15
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Disruption of the Hepcidin/Ferroportin Regulatory System Causes Pulmonary Iron Overload and Restrictive Lung Disease

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          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.

          Highlights

          • 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.

          Related collections

          Most cited references29

          • Record: found
          • Abstract: found
          • Article: not found

          Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network.

          The regulation and maintenance of systemic iron homeostasis is critical to human health. Iron overload and deficiency diseases belong to the most common nutrition-related pathologies across the globe. It is now well appreciated that the hormonal hepcidin/ferroportin system plays an important regulatory role for systemic iron metabolism. We review recent data that uncover the importance of the cellular iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network in systemic iron homeostasis. We also discuss how the IRE/IRP regulatory system communicates with the hepcidin/ferroportin system to connect the control networks for systemic and cellular iron balance.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Mammalian iron metabolism and its control by iron regulatory proteins.

            Cellular iron homeostasis is maintained by iron regulatory proteins 1 and 2 (IRP1 and IRP2). IRPs bind to iron-responsive elements (IREs) located in the untranslated regions of mRNAs encoding protein involved in iron uptake, storage, utilization and export. Over the past decade, significant progress has been made in understanding how IRPs are regulated by iron-dependent and iron-independent mechanisms and the pathological consequences of IRP2 deficiency in mice. The identification of novel IREs involved in diverse cellular pathways has revealed that the IRP-IRE network extends to processes other than iron homeostasis. A mechanistic understanding of IRP regulation will likely yield important insights into the basis of disorders of iron metabolism. This article is part of a Special Issue entitled: Cell Biology of Metals. Copyright © 2012 Elsevier B.V. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease.

              Hemolytic diseases, such as sickle cell anemia and thalassemia, are characterized by enhanced release of hemoglobin and heme into the circulation, heme-iron loading of reticulo-endothelial system macrophages, and chronic inflammation. Here we show that in addition to activating the vascular endothelium, hemoglobin and heme excess alters the macrophage phenotype in sickle cell disease. We demonstrate that exposure of cultured macrophages to hemolytic aged red blood cells, heme, or iron causes their functional phenotypic change toward a proinflammatory state. In addition, hemolysis and macrophage heme/iron accumulation in a mouse model of sickle disease trigger similar proinflammatory phenotypic alterations in hepatic macrophages. On the mechanistic level, this critically depends on reactive oxygen species production and activation of the Toll-like receptor 4 signaling pathway. We further demonstrate that the heme scavenger hemopexin protects reticulo-endothelial macrophages from heme overload in heme-loaded Hx-null mice and reduces production of cytokines and reactive oxygen species. Importantly, in sickle mice, the administration of human exogenous hemopexin attenuates the inflammatory phenotype of macrophages. Taken together, our data suggest that therapeutic administration of hemopexin is beneficial to counteract heme-driven macrophage-mediated inflammation and its pathophysiologic consequences in sickle cell disease.
                Bookmark

                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                29 April 2017
                June 2017
                29 April 2017
                : 20
                : 230-239
                Affiliations
                [a ]Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Im Neuenheimer Feld 350, D-69120 Heidelberg, Germany
                [b ]Molecular Medicine Partnership Unit, D-69120 Heidelberg, Germany
                [c ]Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4050-343 Porto, Portugal
                [d ]Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, D-69120 Heidelberg, Germany
                [e ]Department of Translational Pulmonology, University of Heidelberg, D-69120 Heidelberg, Germany
                [f ]Justus-Liebig University of Giessen (JLUG), Excellence Cluster Cardiopulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Germany
                [g ]Institute of Functional and Applied Anatomy, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, D-30625 Hannover, Germany
                Author notes
                [1]

                Equal contribution.

                Article
                S2352-3964(17)30191-3
                10.1016/j.ebiom.2017.04.036
                5478206
                28499927
                2d87eca2-d730-4e41-a835-1512e2daa1f6
                © 2017 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 19 January 2017
                : 27 April 2017
                : 28 April 2017
                Categories
                Research Paper

                restrictive lung disease,ferroportin,hereditary hemochromatosis,iron overload,hepcidin resistance

                Comments

                Comment on this article