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 1

AT2 dysfunction in the lung.

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AT2 dysfunction in the lung. A schematic overview of the main interactio...
A schematic overview of the main interactions and signaling pathways involved in AT2 self-renewal, proliferation, and differentiation into AT1 cells. In a self-renewing state, WNT canonical and FGFR/AKT pathways primarily maintain AT2 identity and function. During differentiation, AT2 cell transition is marked by Krt8+ cells (also called damage-associated transient progenitor [DATP] cells). In this state, metabolic changes occur, along with integrated stress responses (ISR) and increased Notch signaling. Activation of YAP/Taz signaling promotes differentiation, and the secretion of TGF-β and IL-1β from AT2 cells in specific contexts can interact with macrophages and fibroblasts to produce factors, such as FGF7 and FGF10, that support AT2 identity. Macrophages release cytokines, such as IL-1β and TNF-α, to enhance AT2 cell proliferation and differentiation. Disruptions in the alveolar epithelial repair process can cause pathological outcomes, including bronchiolization of the alveoli, immune infiltration, increased barrier permeability, failed repair and regeneration, and the development of senescence and fibrosis within the alveolar space. Created in BioRender.