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 (Slc40a1 C326S), 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 Slc40a1 C326S/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.