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      Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice

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      1 , 2 , 3 , 4 , 5 , 2 , 2 , 6 , 1 , 7 , 2 , 8 , 9 , 1 , 10 , 1 , 1 , 2 , 11 , 12 , 1 , 1 , 2 , 13 , 14 , 15 , 3 , 4 , 6 , 2 , 5 , 11 , 14 , 15 , 16 , 17 , 18 , 7 , 3 , 4 , 5 , 6 , 2 , 5 , 2 , 8 , 1 , 2
      Nature medicine
      COPD, Mitochondria, Iron, IRP2, Lung

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          Abstract

          Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 ( IRP2) as an important COPD susceptibility gene, with IRP2 protein increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase ( Sco2)-deficient mice with reduced COX were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.

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          Most cited references61

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          Chronic obstructive pulmonary disease: molecular and cellular mechanisms.

          Chronic obstructive pulmonary disease is a leading cause of death and disability, but has only recently been extensively explored from a cellular and molecular perspective. There is a chronic inflammation that leads to fixed narrowing of small airways and alveolar wall destruction (emphysema). This is characterised by increased numbers of alveolar macrophages, neutrophils and cytotoxic T-lymphocytes, and the release of multiple inflammatory mediators (lipids, chemokines, cytokines, growth factors). A high level of oxidative stress may amplify this inflammation. There is also increased elastolysis and evidence for involvement of several elastolytic enzymes, including serine proteases, cathepsins and matrix metalloproteinases. The inflammation and proteolysis in chronic obstructive pulmonary disease is an amplification of the normal inflammatory response to cigarette smoke. This inflammation, in marked contrast to asthma, appears to be resistant to corticosteroids, prompting a search for novel anti-inflammatory therapies that may prevent the relentless progression of the disease.
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            Gene Ontology Annotations and Resources

            The Gene Ontology (GO) Consortium (GOC, http://www.geneontology.org) is a community-based bioinformatics resource that classifies gene product function through the use of structured, controlled vocabularies. Over the past year, the GOC has implemented several processes to increase the quantity, quality and specificity of GO annotations. First, the number of manual, literature-based annotations has grown at an increasing rate. Second, as a result of a new ‘phylogenetic annotation’ process, manually reviewed, homology-based annotations are becoming available for a broad range of species. Third, the quality of GO annotations has been improved through a streamlined process for, and automated quality checks of, GO annotations deposited by different annotation groups. Fourth, the consistency and correctness of the ontology itself has increased by using automated reasoning tools. Finally, the GO has been expanded not only to cover new areas of biology through focused interaction with experts, but also to capture greater specificity in all areas of the ontology using tools for adding new combinatorial terms. The GOC works closely with other ontology developers to support integrated use of terminologies. The GOC supports its user community through the use of e-mail lists, social media and web-based resources.
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              Topographic distance and watershed lines

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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                9 December 2015
                11 January 2016
                February 2016
                01 August 2016
                : 22
                : 2
                : 163-174
                Affiliations
                [1 ]Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY, USA
                [2 ]Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
                [3 ]Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
                [4 ]Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA
                [5 ]Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
                [6 ]Department of Radiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
                [7 ]Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA
                [8 ]Lovelace Respiratory Research institute, Albuquerque, NM, USA
                [9 ]Pulmonary Department, University of Parma, Parma, Italy
                [10 ]First Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, University of Athens, Medical School, Athens, Greece
                [11 ]Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD, USA
                [12 ]Department of Biomedical Engineering, Boston University, Boston, MA, USA
                [13 ]Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, China
                [14 ]Department of Anesthesiology, Columbia University, New York, NY, USA
                [15 ]Department of Medicine, Columbia University, New York, NY, USA
                [16 ]Department of Physiology & Cellular Biophysics, Columbia University, New York, NY, USA
                [17 ]Department of Neurology, Columbia University Medical Center, New York, NY, USA
                [18 ]Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA
                Author notes
                Correspondence to: Augustine M.K. Choi: amc2056@ 123456med.cornell.edu , Sanford I. Weill Chairman and Professor of Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, Physician-in-Chief, New York-Presbyterian Hospital-Weill Cornell Medical Center, 525 East 68th Street, Room M-522, Box 130, New York, NY 10065
                Article
                NIHMS743018
                10.1038/nm.4021
                4742374
                26752519
                1ccfec2b-7a58-4138-8670-d1d60d3e4d08

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                Medicine
                copd,mitochondria,iron,irp2,lung
                Medicine
                copd, mitochondria, iron, irp2, lung

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