Abstract
Free iron in lung can cause the generation of reactive oxygen species, an important factor in chronic obstructive pulmonary disease (COPD) pathogenesis. Iron accumulation has been implicated in oxidative stress in other diseases, such as Alzheimer’s and Parkinson’s diseases, but little is known about iron accumulation in COPD. We sought to determine if iron content and the expression of iron transport and/or storage genes in lung differ between controls and COPD subjects, and whether changes in these correlate with airway obstruction. Explanted lung tissue was obtained from transplant donors, GOLD 2–3 COPD subjects, and GOLD 4 lung transplant recipients, and bronchoalveolar lavage (BAL) cells were obtained from non-smokers, healthy smokers, and GOLD 1–3 COPD subjects. Iron-positive cells were quantified histologically, and the expression of iron uptake (transferrin and transferrin receptor), storage (ferritin) and export (ferroportin) genes was examined by real-time RT-PCR assay. Percentage of iron-positive cells and expression levels of iron metabolism genes were examined for correlations with airflow limitation indices (forced expiratory volume in the first second (FEV1) and the ratio between FEV1 and forced vital capacity (FEV1/FVC)). The alveolar macrophage was identified as the predominant iron-positive cell type in lung tissues. Futhermore, the quantity of iron deposit and the percentage of iron positive macrophages were increased with COPD and emphysema severity. The mRNA expression of iron uptake and storage genes transferrin and ferritin were significantly increased in GOLD 4 COPD lungs compared to donors (6.9 and 3.22 fold increase, respectively). In BAL cells, the mRNA expression of transferrin, transferrin receptor and ferritin correlated with airway obstruction. These results support activation of an iron sequestration mechanism by alveolar macrophages in COPD, which we postulate is a protective mechanism against iron induced oxidative stress.
Highlights
Iron is critical for the maintenance of cell homeostasis, having important roles in respiration, DNA synthesis, energy production, and metabolism
Lung samples were obtained from 20 GOLD 4 Chronic obstructive pulmonary disease (COPD) subjects receiving lung transplant, 9 GOLD 2–3 COPD subjects undergoing resection of lung cancer, and 8 non-COPD lung donors obtained following size adjustment for transplantation as controls
In addition to lung tissue samples, bronchoalveolar lavage (BAL) cells were obtained from another set of subjects: 8 healthy non-smokers, 8 healthy smokers, and 10 GOLD 1–3 COPD subjects
Summary
Iron is critical for the maintenance of cell homeostasis, having important roles in respiration, DNA synthesis, energy production, and metabolism. Oxidative stress induced by the free radicals in tobacco smoke and produced by inflammatory cells has been strongly implicated in the pathogenesis of COPD. Excess iron accumulation in the lung has been reported in association with cigarette smoke [4,5,6] and severe emphysema [7]. Cigarette smoke can alter lung iron metabolism in animal models [8]. It is unknown where iron accumulates in lungs of COPD subjects, if expression of iron uptake and storage genes in the lung differs between controls and subjects with COPD, and whether changes in iron metabolism correlate with disease severity
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