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

Md Khadem Ali, Richard Y. Kim, Alexandra C. Brown, Chantal Donovan, Kanth S. Vanka, Jemma R. Mayall, Gang Liu, Amber L. Pillar, Bernadette Jones-Freeman, Dikaia Xenaki, Theo Borghuis, Rafia Karim, James W. Pinkerton, Ritambhara Aryal, Moones Heidari, Kristy L. Martin, Janette K. Burgess, Brian G. Oliver, Debbie Trinder, Daniel M. JohnstoneElizabeth A. Milward, Philip M. Hansbro, Jay C. Horvat

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)49-62
Number of pages14
JournalJournal of Pathology
Volume251
Issue number1
DOIs
Publication statusPublished - 1 May 2020

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