|
1
|
Navidifar T, Meftah E, Baghsheikhi H, Kazemzadeh K, Karimi H, Rezaei N. Dual role of hepcidin in response to pathogens. Microb Pathog 2025; 203:107496. [PMID: 40118299 DOI: 10.1016/j.micpath.2025.107496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 03/15/2025] [Accepted: 03/19/2025] [Indexed: 03/23/2025]
Abstract
Hepcidin is the primary regulator of vertebrate iron homeostasis. Its production is stimulated by systemic iron levels and inflammatory signals. Although the role of hepcidin in iron homeostasis is well characterized, its response to pathogenic agents is complex and diverse. In this review, we examine studies that investigate the role of hepcidin in response to infectious agents. Interleukin-6 (IL-6) is a key factor responsible for the induction of hepcidin expression. During infection, hepcidin-mediated depletion of extracellular iron serves as a protective mechanism against a variety of pathogens. However, accumulation of iron in macrophages through hepcidin-mediated pathways may increase susceptibility to intracellular pathogens such as Mycobacterium tuberculosis. Prolonged elevation of hepcidin production can lead to anemia due to reduced iron availability for erythropoiesis, a condition referred to as anemia of inflammation. In addition, we highlight the role of hepcidin upregulation in several infectious contexts, including HIV-associated anemia, iron deficiency anemia in Helicobacter pylori infection, and post-malarial anemia in pediatric patients. In addition, we show that certain infectious agents, such as hepatitis C virus (HCV), can suppress hepcidin production during both the acute and chronic phases of infection, while hepatitis B virus (HBV) exhibits similar suppression during the chronic phase.
Collapse
Affiliation(s)
- Tahereh Navidifar
- Department of Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran; Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Elahe Meftah
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hediyeh Baghsheikhi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Kazemzadeh
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanie Karimi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Science, Tehran, Iran.
| |
Collapse
|
|
2
|
Choi G, Bessman NJ. Iron at the crossroads of host-microbiome interactions in health and disease. Nat Microbiol 2025:10.1038/s41564-025-02001-y. [PMID: 40399686 DOI: 10.1038/s41564-025-02001-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 03/31/2025] [Indexed: 05/23/2025]
Abstract
Iron is an essential dietary micronutrient for both humans and microorganisms. Disruption of iron homeostasis is closely linked, as both a cause and an effect, to the development and progression of gut microbiota dysbiosis and multiple diseases. Iron absorption in humans is impacted by diverse environmental factors, including diet, medication and microbiota-derived molecules. Accordingly, treatment outcomes for iron-associated diseases may depend on an individual patient's microbiome. Here we describe various iron acquisition strategies used by the host, commensal microorganisms and pathogens to benefit or outcompete each other in the complex gut environment. We further explore recently discovered microbial species and metabolites modulating host iron absorption, which represent potential effectors of disease and therapeutic targets. Finally, we discuss the need for mechanistic studies on iron-host-microbiome interactions that can affect disease and treatment outcomes, with the ultimate aim of supporting the development of microbiome-based personalized medicine.
Collapse
Affiliation(s)
- Garam Choi
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ, USA
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Nicholas J Bessman
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ, USA.
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA.
| |
Collapse
|
|
3
|
Fisher AL, Phillips S, Wang CY, Paulo JA, Xiao X, Xu Y, Moschetta GA, Xue Y, Mancias JD, Babitt JL. The hepcidin-ferroportin axis modulates liver endothelial cell BMP expression to influence iron homeostasis in mice. Blood 2025; 145:625-634. [PMID: 39437541 DOI: 10.1182/blood.2024024795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 09/18/2024] [Accepted: 09/21/2024] [Indexed: 10/25/2024] Open
Abstract
ABSTRACT The liver hormone hepcidin regulates systemic iron homeostasis to provide enough iron for vital processes while limiting toxicity. Hepcidin acts by degrading its receptor ferroportin (encoded by Slc40a1) to decrease iron export to plasma. Iron controls hepcidin production in part by inducing liver endothelial cells (LECs) to produce bone morphogenetic proteins (BMPs) that activate hepcidin transcription in hepatocytes. Here, we used in vitro and in vivo models to investigate whether ferroportin contributes to LEC intracellular iron content to modulate BMP expression and, thereby, hepcidin. Quantitative proteomics of LECs from mice fed different iron diets demonstrated an inverse relationship between dietary iron and endothelial ferroportin expression. Slc40a1 knockdown primary mouse LECs and endothelial Slc40a1 knockout mice exhibited increased LEC iron and BMP ligand expression. Endothelial Slc40a1 knockout mice also exhibited altered systemic iron homeostasis with decreased serum and total liver iron but preserved erythropoiesis. Although endothelial Slc40a1 knockout mice had similar hepcidin expression to control mice, hepcidin levels were inappropriately high relative to iron levels. Moreover, when iron levels were equalized with iron treatment, hepcidin levels were higher in endothelial Slc40a1 knockout mice than in controls. Finally, LEC ferroportin levels were inversely correlated with hepcidin levels in multiple mouse models, and treatment of hepcidin-deficient mice with mini-hepcidin decreased LEC ferroportin expression. Overall, these data show that LEC ferroportin modulates LEC iron and consequently BMP expression to influence hepcidin production. Furthermore, LEC ferroportin expression is regulated by hepcidin, demonstrating a bidirectional communication between LECs and hepatocytes to orchestrate systemic iron homeostasis.
Collapse
Affiliation(s)
- Allison L Fisher
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Sydney Phillips
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Chia-Yu Wang
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Joao A Paulo
- Department of Cell Biology, Harvard Medical School, Boston, MA
| | - Xia Xiao
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Yang Xu
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Gillian A Moschetta
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Yongqiang Xue
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Joseph D Mancias
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Jodie L Babitt
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| |
Collapse
|
|
4
|
Park MY, Agoro R, Jankauskas SS, Le Henaff C, Sitara D. Phosphorus-independent role of FGF23 in erythropoiesis and iron homeostasis. PLoS One 2024; 19:e0315228. [PMID: 39666728 PMCID: PMC11637385 DOI: 10.1371/journal.pone.0315228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 11/21/2024] [Indexed: 12/14/2024] Open
Abstract
A number of studies have reported an association between phosphorus, red blood cell (RBC) production, and iron metabolism. However, it is difficult to distinguish whether the effect of phosphorus is direct or through the actions of FGF23, and it is not clear whether phosphorus is positively or negatively associated with RBC production. In the present study, we investigated the effects of a) increased phosphorus load and b) phosphorus deficiency on erythropoiesis and iron metabolism in association with FGF23. Mice were fed either a 1.2% or 1.65% phosphorus diet and compared to mice fed a control diet containing 0.6% of phosphorus. Moreover, we used two mouse models of hypophosphatemia-induced either by dietary intervention in the form of a low phosphorus (LP) diet (0.02% of Pi) or genetically in a mouse model of X-linked hypophosphatemia (XLH)-that had opposite FGF23 levels. Phosphorus supplementation appropriately increased FGF23 levels leading to excretion of excess phosphorus and normalization of serum phosphorus levels. We also found that a phosphorus-rich diet results in inflammation-induced hypoferremia associated with reduced iron export leading to tissue iron overload. Moreover, high phosphorus intake results in ineffective erythropoiesis caused by decreased production (decreased RBCs, hemoglobin, hematocrit, and erythroid progenitors in the bone marrow) and increased destruction of RBCs, leading to anemia despite increased EPO secretion. These complications occur through the actions of elevated FGF23 in the presence of normophosphatemia. Our data also show that LP diet induces a decrease in the serum concentrations of phosphorus and FGF23, resulting in increased RBC counts, hemoglobin concentration, and hematocrit compared to mice fed normal diet. Moreover, serum iron and transferrin saturation were increased and positively correlated with serum ferritin, liver ferritin protein and mRNA expression in mice fed LP diet. However, hyp mice, the murine model of XLH, exhibit hypophosphatemia and high serum FGF23 levels, along with low number of circulating RBCs, hemoglobin, and hematocrit compared to wild-type mice. In the bone marrow, hyp mice showed reduced number of erythroid progenitors and formed significantly less BFU-E colonies compared to control mice. Serum iron levels and transferrin saturation were also decreased in hyp mice in comparison to control mice. Taken together, our data show that FGF23 acts independent of phosphorus levels to regulate erythropoiesis and iron homeostasis.
Collapse
Affiliation(s)
- Min Young Park
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, United States of America
| | - Rafiou Agoro
- Department of Mammalian Genetics, The Jackson Laboratory, Bar Harbor, ME, United States of America
| | | | - Carole Le Henaff
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, United States of America
| | - Despina Sitara
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, United States of America
- Department of Medicine, Holman Division of Endocrinology, Diabetes and Metabolism, New York University Grossman School of Medicine, New York, NY, United States of America
| |
Collapse
|
|
5
|
Dou J, Chen X, Zhang J, Yang L, Lin J, Zhu W, Huang D, Tan X. P. Gingivalis induce macrophage polarization by regulating hepcidin expression in chronic apical periodontitis. Int Immunopharmacol 2024; 142:113139. [PMID: 39278061 DOI: 10.1016/j.intimp.2024.113139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/07/2024] [Accepted: 09/08/2024] [Indexed: 09/17/2024]
Abstract
INTRODUCTION Hepcidin, a central regulatory molecule of iron metabolism, is upregulated through the IL-6/STAT3 signaling pathway in inflammatory and infectious states, contributing to the pathogenesis of various diseases. In chronic apical periodontitis (CAP), Porphyromonas gingivalis (P. gingivalis) and its lipopolysaccharides (LPS) activate various immune responses in vivo, contributing to disease progression. This study evaluated the role and mechanism of hepcidin in P. gingivalis-induced bone tissue damage in CAP, focusing on its promotion of macrophage M1 polarization via the IL-6/STAT3 signaling pathway. METHODS We analyzed a GSE77459 dataset from the GEO database, containing data from inflammatory and normal dental pulp tissues. RT-qPCR and immunofluorescence staining were used to detect the expression of hepcidin in human CAP tissues and its relationship with macrophages. Mouse bone marrow derived macrophages (BMDMs) were cultured in vitro and stimulated with P. gingivalis LPS. The effects of Stattic on macrophage hepcidin expression, IL-6 expression, STAT3 phosphorylation, and macrophage polarization were detected by ELISA, western blotting, RT-qPCR, and flow cytometry, respectively. RESULTS Hepcidin expression in human inflammatory dental pulp tissues was upregulated via the IL-6/STAT3 pathway and correlated with macrophage polarization. Hepcidin-encoding genes were found to be highly expressed and primarily associated with M1 macrophages in CAP tissues. In vitro experiments revealed that P. gingivalis LPS stimulation induced macrophages to express hepcidin through the IL-6/STAT3 pathway and polarize to M1. Additionally, the IL-6/STAT3 pathway inhibitor Stattic suppressed these changes. CONCLUSIONS Our study demonstrates that in CAP, macrophages highly express hepcidin, which subsequently alters macrophage metabolism, regulates M1 polarization, and leads to bone tissue destruction.
Collapse
Affiliation(s)
- Jinge Dou
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Xuan Chen
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China; Department of Endodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, 510182 Guangdong, China
| | - Jinglan Zhang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Lei Yang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Jie Lin
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Wanling Zhu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| | - Dingming Huang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
| | - Xuelian Tan
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
| |
Collapse
|
|
6
|
Ru Q, Li Y, Chen L, Wu Y, Min J, Wang F. Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal Transduct Target Ther 2024; 9:271. [PMID: 39396974 PMCID: PMC11486532 DOI: 10.1038/s41392-024-01969-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 08/08/2024] [Accepted: 09/02/2024] [Indexed: 10/15/2024] Open
Abstract
Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.
Collapse
Affiliation(s)
- Qin Ru
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lin Chen
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yuxiang Wu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China.
