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Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis

Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal comp...

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Autores principales: Lehmann, Christian, Aali, Maral, Zhou, Juan, Holbein, Bruce
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830599/
https://www.ncbi.nlm.nih.gov/pubmed/33466819
http://dx.doi.org/10.3390/life11010057
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author Lehmann, Christian
Aali, Maral
Zhou, Juan
Holbein, Bruce
author_facet Lehmann, Christian
Aali, Maral
Zhou, Juan
Holbein, Bruce
author_sort Lehmann, Christian
collection PubMed
description Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal component of innate host defenses and that bacterial pathogens have acquired increasing levels of antibiotic resistance, targeting infection and sepsis through use of appropriate iron chelators has potential to provide new therapeutics. We have directly compared the effects of three Food and Drug Administration (FDA)-approved chelators (deferoxamine—DFO; deferiprone—DFP; and deferasirox—DFX), as were developed for treating hematological iron overload conditions, to DIBI, a novel purpose-designed, anti-infective and anti-inflammatory water-soluble hydroxypyridinone containing iron-selective copolymers. Two murine sepsis models, endotoxemia and polymicrobial abdominal sepsis, were utilized to help differentiate anti-inflammatory versus anti-infective activities of the chelators. Leukocyte adhesion, as measured by intravital microscopy, was observed in both models, with DIBI providing the most effective reduction and DFX the poorest. Inflammation in the abdominal sepsis model, assessed by cytokine measurements, indicated exacerbation by DFX and DFO for plasma Interleukin (IL)-6 and reductions to near-control levels for DIBI and DFP. Peritoneal infection burden was reduced 10-fold by DIBI while DFX and DFP provided no reductions. Overall, the results, together with those from other studies, revealed serious limitations for each of the three hematological chelators, i.e., as potentially repurposed for treating infection/sepsis. In contrast, DIBI provided therapeutic benefits, consistent with various in vitro and in vivo results from other studies, supporting the potential for its use in treating sepsis.
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spelling pubmed-78305992021-01-26 Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis Lehmann, Christian Aali, Maral Zhou, Juan Holbein, Bruce Life (Basel) Article Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal component of innate host defenses and that bacterial pathogens have acquired increasing levels of antibiotic resistance, targeting infection and sepsis through use of appropriate iron chelators has potential to provide new therapeutics. We have directly compared the effects of three Food and Drug Administration (FDA)-approved chelators (deferoxamine—DFO; deferiprone—DFP; and deferasirox—DFX), as were developed for treating hematological iron overload conditions, to DIBI, a novel purpose-designed, anti-infective and anti-inflammatory water-soluble hydroxypyridinone containing iron-selective copolymers. Two murine sepsis models, endotoxemia and polymicrobial abdominal sepsis, were utilized to help differentiate anti-inflammatory versus anti-infective activities of the chelators. Leukocyte adhesion, as measured by intravital microscopy, was observed in both models, with DIBI providing the most effective reduction and DFX the poorest. Inflammation in the abdominal sepsis model, assessed by cytokine measurements, indicated exacerbation by DFX and DFO for plasma Interleukin (IL)-6 and reductions to near-control levels for DIBI and DFP. Peritoneal infection burden was reduced 10-fold by DIBI while DFX and DFP provided no reductions. Overall, the results, together with those from other studies, revealed serious limitations for each of the three hematological chelators, i.e., as potentially repurposed for treating infection/sepsis. In contrast, DIBI provided therapeutic benefits, consistent with various in vitro and in vivo results from other studies, supporting the potential for its use in treating sepsis. MDPI 2021-01-14 /pmc/articles/PMC7830599/ /pubmed/33466819 http://dx.doi.org/10.3390/life11010057 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lehmann, Christian
Aali, Maral
Zhou, Juan
Holbein, Bruce
Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis
title Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis
title_full Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis
title_fullStr Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis
title_full_unstemmed Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis
title_short Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis
title_sort comparison of treatment effects of different iron chelators in experimental models of sepsis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830599/
https://www.ncbi.nlm.nih.gov/pubmed/33466819
http://dx.doi.org/10.3390/life11010057
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