Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1+ macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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铁积累在纤维化肺病发病机理中的关键作用。

在几种肺部疾病中，铁水平升高和铁稳态失调或两者兼而有之。在这里，使用铁超负荷和博来霉素诱导的肺纤维化的鼠模型，用铁治疗的原代人肺成纤维细胞以及来自患有肝炎的患者的组织学样本，研究了铁蓄积对肺纤维化发病机理和相关肺功能下降的影响。或无特发性肺纤维化（IPF）。铁超载转铁蛋白受体2（Tfr2）突变小鼠和体内稳态铁调节剂（Hfe）基因缺陷小鼠中的铁水平显着增加，这与气道纤维化增加和肺功能降低有关。此外，在博来霉素诱导的肺纤维化中，纤维化和肺功能下降与肺铁积累有关。此外，我们显示IPF患者的肺切片中铁的积累增加，并且人肺成纤维细胞暴露于铁水平升高时显示出更大的增殖以及细胞因子和细胞外基质反应。重要的是，我们显示从肺铁水平积累起，用铁螯合剂去铁胺（DFO）进行鼻内治疗可防止气道纤维化和实验性肺纤维化中肺功能的下降。肺纤维化与Tfr1 +巨噬细胞增多有关，这些巨噬细胞在疾病中表现出改变的表型，而DFO处理可以改变这些细胞的丰度。这些实验和临床数据表明，肺铁积累的增加在肺纤维化和肺功能下降的发病机理中起关键作用。此外，这些数据突显了在治疗纤维化肺部疾病（如IPF）中针对增加的肺铁进行治疗的潜力。©2020英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版