Iron deposition-induced ferroptosis in alveolar type II cells promotes the development of pulmonary fibrosis

https://doi.org/10.1016/j.bbadis.2021.166204Get rights and content
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Highlights

  • In this study, we found a functional link between BLM-induced large iron deposits in ATII cells and pulmonary fibrosis.

  • Iron deposition and ferroptosis in ATII cells may be involved in the pathogenesis of BLM-induced pulmonary fibrosis.

  • DFO reduces BLM-induced iron deposition, mitochondrial dysfunction, and ferroptosis in MLE-12 cells.

Abstract

Ferroptosis is a newly discovered type of regulated cell death, characterized by the iron-dependent accumulation of lipid reactive oxygen species, which has been implicated in numerous human diseases. However, its role in pulmonary fibrosis, a fatal lung disease with unknown etiology, is largely unknown. Here, we investigated the role of ferroptosis in pulmonary fibrosis. We found a large amount of iron deposition in the lung tissue of patients with pulmonary fibrosis. We observed ferroptosis in alveolar type II (ATII) cells, fibrotic lung tissues of BLM-induced pulmonary fibrosis mice. BLM-induced increase in iron level was accompanied by pathological changes, collagen deposition, and ferroptosis in ATII cells, indicating iron deposition-induced ferroptosis, which promoted the development of pulmonary fibrosis. Moreover, deferoxamine (DFO) completely prevented the pro-fibrosis effects of BLM by reducing iron deposition and ferroptosis in ATII cells. Genes associated with intracellular iron metabolism and homeostasis, such as transferrin receptor 1, divalent metal transporter 1, and ferroportin-1, and showed abnormal expression levels in animal tissues and lung epithelial MLE-12 cells, which responded to BLM stimulation. Overall, we demonstrated that BLM-induced iron deposition in MLE-12 cells is prone to both mitochondrial dysfunction and ferroptosis and that DFO reverses this phenotype. In the future, understanding the role of ferroptosis may shed new light on the etiology of pulmonary fibrosis. Ferroptosis inhibitors or genetic engineering of ferroptosis-related genes might offer potential targets to treat pulmonary fibrosis.

Abbreviations

ATII
alveolar type II
BLM
bleomycin
DFO
deferoxamine
ATI
alveolar type I
ROS
reactive oxygen species
DMT1
divalent metal transporter 1
GF-AAS
Graphite furnace atomic absorption spectrometry
TfR1
Transferrin receptor protein 1
FPN
ferroportin-1
SP-C
surfactant protein C
α-SMA
α-smooth muscle actin
GPX4
glutathione peroxidase 4
ACSL4
Acyl—CoA synthetase long-chain familymember 4
FSP1
Ferroptosis suppressor protein 1
IRP1
iron-binding proteins and mRNA-regulatory proteins 1
IRP2
iron-binding proteins and mRNA-regulatory proteins 2
ΔΨm/MMP
mitochondrial membrane potential
ECM
extracellular matrix
IHC
Immunohistochemistry
Fer-1
Ferrostatin-1
PUFA
polyunsaturated fatty acids
BH
Bleomycin hydrolase
NCOA4
Nuclear receptor coactivator 4
PHD1
prolyl hydroxylase 1
LOX
lipoxygenase
HSPB1
heat shock protein β-1
CISD1
CDGSH iron sulfur domain 1
PRDX6
peroxide reduction enzyme-6
IRP-IRE
Iron regulatory protein (IRP)-iron responsive element (IRE)

Keywords

Pulmonary fibrosis
Ferroptosis
Alveolar type II cells
Iron deposition
Deferoxamine

Cited by (0)

1

The first authors contributed to this work.

2

Ziqiang Luo and Chen Li contributed equally to this work.