title: Iron homeostasis and its disruption in mouse lung in iron deficiency and overload.
abstract: What is the central question of this study? The aim was to explore the role and hitherto unclear mechanisms of action of iron proteins in protecting the lung against the harmful effects of iron accumulation and the ability of pulmonary cells to mobilize iron in iron deficiency. What is the main finding and its importance? We show that pulmonary hepcidin appears not to modify cellular iron mobilization in the lung. We propose pathways for supplying iron to the lung in iron deficiency and for protecting the lung against iron excess in iron overload, mediated by the co-ordinated action of iron proteins, such as divalent metal transporter 1, ZRT-IRE-like-protein 14, transferrin receptor, ferritin, haemochromatosis-associated protein and ferroportin. Iron dyshomeostasis is associated with several forms of chronic lung disease, but its mechanisms of action remain to be elucidated. The aim of the present study was to determine the role of the lung in whole-animal models with iron deficiency and iron overload, studying the divalent metal transporter 1 (DMT1), ZRT-IRE-like protein 14 (ZIP14), transferrin receptor (TfR), haemochromatosis-associated protein (HFE), hepcidin, ferritin and ferroportin (FPN) expression. In each model, adult CF1 mice were divided into the following groups (six mice per group): (i) iron-overload model, iron saccharate i.p. and control group (iron adequate), 0.9% NaCl i.p.; and (ii) iron-deficiency model, induced by repeated bleeding, and control group (sham operated). Proteins were assessed by immunohistochemistry and Western blot. In control mice, DMT1 was localized in the cytoplasm of airway cells, and in iron deficiency and overload it was in the apical membrane. Divalent metal transporter 1 and TfR increased in iron deficiency, without changes in iron overload. ZRT-IRE-like protein 14 decreased in airway cells in iron deficiency and increased in iron overload. In iron deficiency, HFE and FPN were immunolocalized close to the apical membrane. Ferroportin increased in iron overload. Prohepcidin was present in control groups, with no changes in iron deficiency and iron overload. In iron overload, ferritin showed intracytoplasmic localization close to the apical membrane of airway cells and intense immunostaining in macrophage-like cells. The results show that pulmonary hepcidin does not appear to modify cellular iron mobilization in the lung. We propose the following two novel pathways in the lung: (i) for supplying iron in iron deficiency, mediated principally by DMT1 and TfR and regulated by the action of FPN and HFE; and (ii) for iron detoxification in order to protect the lung against iron overload, facilitated by the action of DMT1, ZIP14, FPN and ferritin.
authors.affiliation: Laboratory of Human Physiology, Department of Biology, Biochemistry and Pharmacy, Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR-CONICET), San Juan 670, Universidad Nacional del Sur, Bahía Blanca, Argentina.
authors.forename: Gisela
authors.initials: G
authors.lastname: Giorgi
authors.affiliation: Laboratory of Human Physiology, Department of Biology, Biochemistry and Pharmacy, Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR-CONICET), San Juan 670, Universidad Nacional del Sur, Bahía Blanca, Argentina.
authors.forename: María Cecilia
authors.initials: MC
authors.lastname: D'Anna
authors.affiliation: Laboratory of Human Physiology, Department of Biology, Biochemistry and Pharmacy, Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR-CONICET), San Juan 670, Universidad Nacional del Sur, Bahía Blanca, Argentina.
authors.forename: Marta Elena
authors.initials: ME
authors.lastname: Roque
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D027682:Cation Transport Proteins / Q000378:metabolism; D003677:Deficiency Diseases / Q000097:blood* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005293:Ferritins / Q000378:metabolism; D000071020:Hemochromatosis Protein; D064451:Hepcidins / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006706:Homeostasis; D007501:Iron / Q000097:blood; D000090463:Iron Deficiencies; D019190:Iron Overload / Q000097:blood* / Q000503:physiopathology; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D011990:Receptors, Transferrin / Q000378:metabolism; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D015415:Biomarkers; D027682:Cation Transport Proteins; D005293:Ferritins; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D007501:Iron; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C579599:Hamp protein, mouse; C499535:Hfe protein, mouse; C500556:SLC39A14 protein, mouse