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

Md Khadem Ali; Richard Y. Kim; Alexandra C. Brown; Jemma R. Mayall; Rafia Karim; James W. Pinkerton; Gang Liu; Kristy L. Martin; Malcolm R. Starkey; Amber Pillar; Chantal Donovan; Prabuddha S. Pathinayake; Olivia R. Carroll; Debbie Trinder; Hock L. Tay; Yusef E. Badi; Nazanin Z. Kermani; Yi-Ke Guo; Ritambhara Aryal; Sharon Mumby; Stelios Pavlidis; Ian M. Adcock; Jessica Weaver; Dikaia Xenaki; Brian G. Oliver; Elizabeth G. Holliday; Paul S. Foster; Peter A. Wark; Daniel M. Johnstone; Elizabeth A. Milward; Philip M. Hansbro; Jay C. Horvat

doi:10.1183/13993003.01340-2019

This article has a correction. Please see:

“Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.” M.K. Ali, R.Y. Kim, A.C. Brown et al. Eur Respir J 2020; 55: 1901340. - September 01, 2022

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 (FEV1/FVC). 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, including airway hyper-responsiveness and fibrosis and T2 inflammatory responses, in vivo.

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.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Ali has nothing to disclose.

Conflict of interest: Dr. Kim has nothing to disclose.

Conflict of interest: Dr. Brown has nothing to disclose.

Conflict of interest: Dr. Mayall has nothing to disclose.

Conflict of interest: Dr. Karim has nothing to disclose.

Conflict of interest: Dr. Pinkerton has nothing to disclose.

Conflict of interest: Dr. Liu has nothing to disclose.

Conflict of interest: Dr. Martin has nothing to disclose.

Conflict of interest: Dr. Starkey has nothing to disclose.

Conflict of interest: Dr. Pillar has nothing to disclose.

Conflict of interest: Dr. Donovan has nothing to disclose.

Conflict of interest: Dr. Pathinayake has nothing to disclose.