIED
Martin, Kristy L
UNSPECIFIED
Burgess, Janette K
UNSPECIFIED
Oliver, Brian G
UNSPECIFIED
Trinder, Debbie
UNSPECIFIED
Johnstone, Daniel M
UNSPECIFIED
Milward, Elizabeth A
UNSPECIFIED
Hansbro, Philip M
UNSPECIFIED
Horvat, Jay C
UNSPECIFIED
Last Modified: 04 Jan 2021 04:03
URI: https://eprints.centenary.org.au/id/eprint/729

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