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
| |
Collapse
|
|
7
|
Joseph BC, Sekayan T, Falah N, Barnes RFW, Flood V, De Pablo-Moreno JA, von Drygalski A. Traumatic bleeding and mortality in mice are intensified by iron deficiency anemia and can be rescued with tranexamic acid. Res Pract Thromb Haemost 2024; 8:102543. [PMID: 39286605 PMCID: PMC11403369 DOI: 10.1016/j.rpth.2024.102543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/24/2024] [Accepted: 07/31/2024] [Indexed: 09/19/2024] Open
Abstract
Background Clinical evidence suggests that anemia exacerbates traumatic bleeding and worsens outcomes. Objectives To study the influence of iron deficiency anemia on traumatic bleeding, coagulopathy, and mortality. Methods C57BL/6J mice received an iron-deficient diet (8 weeks; ±1 mg intraperitoneal iron dextran 2 weeks before trauma). Control mice received a normal diet. Iron deficiency anemia was confirmed by hematocrit, red cell indices, and liver iron. Mice received saline or tranexamic acid (TXA; 10 mg/kg) just before liver laceration. Blood loss, coagulopathy (activated partial thromboplastin time, factor [F]II, FV, FVIII, FX, and fibrinogen), D-dimer, thrombin-antithrombin complexes, and plasmin-alpha-2-antiplasmin complexes were analyzed at 15 and 60 minutes, and a cytokine panel was performed at 60 minutes and 6 hours after trauma. Survival was monitored for 7 days. Results Compared with nonanemic mice, anemic mice had lower hematocrit and hepatic iron content. Anemic mice experienced higher blood loss compared with nonanemic mice, which was reduced by TXA. Both groups developed traumatic coagulopathy characterized by activated partial thromboplastin time prolongation, thrombin-antithrombin complex formation, and depletion of FV, FVIII, and fibrinogen. TXA corrected the coagulopathy. However, plasmin-alpha-2-antiplasmin complex formation and D-dimers, markers of fibrinolysis, were higher in anemic mice and were not corrected by TXA. Seven-day survival was low in anemic mice, and rescued by TXA, but high in nonanemic mice without additional improvement by TXA. Among cytokines, only interleukin-6 increased, which was prevented by TXA most notably in anemic mice. Conclusion These observations provide first and critical proof-of-principle evidence that anemia accelerates traumatic bleeding and increases mortality, which could be rescued by anemia correction (parenteral iron) or periprocedural TXA.
Collapse
Affiliation(s)
- Bilgimol Chumappumkal Joseph
- Department of Medicine, Division of Hematology/Oncology, University of California San Diego, La Jolla, California, USA
| | - Tro Sekayan
- Department of Medicine, Division of Hematology/Oncology, University of California San Diego, La Jolla, California, USA
| | - Nicca Falah
- Department of Medicine, Division of Hematology/Oncology, University of California San Diego, La Jolla, California, USA
| | - Richard F W Barnes
- Department of Medicine, Division of Hematology/Oncology, University of California San Diego, La Jolla, California, USA
| | - Veronica Flood
- Versiti Blood Research Institute, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Juan A De Pablo-Moreno
- Department of Genetic, Physiology and Microbiology, Biology School, Complutense University of Madrid, Madrid, Spain
| | - Annette von Drygalski
- Department of Medicine, Division of Hematology/Oncology, University of California San Diego, La Jolla, California, USA
| |
Collapse
|
|
8
|
Hailu BA, Laillou A, Chitekwe S, Beyene J, Baye K. Subnational mapping for targeting anaemia prevention in women of reproductive age in Ethiopia: A coverage-equity paradox. MATERNAL & CHILD NUTRITION 2024; 20 Suppl 5:e13277. [PMID: 34624171 PMCID: PMC11258772 DOI: 10.1111/mcn.13277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 11/28/2022]
Abstract
Anaemia in women of reproductive age (WRA) can be effectively addressed if supported by a better understanding of the spatial variations, magnitude, severity and distribution of anaemia. This study aimed to map the subnational spatial distribution of anaemia (any, moderate and severe forms) among WRA in Ethiopia. We identified and mapped (any, moderate and severe) anaemia hotspots in WRA (n = 14,923) at the subnational level and identified risk factors using multilevel logistic regression. Kulldorff scan statistics were used to identify hotspot regions. Ordinary kringing was used to predict the anaemia prevalence in unmeasured areas. The overall anaemia prevalence increased from 16.6% in 2011 to 23.6% in 2016, a rise that was mostly related to the widening of existing hotspot areas. The primary clusters of (any) anaemia were in Somali and Afar regions. The horn of the Somali region represented a cluster of 330 km where 10% of WRA were severely anaemic. The Oromia-Somali border represented a significant cluster covering 247 km, with 9% severe anaemia. Population-dense areas with low anaemia prevalence had high absolute number of cases. Women education, taking iron-folic-acid tablets during pregnancy and birth-delivery in health facilities reduced the risk of any anaemia (P < 0.05). The local-level mapping of anaemia helped identify clusters that require attention but also highlighted the urgent need to study the aetiology of anaemia to improve the effectiveness and safety of interventions. Both relative and absolute anaemia estimates are critical to determine where additional attention is needed.
Collapse
Affiliation(s)
| | | | | | - Joseph Beyene
- Department of Health Research Methods, Evidence, and ImpactMcMaster UniversityCanada
| | - Kaleab Baye
- Center for Food Science and Nutrition, College of Natural and Computational SciencesAddis Ababa UniversityAddis AbabaEthiopia
- Research Center for Inclusive Development in Africa (RIDA)Addis AbabaEthiopia
| |
Collapse
|
|
9
|
Stoffel NU, Drakesmith H. Effects of Iron Status on Adaptive Immunity and Vaccine Efficacy: A Review. Adv Nutr 2024; 15:100238. [PMID: 38729263 PMCID: PMC11251406 DOI: 10.1016/j.advnut.2024.100238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 05/02/2024] [Accepted: 05/06/2024] [Indexed: 05/12/2024] Open
Abstract
Vaccines can prevent infectious diseases, but their efficacy varies, and factors impacting vaccine effectiveness remain unclear. Iron deficiency is the most common nutrient deficiency, affecting >2 billion individuals. It is particularly common in areas with high infectious disease burden and in groups that are routinely vaccinated, such as infants, pregnant women, and the elderly. Recent evidence suggests that iron deficiency and low serum iron (hypoferremia) not only cause anemia but also may impair adaptive immunity and vaccine efficacy. A report of human immunodeficiency caused by defective iron transport underscored the necessity of iron for adaptive immune responses and spurred research in this area. Sufficient iron is essential for optimal production of plasmablasts and IgG responses by human B-cells in vitro and in vivo. The increased metabolism of activated lymphocytes depends on the high-iron acquisition, and hypoferremia, especially when occurring during lymphocyte expansion, adversely affects multiple facets of adaptive immunity, and may lead to prolonged inhibition of T-cell memory. In mice, hypoferremia suppresses the adaptive immune response to influenza infection, resulting in more severe pulmonary disease. In African infants, anemia and/or iron deficiency at the time of vaccination predict decreased response to diphtheria, pertussis, and pneumococcal vaccines, and response to measles vaccine may be increased by iron supplementation. In this review, we examine the emerging evidence that iron deficiency may limit adaptive immunity and vaccine responses. We discuss the molecular mechanisms and evidence from animal and human studies, highlight important unknowns, and propose a framework of key research questions to better understand iron-vaccine interactions.
Collapse
Affiliation(s)
- Nicole U Stoffel
- Medical Research Council Translational Immune Discovery Unit, Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
| | - Hal Drakesmith
- Medical Research Council Translational Immune Discovery Unit, Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
10
|
Nobs SP, Elinav E. A microbial iron fist to fight tumors. Nat Immunol 2024; 25:720-721. [PMID: 38664584 DOI: 10.1038/s41590-024-01806-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/04/2024]
Affiliation(s)
- Samuel P Nobs
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Eran Elinav
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
- Microbiome & Cancer Division, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| |
Collapse
|
|
11
|
Wacka E, Nicikowski J, Jarmuzek P, Zembron-Lacny A. Anemia and Its Connections to Inflammation in Older Adults: A Review. J Clin Med 2024; 13:2049. [PMID: 38610814 PMCID: PMC11012269 DOI: 10.3390/jcm13072049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 03/29/2024] [Accepted: 03/31/2024] [Indexed: 04/14/2024] Open
Abstract
Anemia is a common hematological disorder that affects 12% of the community-dwelling population, 40% of hospitalized patients, and 47% of nursing home residents. Our understanding of the impact of inflammation on iron metabolism and erythropoiesis is still lacking. In older adults, anemia can be divided into nutritional deficiency anemia, bleeding anemia, and unexplained anemia. The last type of anemia might be caused by reduced erythropoietin (EPO) activity, progressive EPO resistance of bone marrow erythroid progenitors, and the chronic subclinical pro-inflammatory state. Overall, one-third of older patients with anemia demonstrate a nutritional deficiency, one-third have a chronic subclinical pro-inflammatory state and chronic kidney disease, and one-third suffer from anemia of unknown etiology. Understanding anemia's pathophysiology in people aged 65 and over is crucial because it contributes to frailty, falls, cognitive decline, decreased functional ability, and higher mortality risk. Inflammation produces adverse effects on the cells of the hematological system. These effects include iron deficiency (hypoferremia), reduced EPO production, and the elevated phagocytosis of erythrocytes by hepatic and splenic macrophages. Additionally, inflammation causes enhanced eryptosis due to oxidative stress in the circulation. Identifying mechanisms behind age-related inflammation is essential for a better understanding and preventing anemia in older adults.
Collapse
Affiliation(s)
- Eryk Wacka
- Department of Applied and Clinical Physiology, Collegium Medicum University of Zielona Gora, 65-417 Zielona Gora, Poland; (J.N.); (A.Z.-L.)
| | - Jan Nicikowski
- Department of Applied and Clinical Physiology, Collegium Medicum University of Zielona Gora, 65-417 Zielona Gora, Poland; (J.N.); (A.Z.-L.)
| | - Pawel Jarmuzek
- Department of Neurosurgery and Neurology, Collegium Medicum University of Zielona Gora, 65-417 Zielona Gora, Poland;
| | - Agnieszka Zembron-Lacny
- Department of Applied and Clinical Physiology, Collegium Medicum University of Zielona Gora, 65-417 Zielona Gora, Poland; (J.N.); (A.Z.-L.)
| |
Collapse
|
|
12
|
Ganz T, Nemeth E. Hypoferremia of inflammation: Innate host defense against infections. Blood Cells Mol Dis 2024; 104:102777. [PMID: 37391347 DOI: 10.1016/j.bcmd.2023.102777] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/18/2023] [Accepted: 06/19/2023] [Indexed: 07/02/2023]
Abstract
Iron is an essential nutrient for microbes, plants and animals. Multicellular organisms have evolved multiple strategies to control invading microbes by restricting microbial access to iron. Hypoferremia of inflammation is a rapidly-acting organismal response that prevents the formation of iron species that would be readily accessible to microbes. This review takes an evolutionary perspective to explore the mechanisms and host defense function of hypoferremia of inflammation and its clinical implications.
Collapse
Affiliation(s)
- Tomas Ganz
- Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1690, USA; Department of Pathology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1690, USA.
| | - Elizabeta Nemeth
- Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1690, USA
| |
Collapse
|
|
13
|
Grange C, Lux F, Brichart T, David L, Couturier A, Leaf DE, Allaouchiche B, Tillement O. Iron as an emerging therapeutic target in critically ill patients. Crit Care 2023; 27:475. [PMID: 38049866 PMCID: PMC10694984 DOI: 10.1186/s13054-023-04759-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 11/24/2023] [Indexed: 12/06/2023] Open
Abstract
The multiple roles of iron in the body have been known for decades, particularly its involvement in iron overload diseases such as hemochromatosis. More recently, compelling evidence has emerged regarding the critical role of non-transferrin bound iron (NTBI), also known as catalytic iron, in the care of critically ill patients in intensive care units (ICUs). These trace amounts of iron constitute a small percentage of the serum iron, yet they are heavily implicated in the exacerbation of diseases, primarily by catalyzing the formation of reactive oxygen species, which promote oxidative stress. Additionally, catalytic iron activates macrophages and facilitates the growth of pathogens. This review aims to shed light on this underappreciated phenomenon and explore the various common sources of NTBI in ICU patients, which lead to transient iron dysregulation during acute phases of disease. Iron serves as the linchpin of a vicious cycle in many ICU pathologies that are often multifactorial. The clinical evidence showing its detrimental impact on patient outcomes will be outlined in the major ICU pathologies. Finally, different therapeutic strategies will be reviewed, including the targeting of proteins involved in iron metabolism, conventional chelation therapy, and the combination of renal replacement therapy with chelation therapy.
