Increased Iron Sequestration in Alveolar Macrophages in Chronic Obtructive Pulmonary Disease

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.

Plasma Proteomic Signatures in Early Chronic Obstructive Pulmonary Disease

“…Philippot et al. suggest that an active iron sequestration by alveolar macrophages in COPD lungs could represent a protective mechanism to control and preserve the effects of free iron such as the formation of the highly toxic hydroxyl radical . However, besides having antioxidative properties, serotransferrin is a negative acute phase protein.…”

The “Iron”-y of Iron Overload and Iron Deficiency in Chronic Obstructive Pulmonary Disease

“…Both current and former smokers have abnormally high levels of iron as a result of iron having a high affinity for oxygen donor ligands found in CS particles, leading to a higher rate of deposition in the lung (51). Furthermore, total nonheme iron and ferritin levels are increased in BAL fluid and in AMs of smokers compared with nonsmokers (49,(51)(52)(53)(54)(55)(56)(57)(58), and redox-active iron levels in Figure 1. Iron import and export in the lung.…”

“…As is true of smokers, iron content and iron-binding molecules, including ferritin, lipocalin 2, and lactoferrin, are all increased in the lung tissue, sputum, BAL fluid, and AMs of patients with COPD (20,35,38,51,53,55). Iron levels increase with disease severity and with reductions in lung function.…”

Hemosiderin in sputum macrophages may predict infective exacerbations of chronic obstructive pulmonary disease: a retrospective observational study

“…This could lead to iron accumulation in the respiratory tract, which offers a favorable milieu for microbial growth and blunts macrophage function, and thus may contribute to infective AECOPD [29, 30]. On the other hand, it may be a respiratory infection in a predisposed individual that initiates the cycle.…”