| Rescuing iron-overloaded macrophages by conservative relocation of the accumulated metal. | |
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MedLine Citation:
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PMID: 21091647 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE Systemic iron deficiency concomitant with macrophage iron retention is characteristic of iron-refractory anaemias associated with chronic disease. The systemic misdistribution of iron, which is further exacerbated by parenteral iron supplementation, is mainly attributable to iron retention exerted on resident macrophages by hepcidin-mediated down-regulation of the iron exporter ferroportin. We aimed at developing an experimental macrophage-based cell model that recapitulates pathophysiological features of iron misdistribution found in chronic disorders and use it as a screening platform for identifying agents with the potential for relocating the accumulated metal and restoring affected functions. EXPERIMENTAL APPROACH A RAW macrophage subline was selected as cell model of iron retention based on their capacity to take up polymeric iron or aged erythrocytes excessively, resulting in a demonstrable increase of cell labile iron pools and oxidative damage that are aggravated by hepcidin. KEY RESULTS This model provided a three-stage high throughput screening platform for identifying agents with the combined ability to: (i) scavenge cell iron and thereby rescue macrophage cells damaged by iron-overload; (ii) bypass the ferroportin blockade by conveying the scavenged iron to other iron-starved cells in co-culture via transferrin but (iii) without promoting utilization of the scavenged iron by intracellular pathogens. As test agents we used chelators in clinical practice and found the oral chelator deferiprone fulfilled essentially all of the three criteria. CONCLUSIONS AND IMPLICATIONS We provide a proof of principle for conservative iron relocation as complementary therapeutic approach for correcting the misdistribution of iron associated with chronic disease and exacerbated by parenteral iron supplementation. |
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Authors:
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Yang-Sung Sohn; Anna-Maria Mitterstiller; William Breuer; Guenter Weiss; Z Ioav Cabantchik |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: British journal of pharmacology Volume: 164 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-09-02 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 406-18 Citation Subset: IM |
Copyright Information:
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© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Affiliation:
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Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond Safra Campus at Givat Ram, Jerusalem, Israel, and Department for Internal Medicine I, Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Innsbruck, Austria. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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