A double-edged sword: iron regulation in alveolar lung epithelial repair
Ugonna Mbaekwe, Sarah Kenny, Suzanne M. Cloonan, Corrine R. Kliment
Ugonna Mbaekwe, Sarah Kenny, Suzanne M. Cloonan, Corrine R. Kliment
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Review

A double-edged sword: iron regulation in alveolar lung epithelial repair

Abstract

The oxygen-rich milieu of the lungs necessitates precise iron homeostasis and regulation, processes that are fundamental to pulmonary physiology but often receive limited attention. However, in recent years, dysregulation of iron homeostasis has been linked to numerous acute and chronic respiratory diseases. Here, we comprehensively evaluate the mechanisms governing iron homeostasis in the alveolar epithelium of the lung and examine how iron dysregulation contributes to impaired alveolar epithelial repair in respiratory disease. This Review focuses on the effects of iron on alveolar epithelial cell homeostasis and repair and disease pathogenesis. There will be a focus on emerging interventions designed to reestablish iron homeostasis and their potential therapeutic implications related to enhancing lung repair and limiting the progression of lung disease.

Authors

Ugonna Mbaekwe, Sarah Kenny, Suzanne M. Cloonan, Corrine R. Kliment

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Figure 2

General iron homeostasis.

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General iron homeostasis. A schematic diagram showing systemic (top) and...
A schematic diagram showing systemic (top) and cellular iron regulation (bottom). Systemic iron control involves various organs managing absorption, recycling, and distribution to keep levels balanced. In mammals, iron is mainly absorbed in the duodenum as both heme and nonheme iron and then transported across cell membranes and transferred in the blood to other tissues. Macrophages and hepatocytes are vital for recycling iron from red blood cells and adjusting systemic iron levels. Cellular iron regulation includes controlling iron import, export, storage, and use. Low oxygen levels and iron deficiency activate transcription factors and regulatory proteins to boost iron absorption, while iron overload triggers protective pathways to sequester, detoxify, and maintain balance. The key proteins discussed in this Review are shown at the bottom of the figure, including heme carrier protein 1 (HCP1), heme-oxygenase 1 (HMOX1), duodenal cytochrome B (DCYTB), divalent metal transporter 1 (DMT1), ferroportin (FPN), ceruloplasmin (CP), hephaestin (HEPH), transferrin receptor 1 (TfR1), lipocalin (LCN2), poly(rC)-binding protein 1 (PCBP1), mitoferrin-1 and mitoferrin-2 (MFRN1/2), leukemia virus subgroup C cellular receptor 1 (FLVCR1), hypoxia-inducible factor 2 α (HIF2α), hypoxia response element (HRE), iron-sensing E3 ligase (FBXL5), iron regulatory proteins (IRP), nuclear receptor coactivator 4 (NCOA4), and nuclear factor erythroid 2–related factor 2 (NRF2). Created in BioRender.