title: HFE gene variants and iron-induced oxygen radical generation in idiopathic pulmonary fibrosis.
abstract: In idiopathic pulmonary fibrosis (IPF), lung accumulation of excessive extracellular iron and macrophage haemosiderin may suggest disordered iron homeostasis leading to recurring microscopic injury and fibrosing damage. The current study population comprised 89 consistent IPF patients and 107 controls. 54 patients and 11 controls underwent bronchoalveolar lavage (BAL). Haemosiderin was assessed by Perls' stain, BAL fluid malondialdehyde (MDA) by high-performance liquid chromatography, BAL cell iron-dependent oxygen radical generation by fluorimetry and the frequency of hereditary haemochromatosis HFE gene variants by reverse dot blot hybridisation. Macrophage haemosiderin, BAL fluid MDA and BAL cell unstimulated iron-dependent oxygen radical generation were all significantly increased above controls (p<0.05). The frequency of C282Y, S65C and H63D HFE allelic variants was markedly higher in IPF compared with controls (40.4% versus 22.4%, OR 2.35, p=0.008) and was associated with higher iron-dependent oxygen radical generation (HFE variant 107.4±56.0, HFE wild type (wt) 59.4±36.4 and controls 16.7±11.8 fluorescence units per 10(5) BAL cells; p=0.028 HFE variant versus HFE wt, p=0.006 HFE wt versus controls). The data suggest iron dysregulation associated with HFE allelic variants may play an important role in increasing susceptibility to environmental exposures, leading to recurring injury and fibrosis in IPF.
authors.affiliation: Dept of Biomedicine and Prevention, University of Roma Tor Vergata, Rome, Italy. Both authors contributed equally.
authors.forename: Federica
authors.initials: F
authors.lastname: Sangiuolo
authors.affiliation: Dept of Biomedicine and Prevention, University of Roma Tor Vergata, Rome, Italy. Both authors contributed equally.
authors.forename: Ermanno
authors.initials: E
authors.lastname: Puxeddu
authors.affiliation: Division of Respiratory Diseases, University Hospital Tor Vergata, Rome, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pezzuto
authors.affiliation: Postgraduate School in Respiratory Diseases, University of Roma Tor Vergata, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cavalli
authors.affiliation: Dept of Biomedicine and Prevention, University of Roma Tor Vergata, Rome, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Longo
authors.affiliation: Division of Respiratory Diseases, University Hospital Tor Vergata, Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Comandini
authors.affiliation: Dept of Clinical Science and Translation Medicine, University of Roma Tor Vergata, Rome, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Di Pierro
authors.affiliation: Dept of Biomedicine and Prevention, University of Roma Tor Vergata, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pallante
authors.affiliation: Dept of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiation Therapy, University Hospital Tor Vergata, Rome, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Sergiacomi
authors.affiliation: Dept of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiation Therapy, University Hospital Tor Vergata, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Simonetti
authors.affiliation: Dept of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, University of Bologna, Bologna, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zompatori
authors.affiliation: Dept of Anatomic Pathology, University of Roma Tor Vergata, Rome, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
authors.affiliation: Dept of Biomedicine and Prevention, University of Roma Tor Vergata, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Magrini
authors.affiliation: Dept of Biomedicine and Prevention, University of Roma Tor Vergata, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Amicosante
authors.affiliation: Institute Cell Biology and Neurobiology, National Research Council, Monterotondo Scalo, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mariani
authors.affiliation: Division of Respiratory Diseases, University Hospital Tor Vergata, Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Losi
authors.affiliation: Dept of Laboratory Medicine, University Hospital Tor Vergata, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraboni
authors.affiliation: University of Roma La Sapienza, Rome, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bisetti
authors.affiliation: Dept of Biomedicine and Prevention, University of Roma Tor Vergata, Rome, Italy. Division of Respiratory Diseases, University Hospital Tor Vergata, Rome, Italy. Postgraduate School in Respiratory Diseases, University of Roma Tor Vergata, Rome, Italy. saltini@med.uniroma2.it.
authors.forename: Cesare
authors.initials: C
authors.lastname: Saltini
mesh_terms: D000328:Adult; D000483:Alleles; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005470:Fluorometry; D014644:Genetic Variation; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006485:Hemosiderin / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D007249:Inflammation / Q000378:metabolism; D007501:Iron / Q000737:chemistry*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000737:chemistry; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010100:Oxygen / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D006485:Hemosiderin; D007501:Iron; D010100:Oxygen