Iron in airway macrophages and infective exacerbations of chronic obstructive pulmonary disease

Abstract

Background Excess pulmonary iron has been implicated in the pathogenesis of lung disease, including asthma and COPD. An association between higher iron content in sputum macrophages and infective exacerbations of COPD has previously been demonstrated. Objectives To assess the mechanisms of pulmonary macrophage iron sequestration, test the effect of macrophage iron-loading on cellular immune function, and prospectively determine if sputum hemosiderin index can predict infectious exacerbations of COPD. Methods Intra- and extracellular iron was measured in cell-line-derived and in freshly isolated sputum macrophages under various experimental conditions including treatment with exogenous IL-6 and hepcidin. Bacterial uptake and killing were compared in the presence or absence of iron-loading. A prospective cohort of COPD patients with defined sputum hemosiderin indices were monitored to determine the annual rate of severe infectious exacerbations. Results Gene expression studies suggest that airway macrophages have the requisite apparatus of the hepcidin-ferroportin axis. IL-6 and hepcidin play roles in pulmonary iron sequestration, though IL-6 appears to exert its effect via a hepcidin-independent mechanism. Iron-loaded macrophages had reduced uptake of COPD-relevant organisms and were associated with higher growth rates. Infectious exacerbations were predicted by sputum hemosiderin index (β = 0.035, p = 0.035). Conclusions We demonstrate in-vitro and population-level evidence that excess iron in pulmonary macrophages may contribute to recurrent airway infection in COPD. Specifically, IL-6-dependent iron sequestration by sputum macrophages may result in immune cell dysfunction and ultimately lead to increased frequency of infective exacerbation.

Iron Metabolism and Immune Regulation

“…and increase in expressions of some iron metabolism proteins like ferroprotin (FPN), transferrin receptor 1 (TfR1), CD163, ferritin, and HO-1, while M2 polarization appears to be with opposite changes in those proteins ( 24 ). Mechanistically, M1 polarization is usually followed by downregulation of FPN and upregulation of transferrin receptor 1, a membrane receptor that mediates holo-transferrin iron into cells ( 25 ). Similarly, some studies reveled that low expression of FPN and high expression of ferritin, a protein with a function of storing intracellular iron, could induce M1 polarizations ( 24 ).…”

Bronchoalveolar lavage hemosiderosis in lightly active or sedentary horses

“…Hemosiderin functions to limit oxidative damage caused by iron‐induced free radicals in the lung, 29 and has been found to be closely associated with pathology involving pulmonary oxidative damage in steel workers, smokers, individuals with exposure to lung pollution, 5 chronic obstructive pulmonary disease (COPD), those with lung cancer, 6,30 and cystic fibrosis 31 . Individuals with COPD have increased concentrations of the inflammatory cytokine interleukin‐6 that initiates the process of iron sequestration in pulmonary macrophages and consequently weakens macrophage immune function 32,33 . Case studies in humans have found that conditions such as idiopathic pulmonary fibrosis and bronchiolitis obliterans, in which the lower airways develop severe inflammation secondary to previous injury, can result in pulmonary hemosiderosis 34,35 .…”

Metal Exposure-Related Welder’s Pneumoconiosis and Lung Function: A Cross-Sectional Study in a Container Factory of China

“…Fe is an essential metal for haemoglobin synthesis of erythrocytes, oxidation–reduction reactions, and cellular proliferation. The excessive accumulation of Fe has been implicated in the pathogenesis of lung diseases, including asthma and COPD [ 51 ]. However, urinary Fe was reported to have positive dose–response associations with FEV1 and FEV1/FVC in the Wuhan cohort [ 52 ], which was consistent with our findings.…”