Collapse
Affiliation(s)
- Coralie Grange
- MexBrain, 13 Avenue Albert Einstein, Villeurbanne, France
- Institut Lumière-Matière, UMR 5306, Université Claude Bernard Lyon1-CNRS, Villeurbanne Cedex, France
| | - François Lux
- Institut Lumière-Matière, UMR 5306, Université Claude Bernard Lyon1-CNRS, Villeurbanne Cedex, France.
- Institut Universitaire de France (IUF), 75231, Paris, France.
| | | | - Laurent David
- Institut National des Sciences Appliquées, CNRS UMR 5223, Ingénierie des Matériaux Polymères, Univ Claude Bernard Lyon 1, Université Jean Monnet, 15 bd Latarjet, 69622, Villeurbanne, France
| | - Aymeric Couturier
- MexBrain, 13 Avenue Albert Einstein, Villeurbanne, France
- Nephrology, American Hospital of Paris, Paris, France
| | - David E Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Bernard Allaouchiche
- University of Lyon, University Lyon I Claude Bernard, APCSe VetAgro Sup UP, 2021. A10, Marcy L'Étoile, France
| | - Olivier Tillement
- Institut Lumière-Matière, UMR 5306, Université Claude Bernard Lyon1-CNRS, Villeurbanne Cedex, France
| |
Collapse
|
|
14
|
Brittenham GM, Moir-Meyer G, Abuga KM, Datta-Mitra A, Cerami C, Green R, Pasricha SR, Atkinson SH. Biology of Anemia: A Public Health Perspective. J Nutr 2023; 153 Suppl 1:S7-S28. [PMID: 37778889 DOI: 10.1016/j.tjnut.2023.07.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 05/04/2023] [Accepted: 07/31/2023] [Indexed: 10/03/2023] Open
Abstract
Our goal is to present recent progress in understanding the biological mechanisms underlying anemia from a public health perspective. We describe important advances in understanding common causes of anemia and their interactions, including iron deficiency (ID), lack of other micronutrients, infection, inflammation, and genetic conditions. ID develops if the iron circulating in the blood cannot provide the amounts required for red blood cell production and tissue needs. ID anemia develops as iron-limited red blood cell production fails to maintain the hemoglobin concentration above the threshold used to define anemia. Globally, absolute ID (absent or reduced body iron stores that do not meet the need for iron of an individual but may respond to iron supplementation) contributes to only a limited proportion of anemia. Functional ID (adequate or increased iron stores that cannot meet the need for iron because of the effects of infection or inflammation and does not respond to iron supplementation) is frequently responsible for anemia in low- and middle-income countries. Absolute and functional ID may coexist. We highlight continued improvement in understanding the roles of infections and inflammation in causing a large proportion of anemia. Deficiencies of nutrients other than iron are less common but important in some settings. The importance of genetic conditions as causes of anemia depends upon the specific inherited red blood cell abnormalities and their prevalence in the settings examined. From a public health perspective, each setting has a distinctive composition of components underlying the common causes of anemia. We emphasize the coincidence between regions with a high prevalence of anemia attributed to ID (both absolute and functional), those with endemic infections, and those with widespread genetic conditions affecting red blood cells, especially in sub-Saharan Africa and regions in Asia and Oceania.
Collapse
Affiliation(s)
- Gary M Brittenham
- Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, United States.
| | - Gemma Moir-Meyer
- Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Kelvin Mokaya Abuga
- Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme, Kilifi, Kenya
| | - Ananya Datta-Mitra
- Department of Pathology and Laboratory Medicine, University of California, Davis, CA, United States
| | - Carla Cerami
- The Medical Research Council Unit, The Gambia, London School of Hygiene and Tropical Medicine, London, UK
| | - Ralph Green
- Department of Pathology and Laboratory Medicine, University of California, Davis, CA, United States
| | - Sant-Rayn Pasricha
- Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia; Diagnostic Haematology, The Royal Melbourne Hospital; and Clinical Haematology at the Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Parkville, VIC Australia
| | - Sarah H Atkinson
- Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme, Kilifi, Kenya; Department of Paediatrics, University of Oxford, Oxford, UK
| |
Collapse
|
|
15
|
Stefanache A, Lungu II, Butnariu IA, Calin G, Gutu C, Marcu C, Grierosu C, Bogdan Goroftei ER, Duceac LD, Dabija MG, Popa F, Damir D. Understanding How Minerals Contribute to Optimal Immune Function. J Immunol Res 2023; 2023:3355733. [PMID: 37946846 PMCID: PMC10632063 DOI: 10.1155/2023/3355733] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/16/2023] [Accepted: 09/09/2023] [Indexed: 11/12/2023] Open
Abstract
Sufficient mineral supply is vital not only for the innate immune system but also for the components of the adaptive immune defense, which encompass defense mechanisms against pathogens and the delicate balance of pro- and anti-inflammatory regulation in the long term. Generally, a well-balanced diet is capable of providing the necessary minerals to support the immune system. Nevertheless, specific vulnerable populations should be cautious about obtaining adequate amounts of minerals such as magnesium, zinc, copper, iron, and selenium. Inadequate levels of these minerals can temporarily impair immune competence and disrupt the long-term regulation of systemic inflammation. Therefore, comprehending the mechanisms and sources of these minerals is crucial. In exceptional circumstances, mineral deficiencies may necessitate supplementation; however, excessive intake of supplements can have adverse effects on the immune system and should be avoided. Consequently, any supplementation should be approved by medical professionals and administered in recommended doses. This review emphasizes the crucial significance of minerals in promoting optimal functioning of the immune system. It investigates the indispensable minerals required for immune system function and the regulation of inflammation. Moreover, it delves into the significance of maintaining an optimized intake of minerals from a nutritional standpoint.
Collapse
Affiliation(s)
- Alina Stefanache
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Ionut-Iulian Lungu
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | | | - Gabriela Calin
- Faculty of Dental Medicine, “Apollonia” University of Iasi, 11 Pacurari Street, Iasi 700511, Romania
| | - Cristian Gutu
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Constantin Marcu
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Carmen Grierosu
- Faculty of Dental Medicine, “Apollonia” University of Iasi, 11 Pacurari Street, Iasi 700511, Romania
| | | | - Letitia-Doina Duceac
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | | | - Florina Popa
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Daniela Damir
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| |
Collapse
|
|
16
|
Sangkhae V, Fisher AL, Ganz T, Nemeth E. Iron Homeostasis During Pregnancy: Maternal, Placental, and Fetal Regulatory Mechanisms. Annu Rev Nutr 2023; 43:279-300. [PMID: 37253681 PMCID: PMC10723031 DOI: 10.1146/annurev-nutr-061021-030404] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Pregnancy entails a large negative balance of iron, an essential micronutrient. During pregnancy, iron requirements increase substantially to support both maternal red blood cell expansion and the development of the placenta and fetus. As insufficient iron has long been linked to adverse pregnancy outcomes, universal iron supplementation is common practice before and during pregnancy. However, in high-resource countries with iron fortification of staple foods and increased red meat consumption, the effects of too much iron supplementation during pregnancy have become a concern because iron excess has also been linked to adverse pregnancy outcomes. In this review, we address physiologic iron homeostasis of the mother, placenta, and fetus and discuss perturbations in iron homeostasis that result in pathological pregnancy. As many mechanistic regulatory systems have been deduced from animal models, we also discuss the principles learned from these models and how these may apply to human pregnancy.
Collapse
Affiliation(s)
- Veena Sangkhae
- Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA;
| | - Allison L Fisher
- Endocrine Unit and Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Tomas Ganz
- Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA;
| | - Elizabeta Nemeth
- Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA;
| |
Collapse
|
|
17
|
Abstract
Iron overload remains a lethal complication of β-thalassemia and other anemias caused by ineffective erythropoiesis. This review discusses the pathogenetic mechanisms of iron overload in thalassemia, at organismal, cellular, and molecular levels.
Collapse
Affiliation(s)
- Tomas Ganz
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA.
| | - Elizabeta Nemeth
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA
| |
Collapse
|
|
18
|
Ginzburg YZ. Hepcidin and its multiple partners: Complex regulation of iron metabolism in health and disease. VITAMINS AND HORMONES 2023; 123:249-284. [PMID: 37717987 DOI: 10.1016/bs.vh.2023.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
Abstract
The peptide hormone hepcidin is central to the regulation of iron metabolism, influencing the movement of iron into the circulation and determining total body iron stores. Its effect on a cellular level involves binding ferroportin, the main iron export protein, preventing iron egress and leading to iron sequestration within ferroportin-expressing cells. Hepcidin expression is enhanced by iron loading and inflammation and suppressed by erythropoietic stimulation. Aberrantly increased hepcidin leads to systemic iron deficiency and/or iron restricted erythropoiesis as occurs in anemia of chronic inflammation. Furthermore, insufficiently elevated hepcidin occurs in multiple diseases associated with iron overload such as hereditary hemochromatosis and iron loading anemias. Abnormal iron metabolism as a consequence of hepcidin dysregulation is an underlying factor resulting in pathophysiology of multiple diseases and several agents aimed at manipulating this pathway have been designed, with some already in clinical trials. In this chapter, we assess the complex regulation of hepcidin, delineate the many binding partners involved in its regulation, and present an update on the development of hepcidin agonists and antagonists in various clinical scenarios.
Collapse
Affiliation(s)
- Yelena Z Ginzburg
- Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United Sates.
| |
Collapse
|
|
19
|
Hamilton F, Mitchell R, Ahmed H, Ghazal P, Timpson NJ. An observational and Mendelian randomisation study on iron status and sepsis. Sci Rep 2023; 13:2867. [PMID: 36808173 PMCID: PMC9938246 DOI: 10.1038/s41598-023-29641-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 02/08/2023] [Indexed: 02/19/2023] Open
Abstract
Iron deficiency is associated with a substantial burden of morbidity. However, supplementation of iron has been linked to increased rates of serious infection in randomised trials of children in sub-Saharan Africa. Randomised trials in other settings have been inconclusive and it is unknown if changes in levels of iron biomarkers are linked to sepsis in these other settings. We used genetic variants associated with levels of iron biomarkers as instrumental variables in a Mendelian randomisation (MR) analysis to test the hypothesis that increasing levels of iron biomarkers increase the risk of sepsis. In observational and MR analyses we found that increases in iron biomarkers increase the odds of sepsis. In stratified analyses, we show that this risk may be larger in those with iron deficiency and/or anaemia. Taken together, results here suggest a required caution in supplementation of iron and underline the role of iron homeostasis in severe infection.
Collapse
Affiliation(s)
- Fergus Hamilton
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
- Infection Sciences, North Bristol NHS Trust, Bristol, UK.
| | - Ruth Mitchell
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
| | - Haroon Ahmed
- Division of Population Medicine, Cardiff University Medical School, Cardiff, UK
| | - Peter Ghazal
- System Immunity Research Institute, Division of Infection and Immunity, Cardiff University, Cardiff, UK
| | - Nicholas J Timpson
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK
| |
Collapse
|
|
20
|
Abuga KM, Nairz M, MacLennan CA, Atkinson SH. Severe anaemia, iron deficiency, and susceptibility to invasive bacterial infections. Wellcome Open Res 2023; 8:48. [PMID: 37600584 PMCID: PMC10439361 DOI: 10.12688/wellcomeopenres.18829.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2023] [Indexed: 08/22/2023] Open
Abstract
Severe anaemia and invasive bacterial infections remain important causes of hospitalization and death among young African children. The emergence and spread of antimicrobial resistance demand better understanding of bacteraemia risk factors to inform prevention strategies. Epidemiological studies have reported an association between severe anaemia and bacteraemia. In this review, we explore evidence that severe anaemia is associated with increased risk of invasive bacterial infections in young children. We describe mechanisms of iron dysregulation in severe anaemia that might contribute to increased risk and pathogenesis of invasive bacteria, recent advances in knowledge of how iron deficiency and severe anaemia impair immune responses to bacterial infections and vaccines, and the gaps in our understanding of mechanisms underlying severe anaemia, iron deficiency, and the risk of invasive bacterial infections.
