Disruption of the hepcidin/ferroportin regulatory circuitry causes increased pulmonary iron content and restrictive lung disease

All cell types of the lung, including airways, parenchyma and inflammatory cells need iron for metabolic processes. However, they must prevent iron overload which causes cellular damage due to the generation of reactive oxygen species (ROS). The risk for oxidative damage in the lung is exacerbated by its continuous exposure to high oxygen levels making iron detoxification within airway epithelial cells and alveolar macrophages an essential mechanism to prevent lung failure.

The aim of our study is to determine the (patho)physiological consequences of unbalanced iron homeostasis in the lung. For this purpose, we analyzed a mouse model with a disruption in the hepcidin/ferroportin circuitry (FPN C326S mice), the regulatory system that controls systemic iron levels. Biochemical and histological analysis of the lung demonstrates that FPN C326S mice exhibit an age dependent increase in pulmonary iron content localized in ciliated airway epithelial cells, alveolar macrophages, alveolar type II cells and smooth muscle cells surrounding pulmonary arteries. Increased pulmonary iron levels correlate with an increase in ROS-mediated lipid peroxidation, suggesting that iron-mediated oxidative stress could contribute to the pathogenesis of lung diseases. To investigate this hypothesis, we performed measurements of lung function and blood oxygen saturation. These analyses revealed signs of restrictive lung disease in FPN C326S mice, with a decrease in total lung capacity and lung compliance. Interestingly, when compared with wild-type littermates, FPN C326S mice present a significant reduction in blood oxygen saturation. Experiments are ongoing to better understand the development of restrictive lung disease and decreased blood oxygen saturation.

*Presenting author