Division of Pulmonary and Critical Care Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
Priority Research Centre for Healthy Lungs and School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
J Pathol. 2020 May;251(1):49-62. doi: 10.1002/path.5401. Epub 2020 Mar 30.
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.
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，使用铁过载和博来霉素诱导的肺纤维化的小鼠模型组合、用铁处理的原代人肺成纤维细胞以及有无特发性肺纤维化（IPF）的患者的组织学样本，研究了铁积累对肺纤维化发病机制和相关肺功能下降的影响。铁水平在铁过载转铁蛋白受体 2（Tfr2）突变小鼠和稳态铁调节剂（Hfe）基因缺陷小鼠中显着增加，并且与气道纤维化增加和肺功能降低有关。此外，纤维化和肺功能下降与博来霉素诱导的肺纤维化中的肺铁积累有关。此外，我们还表明，IPF 患者的肺组织切片中的铁积累增加，并且当暴露于更高的铁水平时，人肺成纤维细胞显示出更高的增殖以及细胞因子和细胞外基质反应。重要的是，我们表明，从肺铁水平开始积累时，用铁螯合剂去铁胺（DFO）进行鼻内治疗可防止实验性肺纤维化中的气道纤维化和肺功能下降。肺纤维化与 Tfr1 巨噬细胞的增加有关，这些细胞在疾病中表现出改变的表型，DFO 治疗改变了这些细胞的丰度。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制中起关键作用。此外，这些数据强调了针对特发性肺纤维化等纤维性肺疾病中增加的肺铁进行治疗靶向的潜力。