Collapse
Affiliation(s)
- Kelvin M. Abuga
- Kenya Medical Research Institute (KEMRI) Centre for Geographical Medicine Research-Coast, KEMRI-Wellcome Trust Research Programme, Kilifi, 80108, Kenya
- Open University, KEMRI-Wellcome Trust Research Programme – Accredited Research Centre, Kilifi, 80108, Kenya
| | - Manfred Nairz
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, 6020, Austria
| | - Calman A. MacLennan
- Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK
| | - Sarah H. Atkinson
- Kenya Medical Research Institute (KEMRI) Centre for Geographical Medicine Research-Coast, KEMRI-Wellcome Trust Research Programme, Kilifi, 80108, Kenya
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7LG, UK
- Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK
| |
Collapse
|
|
21
|
Abstract
Hepcidin, the iron-regulatory hormone, determines plasma iron concentrations and total body iron content. Hepcidin, secreted by hepatocytes, functions by controlling the activity of the cellular iron exporter ferroportin, which delivers iron to plasma from intestinal iron absorption and from iron stores. Hepcidin concentration in plasma is increased by iron loading and inflammation and is suppressed by erythropoietic stimulation and during pregnancy. Hepcidin deficiency causes iron overload in hemochromatosis and anemias with ineffective erythropoiesis. Hepcidin excess causes iron-restrictive anemias including anemia of inflammation. The development of hepcidin diagnostics and therapeutic agonists and antagonists should improve the treatment of iron disorders.
Collapse
Affiliation(s)
- Elizabeta Nemeth
- Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA;
| | - Tomas Ganz
- Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA;
| |
Collapse
|
|
22
|
Shi G, Ni Q, Miao Y, Huang H, Yin Z, Shi W, Shi M. Identification of WD-Repeat Protein 72 as a Novel Prognostic Biomarker in Non-Small-Cell Lung Cancer. Mediators Inflamm 2023; 2023:2763168. [PMID: 37197572 PMCID: PMC10185422 DOI: 10.1155/2023/2763168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 02/18/2023] [Accepted: 04/05/2023] [Indexed: 05/19/2023] Open
Abstract
WD-repeat protein 72(WDR72; OMIM∗613214), a scaffolding protein lacking intrinsic enzymatic activity, produces numerous β-propeller blade formations, serves as a binding platform to assemble protein complexes and is critical for cell growth, differentiation, adhesion, and migration. Despite evidence supporting a basic role of WDR72 in the tumorigenesis of particular cancers, the value of WDR72 in non-small-cell lung cancer (NSCLC), the tumor with the highest mortality rate globally, is undocumented. We investigated the prognostic value of WDR72 in NSCLC and studied its potential immune function and its correlation with ferroptosis. According to The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype-Tissue Expression, and Gene Set Cancer Analysis, we used multiple bioinformatic strategies to investigate the possible oncogenic role of WDR72, analyze WDR72 and prognosis, and immune cell infiltration in different tumors correlation. WDR72 exhibited a high expression in NSCLC and a positive association with prognosis. WDR72 expression was related to immune cell infiltration and tumor immune microenvironment in NSCLC. Finally, we validated WDR72 in human NSCLC; it has a predictive value in NSCLC related to its function in tumor progression and immunity. The significance of our study is that WDR72 can be used as a potential indicator of lung cancer prognosis. Helping physicians more accurately predict patient survival and risk of disease progression.
Collapse
Affiliation(s)
- Guanglin Shi
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
- Department of Respiratory Diseases, The Sixth People's Hospital of Nantong (Affiliated Nantong Hospital of Shanghai University), Nantong, Jiangsu 226011, China
| | - Qinggan Ni
- Department of Burns and Plastic Surgery, Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng 224000, China
| | - Yuqing Miao
- Department of Respiratory Diseases, The Sixth People's Hospital of Nantong (Affiliated Nantong Hospital of Shanghai University), Nantong, Jiangsu 226011, China
| | - Hua Huang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226011, China
| | - Zhongbo Yin
- Department of Pathology, The Sixth People's Hospital of Nantong (Affiliated Nantong Hospital of Shanghai University), Nantong, Jiangsu 226011, China
| | - Weirong Shi
- Department of Thoracic Surgery, The Sixth People's Hospital of Nantong (Affiliated Nantong Hospital of Shanghai University), Nantong (Affiliated Nantong Hospital of Shanghai University), Jiangsu 226011, China
| | - Minhua Shi
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| |
Collapse
|
|
23
|
Xie Y, Liu F, Zhang X, Jin Y, Li Q, Shen H, Fu H, Mao J. Benefits and risks of essential trace elements in chronic kidney disease: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1400. [PMID: 36660676 PMCID: PMC9843383 DOI: 10.21037/atm-22-5969] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 12/19/2022] [Indexed: 01/01/2023]
Abstract
Background and Objective Chronic kidney disease (CKD) is an important public health concern. With the decline of renal function, CKD patients gradually progress to end-stage kidney disease and need to undergo dialysis or kidney transplantation to maintain life, bringing a heavy economic burden to the family and society. Therefore, it is necessary to effectively prevent and delay the progression of CKD. Essential trace elements play an indispensable role in CKD, and the objective of this study is to systematically review their benefits in the disease and summarize the risks of their excess. Methods The keywords "trace elements", "chronic kidney disease", "dialysis", "inflammation", and "fibrosis" and their combinations were used to search for relevant literature published in the PubMed database and Web of Science. We then summarized the role of trace element abnormalities in CKD patients in anemia, oxidative stress, inflammation, and chronic fibrosis, and the risk of their excess. Key Content and Findings Imbalance of essential trace elements is a common complication of CKD and a risk factor for CKD progression, cardiovascular events, and death. This article reviews the effects of essential trace elements (iron, zinc, selenium, copper, iodine, and manganese) on CKD. We analyze literature and discuss the advantages and disadvantages of various essential trace elements. Conclusions Research shows CKD patients have an imbalance of essential trace elements, and treatment based on these is an important direction for future exploration. A knowledge of the homeostasis of trace elements is important to improving the prognosis of CKD patients and delaying the progression of the disease.
Collapse
Affiliation(s)
- Yi Xie
- Department of Nephrology, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Fei Liu
- Department of Nephrology, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Xiaojing Zhang
- Department of Nephrology, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Yanyan Jin
- Department of Nephrology, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Qiuyu Li
- Department of Nephrology, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Huijun Shen
- Department of Nephrology, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Haidong Fu
- Department of Nephrology, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Jianhua Mao
- Department of Nephrology, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| |
Collapse
|
|
24
|
The role of iron in chronic inflammatory diseases: from mechanisms to treatment options in anemia of inflammation. Blood 2022; 140:2011-2023. [PMID: 35994752 DOI: 10.1182/blood.2021013472] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/09/2022] [Indexed: 11/20/2022] Open
Abstract
Anemia of inflammation (AI) is a highly prevalent comorbidity in patients affected by chronic inflammatory disorders, such as chronic kidney disease, inflammatory bowel disease, or cancer, that negatively affect disease outcome and quality of life. The pathophysiology of AI is multifactorial, with inflammatory hypoferremia and iron-restricted erythropoiesis playing a major role in the context of disease-specific factors. Here, we review the recent progress in our understanding of the molecular mechanisms contributing to iron dysregulation in AI, the impact of hypoferremia and anemia on the course of the underlying disease, and (novel) therapeutic strategies applied to treat AI.
Collapse
|
|
25
|
Forceville X, Van Antwerpen P, Annane D, Vincent JL. Selenocompounds and Sepsis-Redox Bypass Hypothesis: Part B-Selenocompounds in the Management of Early Sepsis. Antioxid Redox Signal 2022; 37:998-1029. [PMID: 35287478 DOI: 10.1089/ars.2020.8062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Significance: Endothelial barrier damage, which is in part caused by excess production of reactive oxygen, halogen and nitrogen species (ROHNS), especially peroxynitrite (ONOO-), is a major event in early sepsis and, with leukocyte hyperactivation, part of the generalized dysregulated immune response to infection, which may even become a complex maladaptive state. Selenoenzymes have major antioxidant functions. Their synthesis is related to the need to limit deleterious oxidant redox cycling by small selenocompounds, which may be of therapeutic cytotoxic interest. Plasma selenoprotein-P is crucial for selenium transport from the liver to the tissues and for antioxidant endothelial protection, especially against ONOO-. Above micromolar concentrations, sodium selenite (Na2SeO3) becomes cytotoxic, with a lower cytotoxicity threshold in activated cells, which has led to cancer research. Recent Advances: Plasma selenium (<2% of total body selenium) is mainly contained in selenoprotein-P, and concentrations decrease rapidly in the early phase of sepsis, because of increased selenoprotein-P binding and downregulation of hepatic synthesis and excretion. At low concentrations, Na2SeO3 acts as a selenium donor, favoring selenoprotein-P synthesis in physiology, but probably not in the acute phase of sepsis. Critical Issues: The cytotoxic effects of Na2SeO3 against hyperactivated leukocytes, especially the most immature forms that liberate ROHNS, may be beneficial, but they may also be harmful for activated endothelial cells. Endothelial protection against ROHNS by selenoprotein-P may reduce Na2SeO3 toxicity, which is increased in sepsis. Future Direction: The combination of selenoprotein-P for endothelial protection and the cytotoxic effects of Na2SeO3 against hyperactivated leukocytes may be a promising intervention for early sepsis. Antioxid. Redox Signal. 37, 998-1029.
Collapse
Affiliation(s)
- Xavier Forceville
- Medico-surgical Intensive Care Unit, Great Hospital of East Francilien - Meaux site, Meaux, France.,Clinical Investigation Centre (CIC Inserm1414) CHU de Rennes - Université de Rennes 1, Rennes, France
| | - Pierre Van Antwerpen
- Pharmacognosy, Bioanalysis and Drug Discovery and Analytical Platform of the Faculty of Pharmacy, Univesité libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Djillali Annane
- Service de Réanimation Médicale, Hôpital Raymond Poincaré (APHP), Garches, France.,U1173 Lab. of Inflammation & Infection, (Fédération Hospitalo-Universitaire) FHU SEPSIS, Université Paris Saclay-campus (Université de Versailles Saint-Quentin-en-Yvelines) UVSQ, Versailles, France
| | - Jean Louis Vincent
- Department of Intensive Care, Erasme University Hospital, Université libre de Bruxelles, Brussels, Belgium
| |
Collapse
|
|
26
|
Frost JN, Wideman SK, Preston AE, Teh MR, Ai Z, Wang L, Cross A, White N, Yazicioglu Y, Bonadonna M, Clarke AJ, Armitage AE, Galy B, Udalova IA, Drakesmith H. Plasma iron controls neutrophil production and function. SCIENCE ADVANCES 2022; 8:eabq5384. [PMID: 36197985 PMCID: PMC9534512 DOI: 10.1126/sciadv.abq5384] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 08/18/2022] [Indexed: 05/31/2023]
Abstract
Low plasma iron (hypoferremia) induced by hepcidin is a conserved inflammatory response that protects against infections but inhibits erythropoiesis. How hypoferremia influences leukocytogenesis is unclear. Using proteomic data, we predicted that neutrophil production would be profoundly more iron-demanding than generation of other white blood cell types. Accordingly in mice, hepcidin-mediated hypoferremia substantially reduced numbers of granulocytes but not monocytes, lymphocytes, or dendritic cells. Neutrophil rebound after anti-Gr-1-induced neutropenia was blunted during hypoferremia but was rescued by supplemental iron. Similarly, hypoferremia markedly inhibited pharmacologically stimulated granulopoiesis mediated by granulocyte colony-stimulating factor and inflammation-induced accumulation of neutrophils in the spleen and peritoneal cavity. Furthermore, hypoferremia specifically altered neutrophil effector functions, suppressing antibacterial mechanisms but enhancing mitochondrial reactive oxygen species-dependent NETosis associated with chronic inflammation. Notably, antagonizing endogenous hepcidin during acute inflammation enhanced production of neutrophils. We propose plasma iron modulates the profile of innate immunity by controlling monocyte-to-neutrophil ratio and neutrophil activity in a therapeutically targetable system.
