Disruption of the Hepcidin/Ferroportin Regulatory System Causes Pulmonary Iron Overload and Restrictive Lung Disease.
Disruption of the Hepcidin/Ferroportin Regulatory System Causes Pulmonary Iron Overload and Restrictive Lung Disease.
复制标题
Hepcidin/铁转运蛋白调控系统的破坏导致肺铁超载和限制性肺疾病。
DOI：
10.1016/j.ebiom.2017.04.036
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发表时间：
2017-06
期刊：
影响因子：
11.1
通讯作者：
Muckenthaler MU
中科院分区：
文献类型：
--
作者：
Neves J;Leitz D;Kraut S;Brandenberger C;Agrawal R;Weissmann N;Mühlfeld C;Mall MA;Altamura S;Muckenthaler MU
新的证据表明，肺部铁积累与一系列慢性肺部疾病有关。然而，肺铁沉积的机制及其在肺部疾病体内发病机制中的作用仍不清楚。在这里，我们发现，导致遗传性4型血色素沉着症（Slc40a1C326S）的小鼠铁转运蛋白基因的点突变会增加肺泡巨噬细胞、传导气道和肺实质内壁上皮细胞以及血管平滑肌细胞中的铁水平。与野生型对照相比，纯合子 Slc40a1C326S/C326S 小鼠的肺铁超负荷与氧化应激、限制性肺病、总肺活量降低和血氧饱和度降低有关。这些发现表明铁与肺部病理学有关，迄今为止，肺部病理学并不被认为是一种典型的与铁相关的疾病。铁转运蛋白对铁调素结合的抵抗导致肺铁过载。肺铁的积累仅限于特定的细胞类型。铁超载会导致限制性肺部疾病和血氧饱和度降低。肺部铁蓄积与多种肺部疾病有关，例如慢性阻塞性肺病和囊性纤维化。据报道，重型地中海贫血患者的肺功能受损，这是一种以输血铁超负荷为特征的疾病。迄今为止，导致肺铁沉积的机制及其在疾病发生和进展中的作用仍不清楚。我们的研究表明，在小鼠疾病模型中，全身铁稳态的控制被破坏，铁在肺部积聚，并与氧化应激、限制性肺病和血氧饱和度降低相关。这些发现表明肺部病理学中铁超载，这不被认为是典型的铁相关疾病。
Emerging evidence suggests that pulmonary iron accumulation is implicated in a spectrum of chronic lung diseases. However, the mechanism(s) involved in pulmonary iron deposition and its role in the in vivo pathogenesis of lung diseases remains unknown. Here we show that a point mutation in the murine ferroportin gene, which causes hereditary hemochromatosis type 4 (Slc40a1C326S), increases iron levels in alveolar macrophages, epithelial cells lining the conducting airways and lung parenchyma, and in vascular smooth muscle cells. Pulmonary iron overload is associated with oxidative stress, restrictive lung disease with decreased total lung capacity and reduced blood oxygen saturation in homozygous Slc40a1C326S/C326S mice compared to wild-type controls. These findings implicate iron in lung pathology, which is so far not considered a classical iron-related disorder. Ferroportin resistance to hepcidin binding leads to pulmonary iron overload. Lung iron accumulation is restricted to specific cell types. Iron overload causes restrictive lung disease and decreased blood oxygen saturation. Pulmonary iron accumulation is associated with a wide spectrum of lung diseases, such as chronic obstructive pulmonary disease and cystic fibrosis. Impaired lung function was further reported in patients with thalassemia major, a disease hallmarked by transfusional iron overload. So far, the mechanism(s) leading to pulmonary iron deposition and its role in disease onset and progression are still unknown. Our study shows that in a murine disease model, in which the control of systemic iron homeostasis is disrupted, iron accumulates in the lung and correlates with oxidative stress, restrictive lung disease and decreased blood oxygen saturation. These findings implicate iron overload in lung pathology, which is not considered a classical iron-related disorder.