A new study has assessed the role of iron overload and ferroptosis in the pathogenesis of idiopathic pulmonary fibrosis (IPF).

The study, published in Redox Biology, observed that iron accumulation and ferroptosis lead to fibroblast activation in IPF, and that ferroptosis inhibitors could be an effective treatment approach.

“Both lipid peroxidation accumulation and iron overload are observed during the progress of bleomycin-induced pulmonary fibrosis,” the authors wrote. “In an early inflammatory phase, bleomycin and lipopolysaccharide [LPS] directly induce ferroptosis in lung epithelial cells, while the ferroptosis inhibitor displays significant resolution for bleomycin- and LPS-induced cell death of type II alveolar epithelial [ATII] cells and lung injury.”


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The research team isolated and cultured primary lung fibroblasts from wild-type C57 mice and induced iron overload and ferroptosis in additional mice using bleomycin and LPS. The resulting epithelial damage was consistent with the early inflammatory stage of pulmonary fibrosis. The authors speculate that the underlying mechanism involves the promotion of fibroblast-to-myofibroblast transformation late in the fibrotic process.

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They then observed that treatment with liproxstatin-1 inhibited the accumulation of lipid peroxides and ameliorated bleomycin- and LPS-induced ferroptosis and the subsequent development of fibrosis in the mice. Furthermore, the iron chelator deferoxamine inhibited fibroblast activation and reduced collagen deposition in the mice with bleomycin-induced fibrosis.

The authors attribute these effects to the prevention of iron accumulation in both the early inflammatory phase and the fibrotic phase, indicating both ferroptosis and iron homeostasis are essentially involved in the onset and progression of pulmonary fibrosis.

The evidence obtained suggests that treatment strategies that target ferroptosis and disorders of iron homeostasis could be effective in diseases associated with iron overload, including pulmonary fibrosis.  

Reference

Pei Z, Qin Y, Fu X, et al. Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model. Redox Biol. Published online November 2022. doi:10.1016/j.redox.2022.102509