Collapse
Affiliation(s)
- Joe N. Frost
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Sarah K. Wideman
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Alexandra E. Preston
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Megan R. Teh
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Zhichao Ai
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Lihui Wang
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Amy Cross
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DS, UK
| | - Natasha White
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Yavuz Yazicioglu
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Michael Bonadonna
- German Cancer Research Center, “Division of Virus-Associated Carcinogenesis”, Im Neuenheimer Feld 280, 69120, 69120 Heidelberg, Germany
- Biosciences Faculty, University of Heidelberg, 69120 Heidelberg, Germany
| | - Alexander J. Clarke
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Andrew E. Armitage
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Bruno Galy
- German Cancer Research Center, “Division of Virus-Associated Carcinogenesis”, Im Neuenheimer Feld 280, 69120, 69120 Heidelberg, Germany
| | - Irina A. Udalova
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Hal Drakesmith
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
| |
Collapse
|
|
27
|
Hegelund MH, Glenthøj A, Ryrsø CK, Ritz C, Dungu AM, Sejdic A, List KCK, Krogh-Madsen R, Lindegaard B, Kurtzhals JAL, Faurholt-Jepsen D. Biomarkers for iron metabolism among patients hospitalized with community-acquired pneumonia caused by infection with SARS-CoV-2, bacteria, and influenza. APMIS 2022; 130:590-596. [PMID: 35751642 PMCID: PMC9349447 DOI: 10.1111/apm.13259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 06/22/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Ferritin, the central iron storage protein, has attracted attention as a biomarker of severe COVID-19. Few studies have investigated regulators of iron metabolism in the context of COVID-19. The aim was to evaluate biomarkers for iron metabolism in the acute phase response to community-acquired pneumonia (CAP) caused by SARS-CoV-2 compared to CAP caused by bacteria or influenza virus in hospitalized patients. METHODS A cross-sectional study of 164 patients from the Surviving Pneumonia Cohort recruited between January 8, 2019 and May 26, 2020. Blood samples were collected at admission and analyzed for levels of C-reactive protein (CRP), ferritin, soluble transferrin receptor, erythroferrone, and hepcidin. RESULTS Median (IQR) hepcidin was higher in SARS-CoV-2 with 143.8 (100.7-180.7) ng/mL compared to bacterial and influenza infection with 78.8 (40.1-125.4) and 53.5 (25.2-125.8) ng/mL, respectively. The median ferritin level was more than 2-fold higher in patients with SARS-CoV-2 compared to the other etiologies (p<0.001). Patients with SARS-CoV-2 had lower levels of erythroferrone and CRP compared to those infected with bacteria. CONCLUSION Higher levels of hepcidin and lower levels of erythroferrone despite lower CRP levels among patients with SARS-CoV-2 compared to those infected with bacteria indicate alterations in iron metabolism in patients with SARS-CoV-2 infection.
Collapse
Affiliation(s)
- Maria Hein Hegelund
- Department of Pulmonary and Infectious Diseases, Nordsjaellands Hospital, Hillerød, Denmark
| | | | - Camilla Koch Ryrsø
- Department of Pulmonary and Infectious Diseases, Nordsjaellands Hospital, Hillerød, Denmark.,Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Christian Ritz
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Arnold Matovu Dungu
- Department of Pulmonary and Infectious Diseases, Nordsjaellands Hospital, Hillerød, Denmark
| | - Adin Sejdic
- Department of Pulmonary and Infectious Diseases, Nordsjaellands Hospital, Hillerød, Denmark
| | | | - Rikke Krogh-Madsen
- Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.,Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark
| | - Birgitte Lindegaard
- Department of Pulmonary and Infectious Diseases, Nordsjaellands Hospital, Hillerød, Denmark.,Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.,Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen Anders Lindholm Kurtzhals
- Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark.,Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | | |
Collapse
|
|
28
|
Herdes RE, Oliveira SB, Kocoshis SA, Bernieh A, Namjoshi SS. Pitfalls of Iron Supplementation in Parenteral Nutrition Admixtures for Children with Intestinal Failure. JPEN J Parenter Enteral Nutr 2022; 46:1944-1947. [PMID: 35730416 DOI: 10.1002/jpen.2428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 05/21/2022] [Accepted: 06/19/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Pediatric patients with intestinal failure are at increased risk for iron deficiency. Supplementation is not routinely included in parenteral nutrition solutions. There is currently limited research related to the safety of iron supplementation in parenteral nutrition and for intravenous forms used in patients with intestinal failure. Current ASPEN and ESPGHAN guidelines promote the use of enteral iron, acknowledging the risks of using iron supplementation within parenteral nutrition admixtures. METHODS We review a patient case and the current available literature related to iron in parenteral nutrition. RESULTS Five major concerns are identified: peroxidation reactions, incompatibility, hypersensitivity, infection risk, and iron overload. CONCLUSION We propose an argument against the preferential use of iron supplementation within parenteral nutrition in children with intestinal failure when enteral supplementation or intermittent parenteral infusion may be sufficient. CLINICAL RELEVANCY STATEMENT Pediatric patients with intestinal failure are at risk for iron deficiency anemia, anemia due to folate or B12 deficiency, vitamin B6 deficiency, copper deficiency, non-anemic iron deficiency, and anemia of inflammation. Iron status assessment and supplementation for these patients is variable over time. There are several biochemical and physiologic concerns about the safety of adding iron supplementation to parenteral nutrition admixtures. This paper briefly reviews the current available literature. Further research is needed to evaluate best practices for iron supplementation for pediatric patients with intestinal failure. This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
- Rachel E Herdes
- Stanford University School of Medicine, Division of Pediatric Gastroenterology, Hepatology, and Nutrition
| | - Stephanie B Oliveira
- Cincinnati Children's Hospital Medical Center, Division of Pediatric Gastroenterology, Hepatology, and Nutrition
| | - Samuel A Kocoshis
- Cincinnati Children's Hospital Medical Center, Division of Pediatric Gastroenterology, Hepatology, and Nutrition
| | - Anas Bernieh
- Cincinnati Children's Hospital Medical Center, Division of Pathology and Laboratory Medicine
| | - Shweta S Namjoshi
- Stanford University School of Medicine, Division of Pediatric Gastroenterology, Hepatology, and Nutrition
| |
Collapse
|
|
29
|
Ogura J, Sato T, Higuchi K, Sivaprakasam S, Kopel J, Bhutia YD, Ganapathy V. Binding of Citrate-Fe 3+ to Plastic Culture Dishes, an Artefact Useful as a Simple Technique to Screen for New Iron Chelators. Int J Mol Sci 2022; 23:ijms23126657. [PMID: 35743100 PMCID: PMC9223814 DOI: 10.3390/ijms23126657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/05/2022] [Accepted: 06/09/2022] [Indexed: 11/21/2022] Open
Abstract
NaCT mediates citrate uptake in the liver cell line HepG2. When these cells were exposed to iron (Fe3+), citrate uptake/binding as monitored by the association of [14C]-citrate with cells increased. However, there was no change in NaCT expression and function, indicating that NaCT was not responsible for this Fe3+-induced citrate uptake/binding. Interestingly however, the process exhibited substrate selectivity and saturability as if the process was mediated by a transporter. Notwithstanding these features, subsequent studies demonstrated that the iron-induced citrate uptake/binding did not involve citrate entry into cells; instead, the increase was due to the formation of citrate-Fe3+ chelate that adsorbed to the cell surface. Surprisingly, the same phenomenon was observed in culture wells without HepG2 cells, indicating the adsorption of the citrate-Fe3+ chelate to the plastic surface of culture wells. We used this interesting phenomenon as a simple screening technique for new iron chelators with the logic that if another iron chelator is present in the assay system, it would compete with citrate for binding to Fe3+ and prevent the formation and adsorption of citrate-Fe3+ to the culture well. This technique was validated with the known iron chelators deferiprone and deferoxamine, and with the bacterial siderophore 2,3-dihydroxybenzoic acid and the catechol carbidopa.
Collapse
Affiliation(s)
- Jiro Ogura
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (J.O.); (T.S.); (K.H.); (S.S.); (J.K.); (Y.D.B.)
- Graduate School of Pharmaceutical Sciences, Yamagata University, Yamagata 990-8560, Japan
| | - Toshihiro Sato
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (J.O.); (T.S.); (K.H.); (S.S.); (J.K.); (Y.D.B.)
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Kei Higuchi
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (J.O.); (T.S.); (K.H.); (S.S.); (J.K.); (Y.D.B.)
- Department of Pharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
| | - Sathish Sivaprakasam
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (J.O.); (T.S.); (K.H.); (S.S.); (J.K.); (Y.D.B.)
| | - Jonathan Kopel
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (J.O.); (T.S.); (K.H.); (S.S.); (J.K.); (Y.D.B.)
| | - Yangzom D. Bhutia
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (J.O.); (T.S.); (K.H.); (S.S.); (J.K.); (Y.D.B.)
| | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (J.O.); (T.S.); (K.H.); (S.S.); (J.K.); (Y.D.B.)
- Correspondence: ; Tel.: +1-(806)-743-2518
| |
Collapse
|
|
30
|
Sangkhae V, Nemeth E. Quantitating Iron Transport across the Mouse Placenta In Vivo using Nonradioactive Iron Isotopes. JOURNAL OF VISUALIZED EXPERIMENTS : JOVE 2022:10.3791/63378. [PMID: 35635455 PMCID: PMC9927870 DOI: 10.3791/63378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Iron is essential for maternal and fetal health during pregnancy, with approximately 1 g of iron needed in humans to sustain a healthy pregnancy. Fetal iron endowment is entirely dependent on iron transfer across the placenta, and perturbations of this transfer can lead to adverse pregnancy outcomes. In mice, measurement of iron fluxes across the placenta traditionally relied on radioactive iron isotopes, a highly sensitive but burdensome approach. Stable iron isotopes (57Fe and 58Fe) offer a nonradioactive alternative for use in human pregnancy studies. Under physiological conditions, transferrin-bound iron is the predominant form of iron taken up by the placenta. Thus, 58Fe-transferrin was prepared and injected intravenously in pregnant dams to directly assess placental iron transport and bypass maternal intestinal iron absorption as a confounding variable. Isotopic iron was quantitated in the placenta and mouse embryonic tissues by inductively coupled plasma mass spectrometry (ICP-MS). These methods can also be employed in other animal model systems of physiology or disease to quantify in vivo iron dynamics.
Collapse
Affiliation(s)
- Veena Sangkhae
- Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles;
| | - Elizabeta Nemeth
- Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles
| |
Collapse
|
|
31
|
Ganz T. Hepcidin: looking back at two decades of progress. NATURE CARDIOVASCULAR RESEARCH 2022; 1:191-193. [PMID: 39195985 DOI: 10.1038/s44161-022-00034-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Affiliation(s)
- Tomas Ganz
- Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
| |
Collapse
|
|
32
|
Characterization of acquired anemia in children by iron metabolism parameters. Sci Rep 2022; 12:2721. [PMID: 35177695 PMCID: PMC8854386 DOI: 10.1038/s41598-022-06574-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/19/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammatory states are associated with anemia of chronic disease and acute infection. Hepcidin, a regulator of iron metabolism, is involved in iron pathophysiology during inflammation. We investigated biochemical characteristics in children with anemia from different causes. Four patient groups (n = 38; mean age: 12.44 ± 4.35 years) were studied: (1) inflammatory bowel disease (IBD, 10 patients); (2) iron deficiency anemia (IDA, 12); (3) celiac disease (CD, 8); (4) acute infection (AI, 8). Laboratory measurements were evaluated at diagnosis: blood count, serum iron, transferrin, ferritin, vitamin B12, folic acid, CRP, erythropoietin, hepcidin and soluble transferrin receptor (sTfR). IDA patients had the lowest Hgb (6.9 ± 1.7 g/dL), MCV (63.2 ± 7.2 fL), iron (16.8 ± 13.5 µg/dL), ferritin (4.5 ± 4.5 ng/mL) and hepcidin (3.1 ± 0.8 ng/mL) values, and the highest transferrin and sTfR values. AI patients had the highest ferritin (156.2 ± 124.5 ng/mL), CRP (144.6 ± 94 mg/L) and hepcidin (74.67 ± 12.3 ng/ml) values. Overall, hepcidin levels correlated with CRP and with ferritin (r = 0.83 and 0.85, respectively). Elucidating specific etiology-related biochemical profiles in pediatric patients with anemia from different causes using a combination of laboratory biomarkers, including hepcidin, can help physicians treat the anemia.
