- Title
- Critical role for iron accumulation in the pathogenesis of fibrotic lung disease
- Creator
- Ali, Md Khadem; Kim, Richard Y.; Borghuis, Theo; Karim, Rafia; Pinkerton, James W.; Aryal, Ritambhara; Heidari, Moones; Martin, Kristy L.; Burgess, Janette K.; Oliver, Brian G.; Trinder, Debbie; Johnstone, Daniel M.; Brown, Alexandra C.; Milward, Elizabeth A.; Hansbro, Philip M.; Horvat, Jay C.; Donovan, Chantal; Vanka, Kanth S.; Mayall, Jemma R.; Liu, Gang; Pillar, Amber L.; Jones-Freeman, Bernadette; Xenaki, Dikaia
- Relation
- NHMRC.1020437 http://purl.org/au-research/grants/nhmrc/1020437
- Relation
- Journal of Pathology Vol. 251, Issue 1, p. 49-62
- Publisher Link
- http://dx.doi.org/10.1002/path.5401
- Publisher
- Wiley-Blackwell
- Resource Type
- journal article
- Date
- 2020
- Description
- 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.
- Subject
- iron; pulmonary fibrosis; airway remodeling; lung function; bleomycin; airway inflammation; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1440496
- Identifier
- uon:41157
- Identifier
- ISSN:0022-3417
- Rights
- This is the peer reviewed version of the following article: Ali, Md Khadem; Kim, Richard Y.; Borghuis, Theo; Karim, Rafia; Pinkerton, James W.; Aryal, Ritambhara; Heidari, Moones; Martin, Kristy L.; Burgess, Janette K.; Oliver, Brian G.; Trinder, Debbie; Johnstone, Daniel M.; Brown, Alexandra C.; Milward, Elizabeth A.; Hansbro, Philip M.; Horvat, Jay C.; Donovan, Chantal; Vanka, Kanth S.; Mayall, Jemma R.; Liu, Gang; Pillar, Amber L.; Jones-Freeman, Bernadette; Xenaki, Dikaia. “Critical role for iron accumulation in the pathogenesis of fibrotic lung disease”. Journal of Pathology Vol. 251, Issue 1, p. 49-62 (2020), which has been published in final form at http://dx.doi.org/10.1002/path.5401. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
- Language
- eng
- Full Text
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