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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1183/13993003.01340-2019
Journal or Publication Title: European Respiratory Journal
Volume: 55
Number: 4
Page Range: p. 1901340
Date: 2020
Divisions: UTS Centre for Inflammation
Depositing User: General Admin
Identification Number: 10.1183/13993003.01340-2019
ISSN: 0903-1936
Date Deposited: 04 Jan 2021 00:47
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.

Creators:
Creators
Email
Ali, Md. Khadem
UNSPECIFIED
Kim, Richard Y.
UNSPECIFIED
Brown, Alexandra C.
UNSPECIFIED
Mayall, Jemma R.
UNSPECIFIED
Karim, Rafia
UNSPECIFIED
Pinkerton, James W.
UNSPECIFIED
Liu, Gang
UNSPECIFIED
Martin, Kristy L.
UNSPECIFIED
Starkey, Malcolm R.
UNSPECIFIED
Pillar, Amber L.
UNSPECIFIED
Donovan, Chantal
UNSPECIFIED
Pathinayake, Prabuddha S.
UNSPECIFIED
Carroll, Olivia R.
UNSPECIFIED
Trinder, Debbie
UNSPECIFIED
Tay, Hock L.
UNSPECIFIED
Badi, Yusef E.
UNSPECIFIED
Kermani, Nazanin Z.
UNSPECIFIED
Guo, Yi-Ke
UNSPECIFIED
Aryal, Ritambhara
UNSPECIFIED
Mumby, Sharon
UNSPECIFIED
Pavlidis, Stelios
UNSPECIFIED
Adcock, Ian M.
UNSPECIFIED
Weaver, Jessica
UNSPECIFIED
Xenaki, Dikaia
UNSPECIFIED
Oliver, Brian G.
UNSPECIFIED
Holliday, Elizabeth G.
UNSPECIFIED
Foster, Paul S.
UNSPECIFIED
Wark, Peter A.
UNSPECIFIED
Johnstone, Daniel M.
UNSPECIFIED
Milward, Elizabeth A.
UNSPECIFIED
Hansbro, Philip M.
UNSPECIFIED
Horvat, Jay C.
UNSPECIFIED
Last Modified: 04 Jan 2021 00:47
URI: https://eprints.centenary.org.au/id/eprint/799

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