Collapse
|
|
33
|
La Carpia F, Slate A, Bandyopadhyay S, Wojczyk BS, Godbey EA, Francis KP, Prestia K, Hod EA. Red blood cell transfusion-induced non-transferrin-bound iron promotes Pseudomonas aeruginosa biofilms in human sera and mortality in catheterized mice. Br J Haematol 2022; 196:1105-1110. [PMID: 34726258 PMCID: PMC8831455 DOI: 10.1111/bjh.17934] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 10/20/2021] [Indexed: 02/03/2023]
Abstract
Transfusion of storage-damaged red blood cells (RBCs) increases non-transferrin-bound iron (NTBI) levels in humans. This can potentially enhance virulence of microorganisms. In this study, Pseudomonas aeruginosa replication and biofilm production in vitro correlated with NTBI levels of transfused subjects (R2 = 0·80; P < 0·0001). Transfusion of stored RBCs into catheterized mice enhanced P. aeruginosa virulence and mortality in vivo, while pre-administration of apotransferrin reduced NTBI levels improving survival (69% vs 27% mortality; P < 0·05). These results suggest that longer RBC storage, by modulating the bioavailability of iron, may increase the risk of P. aeruginosa biofilm-related infections in transfused patients.
Collapse
Affiliation(s)
- Francesca La Carpia
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Andrea Slate
- Center for Comparative Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Sheila Bandyopadhyay
- Department of Biological Science, Division of Life Science, School of Arts and Science, Rutgers University, Newark, NJ, USA
| | - Boguslaw S. Wojczyk
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Elizabeth A. Godbey
- Department of Pathology, Virginia Commonwealth University Health, Richmond, Virginia, USA
| | | | - Kevin Prestia
- Division of Comparative Medicine, NYU Langone Health, New York, NY, USA
| | - Eldad A. Hod
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| |
Collapse
|
|
34
|
Das S, Saqib M, Meng RC, Chittur SV, Guan Z, Wan F, Sun W. Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis. Proc Natl Acad Sci U S A 2022; 119:e2110166119. [PMID: 34969677 PMCID: PMC8764673 DOI: 10.1073/pnas.2110166119] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2021] [Indexed: 12/19/2022] Open
Abstract
Hemachromatosis (iron-overload) increases host susceptibility to siderophilic bacterial infections that cause serious complications, but the underlying mechanisms remain elusive. The present study demonstrates that oral infection with hyperyersiniabactin (Ybt) producing Yersinia pseudotuberculosis Δfur mutant (termed Δfur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δfur-infected intestine revealed up-regulation in cytokine-cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and down-regulation in cell-adhesion molecules and Toll-like receptor signaling pathways. Further studies indicate that dysregulated interleukin (IL)-1β signaling triggered in hemachromatotic mice infected with Δfur damages the intestinal barrier by activation of myosin light-chain kinases (MLCK) and excessive neutrophilia. Inhibiting MLCK activity or depleting neutrophil infiltration reduces barrier disruption, largely ameliorates immunopathology, and substantially rescues hemochromatotic mice from lethal Δfur infection. Moreover, early intervention of IL-1β overproduction can completely rescue hemochromatotic mice from the lethal infection.
Collapse
Affiliation(s)
- Shreya Das
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208
| | - Mohd Saqib
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208
| | - Ryan C Meng
- Center for Functional Genomics, University at Albany-State University of New York, Rensselaer, NY 12144
| | - Sridar V Chittur
- Center for Functional Genomics, University at Albany-State University of New York, Rensselaer, NY 12144
| | - Ziqiang Guan
- Department of Biochemistry, Duke University Medical Center, Durham, NC 27710
| | - Fengyi Wan
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205
| | - Wei Sun
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208;
| |
Collapse
|
|
35
|
Lanz P, Wieczorek M, Sadlon A, de Godoi Rezende Costa Molino C, Abderhalden LA, Schaer DJ, Spahn DR, Freystätter G, Orav EJ, Egli A, Bischoff-Ferrari HA. Iron Deficiency and Incident Infections among Community-Dwelling Adults Age 70 Years and Older: Results from the DO-HEALTH Study. J Nutr Health Aging 2022; 26:864-871. [PMID: 36156678 DOI: 10.1007/s12603-022-1836-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
OBJECTIVES To assess if baseline iron deficiency, with or without anemia, is associated with incident infections over 3 years among community-dwelling older adults. DESIGN Prospective secondary analysis of DO-HEALTH, a 3-year randomized, double-blind controlled trial. SETTING AND PARTICIPANTS 2157 community-dwelling adults age 70+ from 5 European countries with good cognitive function and mobility and no major health events in the 5 years prior to enrollment Measurements: Incident infections, their severity and type were recorded every 3 months throughout the 3-year follow-up. Iron deficiency was defined as soluble transferrin receptor (sTfR) levels > 28.1 nmol/l and anemia as hemoglobin levels < 120 g/l for women and 130 g/l for men. We applied negative binomial mixed effects regression models with random effects for countries, and controlling for treatment allocation, age, sex, body mass index, polypharmacy, number of comorbidities, smoking status, living situation, alcohol intake, frailty status, and physical activity levels. A pre-defined stratified analysis was performed to explore if the associations between iron deficiency and infections were consistent by baseline anemia status. RESULTS In total, 2141 participants were included in the analyses (mean age 74.9 years, 61.5% of women, 26.8% with iron deficiency). Across all participants, baseline iron deficiency was not associated with incident overall infections, but was associated with a 63% greater rate of incident severe infections requiring hospitalization (incidence rate ratio [IRR] 1.63, 95% Confidence Interval [CI] 1.11-2.41, p=0.01). This association was more pronounced among the 2000 participants who did not have anemia at baseline (IRR=1.80, 95% CI 1.20-2.69, p=0.005). CONCLUSION Based on this prospective study among generally healthy European community-dwelling older adults, iron deficiency was not associated with the incidence rate of overall infections but may increase the incidence of severe infections. Intervention studies are needed to prove the causality of this observation.
Collapse
Affiliation(s)
- P Lanz
- Heike A. Bischoff-Ferrari, University Hospital Zurich, Department of Aging Medicine and Aging Research, Raemistrasse 101, 8091 Zurich, Switzerland, ORCID 0000-0002-4554-658X, Phone: +41-44-255-2757,
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Rund D. Intravenous Iron and Infection Risk-Still an Unanswered Question. JAMA Netw Open 2021; 4:e2134453. [PMID: 34767028 DOI: 10.1001/jamanetworkopen.2021.34453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Deborah Rund
- Haematology Department, Hebrew University-Hadassah Medical Organization, Jerusalem, Israel
| |
Collapse
|
|
37
|
The role of iron homeostasis in remodeling immune function and regulating inflammatory disease. Sci Bull (Beijing) 2021; 66:1806-1816. [PMID: 36654387 DOI: 10.1016/j.scib.2021.02.010] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/31/2020] [Accepted: 01/28/2021] [Indexed: 02/03/2023]
Abstract
The essential trace element iron regulates a wide range of biological processes in virtually all living organisms. Because both iron deficiency and iron overload can lead to various pathological conditions, iron homeostasis is tightly regulated, and understanding this complex process will help pave the way to developing new therapeutic strategies for inflammatory disease. In recent years, significant progress has been made with respect to elucidating the roles of iron and iron-related genes in the development and maintenance of the immune system. Here, we review the timing and mechanisms by which systemic and cellular iron metabolism are regulated during the inflammatory response and during infectious disease, processes in which both the host and the pathogen compete for iron. We also discuss the evidence and implications that immune cells such as macrophages, T cells, and B cells require sufficient amounts of iron for their proliferation and for mediating their effector functions, in which iron serves as a co-factor in toll-like receptor 4 (TLR4) signaling, mitochondrial respiration, posttranslational regulation, and epigenetic modification. In addition, we discuss the therapeutic implications of targeting ferroptosis, iron homeostasis and/or iron metabolism with respect to conferring protection against pathogen infection, controlling inflammation, and improving the efficacy of immunotherapy.
Collapse
|
|
38
|
Iron loading induces cholesterol synthesis and sensitizes endothelial cells to TNFα-mediated apoptosis. J Biol Chem 2021; 297:101156. [PMID: 34480898 PMCID: PMC8463868 DOI: 10.1016/j.jbc.2021.101156] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 07/22/2021] [Accepted: 08/31/2021] [Indexed: 01/06/2023] Open
Abstract
In plasma, iron is normally bound to transferrin, the principal protein in blood responsible for binding and transporting iron throughout the body. However, in conditions of iron overload when the iron-binding capacity of transferrin is exceeded, non-transferrin-bound iron (NTBI) appears in plasma. NTBI is taken up by hepatocytes and other parenchymal cells via NTBI transporters and can cause cellular damage by promoting the generation of reactive oxygen species. However, how NTBI affects endothelial cells, the most proximal cell type exposed to circulating NTBI, has not been explored. We modeled in vitro the effects of systemic iron overload on endothelial cells by treating primary human umbilical vein endothelial cells (HUVECs) with NTBI (ferric ammonium citrate [FAC]). We showed by RNA-Seq that iron loading alters lipid homeostasis in HUVECs by inducing sterol regulatory element-binding protein 2-mediated cholesterol biosynthesis. We also determined that FAC increased the susceptibility of HUVECs to apoptosis induced by tumor necrosis factor-α (TNFα). Moreover, we showed that cholesterol biosynthesis contributes to iron-potentiated apoptosis. Treating HUVECs with a cholesterol chelator hydroxypropyl-β-cyclodextrin demonstrated that depletion of cholesterol was sufficient to rescue HUVECs from TNFα-induced apoptosis, even in the presence of FAC. Finally, we showed that FAC or cholesterol treatment modulated the TNFα pathway by inducing novel proteolytic processing of TNFR1 to a short isoform that localizes to lipid rafts. Our study raises the possibility that iron-mediated toxicity in human iron overload disorders is at least in part dependent on alterations in cholesterol metabolism in endothelial cells, increasing their susceptibility to apoptosis.
Collapse
|
|
39
|
Forceville X, Van Antwerpen P, Preiser JC. Selenocompounds and Sepsis: Redox Bypass Hypothesis for Early Diagnosis and Treatment: Part A-Early Acute Phase of Sepsis: An Extraordinary Redox Situation (Leukocyte/Endothelium Interaction Leading to Endothelial Damage). Antioxid Redox Signal 2021; 35:113-138. [PMID: 33567962 DOI: 10.1089/ars.2020.8063] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Sepsis is a health disaster. In sepsis, an initial, beneficial local immune response against infection evolves rapidly into a generalized, dysregulated response or a state of chaos, leading to multiple organ failure. Use of life-sustaining supportive therapies creates an unnatural condition, enabling the complex cascades of the sepsis response to develop in patients who would otherwise die. Multiple attempts to control sepsis at an early stage have been unsuccessful. Recent Advances: Major events in early sepsis include activation and binding of leukocytes and endothelial cells in the microcirculation, damage of the endothelial surface layer (ESL), and a decrease in the plasma concentration of the antioxidant enzyme, selenoprotein-P. These events induce an increase in intracellular redox potential and lymphocyte apoptosis, whereas apoptosis is delayed in monocytes and neutrophils. They also induce endothelial mitochondrial and cell damage. Critical Issues: Neutrophil production increases dramatically, and aggressive immature forms are released. Leukocyte cross talk with other leukocytes and with damaged endothelial cells amplifies the inflammatory response. The release of large quantities of reactive oxygen, halogen, and nitrogen species as a result of the leukocyte respiratory burst, endothelial mitochondrial damage, and ischemia/reperfusion processes, along with the marked decrease in selenoprotein-P concentrations, leads to peroxynitrite damage of the ESL, reducing flow and damaging the endothelial barrier. Future Directions: Endothelial barrier damage by activated leukocytes is a time-sensitive event in sepsis, occurring within hours and representing the first step toward organ failure and death. Reducing or stopping this event is necessary before irreversible damage occurs.
Collapse
Affiliation(s)
- Xavier Forceville
- Medico-Surgical Intensive Care Unit, Great Hospital of East Francilien-Meaux Site, Hôpital Saint Faron, Meaux, France.,Clinical Investigation Center (CIC Inserm 1414), CHU de Rennes, Université de Rennes 1, Rennes, France
| | - Pierre Van Antwerpen
- Pharmacognosy, Bioanalysis and Drug Discovery and Analytical Platform of the Faculty of Pharmacy, Université libre de Bruxelles (ULB), Bruxelles, Belgium
| | | |
Collapse
|
|
40
|
Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis. Int J Mol Sci 2021; 22:ijms22126493. [PMID: 34204327 PMCID: PMC8235187 DOI: 10.3390/ijms22126493] [Citation(s) in RCA: 261] [Impact Index Per Article: 65.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/14/2021] [Accepted: 06/14/2021] [Indexed: 12/13/2022] Open
Abstract
Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.
Collapse
|
|
41
|
Colucci S, Marques O, Altamura S. 20 years of Hepcidin: How far we have come. Semin Hematol 2021; 58:132-144. [PMID: 34389105 DOI: 10.1053/j.seminhematol.2021.05.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/12/2021] [Accepted: 05/31/2021] [Indexed: 12/20/2022]
Abstract
Twenty years ago the discovery of hepcidin deeply changed our understanding of the regulation of systemic iron homeostasis. It is now clear that hepcidin orchestrates systemic iron levels by controlling the amount of iron exported into the bloodstream through ferroportin. Hepcidin expression is increased in situations where systemic iron levels should be reduced, such as in iron overload and infection. Conversely, hepcidin is repressed during iron deficiency, hypoxia or expanded erythropoiesis, to increase systemic iron availability and sustain erythropoiesis. In this review, we will focus on molecular mechanisms of hepcidin regulation and on the pathological consequences of their disruption.
Collapse
Affiliation(s)
- Silvia Colucci
- Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, EMBL and University of Heidelberg, Heidelberg, Germany
| | - Oriana Marques
- Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, EMBL and University of Heidelberg, Heidelberg, Germany
| | - Sandro Altamura
- Department of Pediatric Hematology, Oncology and Immunology - University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit, EMBL and University of Heidelberg, Heidelberg, Germany..
| |
Collapse
|
|
42
|
Babitt JL, Eisenga MF, Haase VH, Kshirsagar AV, Levin A, Locatelli F, Małyszko J, Swinkels DW, Tarng DC, Cheung M, Jadoul M, Winkelmayer WC, Drüeke TB. Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int 2021; 99:1280-1295. [PMID: 33839163 DOI: 10.1016/j.kint.2021.03.020] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/02/2021] [Accepted: 03/09/2021] [Indexed: 12/11/2022]
Abstract
In chronic kidney disease, anemia and disordered iron homeostasis are prevalent and associated with significant adverse consequences. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) issued an anemia guideline for managing the diagnosis, evaluation, and treatment of anemia in chronic kidney disease. Since then, new data have accrued from basic research, epidemiological studies, and randomized trials that warrant a re-examination of previous recommendations. Therefore, in 2019, KDIGO decided to convene 2 Controversies Conferences to review the latest evidence, explore new and ongoing controversies, assess change implications for the current KDIGO anemia guideline, and propose a research agenda. The first conference, described here, focused mainly on iron-related issues, including the contribution of disordered iron homeostasis to the anemia of chronic kidney disease, diagnostic challenges, available and emerging iron therapies, treatment targets, and patient outcomes. The second conference will discuss issues more specifically related to erythropoiesis-stimulating agents, including epoetins, and hypoxia-inducible factor-prolyl hydroxylase inhibitors. Here we provide a concise overview of the consensus points and controversies resulting from the first conference and prioritize key questions that need to be answered by future research.
Collapse
Affiliation(s)
- Jodie L Babitt
- Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
| | - Michele F Eisenga
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Volker H Haase
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Molecular Physiology and Biophysics and Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University, Uppsala, Sweden
| | - Abhijit V Kshirsagar
- UNC Kidney Center and Division of Nephrology & Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Adeera Levin
- Department of Medicine, Division of Nephrology, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Francesco Locatelli
- Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, ASST Lecco, Lecco, Italy
| | - Jolanta Małyszko
- Department of Nephrology, Dialysis, and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Dorine W Swinkels
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Der-Cherng Tarng
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | | | - Michel Jadoul
- Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Wolfgang C Winkelmayer
- Department of Medicine, Section of Nephrology, Selzman Institute for Kidney Health, Baylor College of Medicine, Houston, Texas, USA
| | - Tilman B Drüeke
- Inserm Unit 1018, Team 5, CESP, Hôpital Paul Brousse, Paris-Sud University (UPS), Villejuif, France; Versailles Saint-Quentin-en-Yvelines University (Paris-Ile-de-France-Ouest University, UVSQ), Villejuif, France.
| |
Collapse
|
|
43
|
Sanyear C, Chiawtada B, Butthep P, Svasti S, Fucharoen S, Masaratana P. The hypoferremic response to acute inflammation is maintained in thalassemia mice even under parenteral iron loading. PeerJ 2021; 9:e11367. [PMID: 33987030 PMCID: PMC8092106 DOI: 10.7717/peerj.11367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 04/07/2021] [Indexed: 11/20/2022] Open
Abstract
Background Hepcidin controls iron homeostasis by inducing the degradation of the iron efflux protein, ferroportin (FPN1), and subsequently reducing serum iron levels. Hepcidin expression is influenced by multiple factors, including iron stores, ineffective erythropoiesis, and inflammation. However, the interactions between these factors under thalassemic condition remain unclear. This study aimed to determine the hypoferremic and transcriptional responses of iron homeostasis to acute inflammatory induction by lipopolysaccharide (LPS) in thalassemic (Hbbth3/+) mice with/without parenteral iron loading with iron dextran. Methods Wild type and Hbbth3/+ mice were intramuscularly injected with 5 mg of iron dextran once daily for two consecutive days. After a 2-week equilibration, acute inflammation was induced by an intraperitoneal injection of a single dose of 1 µg/g body weight of LPS. Control groups for both iron loading and acute inflammation received equal volume(s) of saline solution. Blood and tissue samples were collected at 6 hours after LPS (or saline) injection. Iron parameters and mRNA expression of hepcidin as well as genes involved in iron transport and metabolism in wild type and Hbbth3/+ mice were analyzed and compared by Kruskal–Wallis test with pairwise Mann–Whitney U test. Results We found the inductive effects of LPS on liver IL-6 mRNA expression to be more pronounced under parenteral iron loading. Upon LPS administration, splenic erythroferrone (ERFE) mRNA levels were reduced only in iron-treated mice, whereas, liver bone morphogenetic protein 6 (BMP6) mRNA levels were decreased under both control and parenteral iron loading conditions. Despite the altered expression of the aforementioned hepcidin regulators, the stimulatory effect of LPS on hepcidin mRNA expression was blunt in iron-treated Hbbth3/+ mice. Contrary to the blunted hepcidin response, LPS treatment suppressed FPN1 mRNA expression in the liver, spleen, and duodenum, as well as reduced serum iron levels of Hbbth3/+ mice with parenteral iron loading. Conclusion Our study suggests that a hypoferremic response to LPS-induced acute inflammation is maintained in thalassemic mice with parenteral iron loading in a hepcidin-independent manner.
Collapse
Affiliation(s)
- Chanita Sanyear
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Buraporn Chiawtada
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Punnee Butthep
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Saovaros Svasti
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Suthat Fucharoen
- Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Patarabutr Masaratana
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| |
Collapse
|
|
44
|
Savković M, Simić-Ogrizović S, Dopsaj V. Assessment of positive iron balance in end-stage renal disease: Could hepcidin-25 be useful? Int J Lab Hematol 2021; 43:1159-1167. [PMID: 33835732 DOI: 10.1111/ijlh.13539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 11/30/2022]
Abstract
INTRODUCTION The aim of our study was to examine the relationship of hepcidin-25 with red blood cell and reticulocyte indices and to evaluate the diagnostic properties of hepcidin-25 in the assessment of positive iron balance in end-stage renal disease (ESRD) patients. METHODS Eighty anemic ESRD patients (hemoglobin < 110 g/L) were classified as having iron deficiency (ID, N = 20), iron sufficiency (IS, N = 29), and positive iron balance (PB, N = 31) using the conventional biomarkers for iron status evaluation. Hepcidin-25 was determined by a chemiluminescent direct ELISA. RESULTS Hepcidin-25 was significantly negatively correlated with the proportion of hypochromic erythrocytes (%HYPO) (P = .034) and immature reticulocyte fraction (P = .010) in ID and with the absolute reticulocyte concentration in ID (P = .048) and PB (P = .040). In multivariate models, hepcidin-25 was independently negatively associated with the mean reticulocyte hemoglobin content (CHr; β = -0.493, P = .004) and red blood cell size factor (RSf) (β = -0.334, P = .036) only in the PB group. The best hepcidin-25 value to exclude PB was 66.13 µg/L, showing a sensitivity of 61.3%, a specificity of 75.5%, and an AUC of 0.808. CONCLUSION Our results suggest that hepcidin-25 levels are independently negatively associated with the iron demand for the most recent erythropoiesis only in PB. Hepcidin-25 performed acceptable in discriminating anemic ESRD patients with positive iron balance and may prove to be a useful additional tool in the evaluation of iron status.
Collapse
Affiliation(s)
- Miljan Savković
- Center for Medical Biochemistry, Clinical Center of Serbia, Belgrade, Serbia
| | - Sanja Simić-Ogrizović
- General Hospital Medigroup, Belgrade, Serbia.,Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina
| | - Violeta Dopsaj
- Center for Medical Biochemistry, Clinical Center of Serbia, Belgrade, Serbia.,Department of Medical Biochemistry, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia
| |
Collapse
|
|
45
|
Yang G, Qian C, Zhang C, Bao Y, Liu MY, Jiang F, Li W, Liu Y, Ke Y, Qian ZM. Hepcidin attenuates the iron-mediated secondary neuronal injury after intracerebral hemorrhage in rats. Transl Res 2021; 229:53-68. [PMID: 32932001 DOI: 10.1016/j.trsl.2020.09.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/04/2020] [Accepted: 09/09/2020] [Indexed: 01/01/2023]
Abstract
Iron plays a key role in secondary neuronal injury after intracerebral hemorrhage (ICH), and hepcidin is able to reduce brain iron in iron-overloaded rats by down-regulating iron transport proteins including ferroportin 1 and transferrin receptor 1. These led us to hypothesize that hepcidin might reduce iron-mediated neurotoxicity by inhibiting iron accumulation in ICH brain. Here, we examined effects of Ad-hepcidin (hepcidin expression adenovirus) on the nonheme iron contents, expression of hepcidin, ferritin and iron transport proteins, neuronal cell survival, water contents in the brain and/or cerebrospinal fluid (CSF), and ICH-induced apoptosis, neurological deficit by RT-PCR, Western blot analysis, NeuN Immunofluorescence, TUNEL, Fluoro-Jade B staining, behavioral performance and Morris water-maze tests in 510 rats. We demonstrated that hepcidin could significantly suppress the ICH-induced increase in iron and ferritin in brain tissues and CSF by inhibiting expression of iron transport proteins, increase neuronal survival by attenuating ICH-induced apoptosis, reactive oxygen species, neurodegeneration and brain edema, as well as effectively improve ICH-induced behavioral and cognitive deficit in rats. The findings collectively showed that hepcidin could effectively attenuate iron-mediated secondary neuronal injury after ICH in rats. This naturally existing protein can potentially be developed into a therapeutic drug for the treatment of ICH patients.
Collapse
Affiliation(s)
- Guang Yang
- Institute of Translational and Precision Medicine, Nantong University, Nantong, JS, China; Laboratory of Neuropharmacology of Pharmacy School, and National Clinical Research Center for Aging and Medicine of Huashan Hospital, Fudan University, Shanghai, China; Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei, China
| | - Christopher Qian
- Laboratory of Neuropharmacology of Pharmacy School, and National Clinical Research Center for Aging and Medicine of Huashan Hospital, Fudan University, Shanghai, China; School of Biomedical Sciences and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
| | - Chao Zhang
- Institute of Translational and Precision Medicine, Nantong University, Nantong, JS, China
| | - Yong Bao
- Institute of Translational and Precision Medicine, Nantong University, Nantong, JS, China
| | - Meng-Yue Liu
- Institute of Translational and Precision Medicine, Nantong University, Nantong, JS, China
| | - Fei Jiang
- Institute of Translational and Precision Medicine, Nantong University, Nantong, JS, China
| | - Wei Li
- Institute of Translational and Precision Medicine, Nantong University, Nantong, JS, China
| | - Yong Liu
- Department of Neurology, Xinqiao Hospital, The Army (Third Military) Medical University, Chongqing, China
| | - Ya Ke
- School of Biomedical Sciences and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
| | - Zhong-Ming Qian
- Institute of Translational and Precision Medicine, Nantong University, Nantong, JS, China; Laboratory of Neuropharmacology of Pharmacy School, and National Clinical Research Center for Aging and Medicine of Huashan Hospital, Fudan University, Shanghai, China.
| |
Collapse
|
|
46
|
Neves JV, Gomes AC, Costa DM, Barroso C, Vaulont S, Cordeiro da Silva A, Tavares J, Rodrigues PNS. A role for hepcidin in the anemia caused by Trypanosoma brucei infection. Haematologica 2021; 106:806-818. [PMID: 31919087 PMCID: PMC7927896 DOI: 10.3324/haematol.2019.227728] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Indexed: 12/21/2022] Open
Abstract
Trypanosomiasis is a parasitic disease affecting both humans and animals in the form of Human African Trypanosomiasis and Nagana disease, respectively. Anemia is one of the most common symptoms of trypanosomiasis, and if left unchecked can cause severe complications and even death. Several factors have been associated with the development of this anemia, including dysregulation of iron homeostasis, but little is known about the molecular mechanisms involved. Here, using murine models, we study the involvement of hepcidin, the key regulator of iron metabolism and an important player in the development of anemia of inflammation. Our data show two stages for the progression of anemia, to which hepcidin contributes a first stage when anemia develops, with a likely cytokine-mediated stimulation of hepcidin and subsequent limitation in iron availability and erythropoiesis, and a second stage of recovery, where the increase in hepcidin then declines due to the reduced inflammatory signal and increased production of erythroid regulators by the kidney, spleen and bone marrow, thus leading to an increase in iron release and availability, and enhanced erythropoiesis. In agreement with this, in hepcidin knockout mice, anemia is much milder and its recovery is complete, in contrast to wild-type animals which have not fully recovered from anemia after 21 days. Besides all other factors known to be involved in the development of anemia during trypanosomiasis, hepcidin clearly makes an important contribution to both its development and recovery.
Collapse
Affiliation(s)
- João V Neves
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto,Iron and Innate Immunity, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto,ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto
| | - Ana C Gomes
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto,Iron and Innate Immunity, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto,ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto
| | - David M Costa
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto,Parasite Disease, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto
| | - Carolina Barroso
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto,Iron and Innate Immunity, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto,MCBiology Doctoral Program, ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto
| | - Sophie Vaulont
- INSERM U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris
| | - Anabela Cordeiro da Silva
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto,ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto,Parasite Disease, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto
| | - Joana Tavares
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto,Parasite Disease, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto
| | - Pedro N S Rodrigues
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto,Iron and Innate Immunity, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto,ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto
| |
Collapse
|
|
47
|
Oppen K, Ueland T, Siljan WW, Skadberg Ø, Brede C, Lauritzen T, Aukrust P, Steinsvik T, Husebye E, Michelsen AE, Holter JC, Heggelund L. Hepcidin and Ferritin Predict Microbial Etiology in Community-Acquired Pneumonia. Open Forum Infect Dis 2021; 8:ofab082. [PMID: 33880390 PMCID: PMC8043258 DOI: 10.1093/ofid/ofab082] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 02/15/2021] [Indexed: 11/24/2022] Open
Abstract
Background Iron is crucial for survival and growth of microbes. Consequently, limiting iron availability is a human antimicrobial defense mechanism. We explored iron and iron-related proteins as potential biomarkers in community-acquired pneumonia and hypothesized that infection-induced changes in these potential biomarkers differ between groups of pathogens and could predict microbial etiology. Methods Blood samples from a prospective cohort of 267 patients with community-acquired pneumonia were analyzed for hepcidin, ferritin, iron, transferrin, and soluble transferrin receptor at admission, clinical stabilization, and a 6-week follow-up. A total of 111 patients with an established microbiological diagnosis confined to 1 microbial group (atypical bacterial, typical bacterial, or viral) were included in predictive analyses. Results High admission levels of ferritin predicted atypical bacterial versus typical bacterial etiology (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.18–4.32; P = .014). Furthermore, hepcidin and ferritin predicted atypical bacterial versus viral etiology (hepcidin: OR = 3.12, 95% CI = 1.34–7.28, P = .008; ferritin: OR = 2.38, 95% CI = 1.28–4.45, P = .006). The findings were independent of C-reactive protein and procalcitonin. Conclusions Hepcidin and ferritin are potential biomarkers of microbial etiology in community-acquired pneumonia.
Collapse
Affiliation(s)
- Kjersti Oppen
- Department of Laboratory Medicine, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway
| | | | - Øyvind Skadberg
- Department of Medical Biochemistry, Stavanger University Hospital, Stavanger, Norway
| | - Cato Brede
- Department of Medical Biochemistry, Stavanger University Hospital, Stavanger, Norway.,Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | - Trine Lauritzen
- Department of Laboratory Medicine, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway.,Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Trude Steinsvik
- Department of Laboratory Medicine, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway
| | - Einar Husebye
- Department of Internal Medicine, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway
| | - Annika E Michelsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jan Cato Holter
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Microbiology, Oslo University Hospital, Oslo, Norway
| | - Lars Heggelund
- Department of Internal Medicine, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway.,Department of Clinical Science, Bergen Integrated Diagnostic Stewardship Cluster, Faculty of Medicine, University of Bergen, Bergen, Norway
| |
Collapse
|
|
48
|
Fokam D, Aali M, Dickson K, Scott C, Holbein B, Zhou J, Lehmann C. The novel iron chelator, DIBI, attenuates inflammation and improves outcome in colon ascendens stent peritonitis-induced experimental sepsis. Clin Hemorheol Microcirc 2020; 76:241-261. [PMID: 32925011 DOI: 10.3233/ch-209207] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Sepsis is the result of a dysregulated host immune response to an infection. An ideal therapy would target both the underlying infection and the dysregulated immune response. DIBI, a novel iron-binding polymer, was specifically developed as an antimicrobial agent and has also demonstrated in vivo anti-inflammatory properties. OBJECTIVE This study aimed to further investigate the effects of DIBI with and without the antibiotic imipenem (IMI) in colon ascendens stent peritonitis (CASP)-induced experimental sepsis. METHODS Vehicle, DIBI and/or IMI were administered in C57BL/6 mice after CASP surgery. Intestinal leukocyte activation and capillary perfusion was evaluated by intravital microscopy. Moreover, bacterial load in peritoneal lavage fluid and blood, and plasma cytokine levels were assessed. In a second series of experiments, surgery to repair the colon was performed at 5 hr and these mice were followed for long-term survival over 7 days. RESULTS DIBI reduced leukocyte adhesion, improved capillary blood flow, and decreased key plasma cytokines levels. DIBI also improved survival of infected mice and greatly improved IMI efficacy. Survivors treated with IMI and DIBI were found to be free of systemic infection. CONCLUSIONS DIBI has promising potential for sepsis treatment including its use as a sole or an adjunct therapeutic with antibiotics.
Collapse
Affiliation(s)
- Danielle Fokam
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada
| | - Maral Aali
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada
| | - Kayle Dickson
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Cassidy Scott
- Department of Pharmacology, Dalhousie University, Halifax, NS, Canada
| | - Bruce Holbein
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Chelation Partners Inc., Halifax, NS, Canada
| | - Juan Zhou
- Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada
| | - Christian Lehmann
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada.,Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.,Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada
| |
Collapse
|
|
49
|
Rund D. Intravenous iron: do we adequately understand the short- and long-term risks in clinical practice? Br J Haematol 2020; 193:466-480. [PMID: 33216989 DOI: 10.1111/bjh.17202] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 09/28/2020] [Indexed: 12/31/2022]
Abstract
Intravenous (IV) iron as a therapeutic agent is often administered but not always fully understood. The benefits of IV iron are well proven in many fields, particularly in nephrology. IV iron is beneficial not only for true iron deficiency but also for iron-restricted anaemia (functional iron deficiency). Yet, the literature on intravenous iron has many inconsistencies regarding its adverse effects. Over the last several years, newer forms of iron have been developed, leading to the more regular use of iron and in larger doses. This review will summarize some of the older and newer literature regarding the differences among iron products, including the mechanisms and frequency of their adverse events (AEs). The pathway and frequency of an underrecognized adverse event (hypophosphataemia) will be discussed. Recent insights on infection risk and iron handling by macrophages are examined. Potential but presently unproven risks of iron overload due to IV iron are discussed. The impact of these on the risk:benefit ratio and dosing of intravenous iron are considered in different clinical settings, including pregnancy and cancer. IV iron is an essential component of the therapy of anaemia and understanding these issues will enable more informed treatment decisions and knowledgeable use of these drugs.
Collapse
Affiliation(s)
- Deborah Rund
- Hebrew University-Hadassah Medical Organization, Ein Kerem, Jerusalem, Israel
| |
Collapse
|
|
50
|
Mohamed G, Aboelhassan S, Zaki MES, Wahba Y. Iron Deficiency Anemia and Serum Hepcidin Level in Children with Typhoid Fever: A Case–Control Study. J PEDIAT INF DIS-GER 2020; 15:288-292. [DOI: 10.1055/s-0040-1715856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Abstract
Objective Typhoid fever is a common systemic bacterial infection in children with a complex interplay between serum hepcidin and iron. We investigated the relationship between iron deficiency anemia (IDA) and serum hepcidin level in children with acute typhoid fever.
Methods We conducted a preliminary case–control study in Mansoura University Children's Hospital, Egypt from April 2017 to May 2019 including 30 children aged 5 to 15 years with confirmed acute typhoid fever. We recruited 15 healthy nonanemic children, of comparable ages and sex as controls from the same hospital while attending for nonfebrile complaints. Typhoid fever cases were subdivided according to IDA existence into 16 cases with IDA and 14 non-IDA cases. We excluded all children having diseases which may affect serum iron and hepcidin levels, for example, liver, blood, gastrointestinal, and kidney diseases, and patients receiving drugs interfering with iron metabolism. All participants were subjected to complete blood count, serum ferritin, iron, hepcidin levels, and total iron-binding capacity (TIBC).
Results In non-IDA typhoid fever group, serum iron level was significantly low, while serum hepcidin level was significantly high when compared with controls (p < 0.001 and p = 0.02, respectively). In IDA typhoid fever group, no statistically significant difference existed as regards serum hepcidin level when compared with controls (p = 0.53). No significant correlations were detected between serum hepcidin levels and hemoglobin, serum iron, ferritin, and TIBC values in each group.
Conclusion Preexisting iron status could affect serum hepcidin level in patients with acute typhoid fever. Coexistence of IDA might oppose the up-regulatory effect of acute typhoid fever on serum hepcidin level.
Collapse
Affiliation(s)
- Ghada Mohamed
- Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Samir Aboelhassan
- Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Maysaa El Sayed Zaki
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Yahya Wahba
- Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| |
Collapse
|