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1.
Am J Hematol ; 98(6): 890-899, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36880875

RESUMEN

Anemia of inflammation (AI) is frequently present in subjects with inflammatory disorders, primarily caused by inflammation-driven iron retention in macrophages. So far, only limited data on qualitative and quantitative estimates of tissue iron retention in AI patients exist. We performed a prospective cohort study analyzing splenic, hepatic, pancreatic, and cardiac iron content with MRI-based R2*-relaxometry in AI patients, including subjects with concomitant true iron deficiency (AI+IDA) hospitalized between 05/2020-01/2022. Control groups were individuals without inflammation. Spleen R2* values in AI patients with ferritin ≤200 µg/L (AI+IDA) were comparable with those found in controls. In AI patients with ferritin >200 µg/L, spleen (47.6 s-1 vs. 19.3 s-1 , p < .001) and pancreatic R2* values (32.5 s-1 vs. 24.9 s-1 , p = .011) were significantly higher compared with controls, while liver and heart R2*-values did not differ. Higher spleen R2* values were associated with higher ferritin, hepcidin, CRP, and IL-6 concentrations. Spleen R2* values normalized in AI patients after recovery (23.6 s-1 vs. 47.6 s-1 , p = .008), while no changes were found in patients with baseline AI+IDA. This is the first study investigating tissue iron distribution in patients with inflammatory anemia and AI with concomitant true iron deficiency. The results support the findings in animal models demonstrating iron retention in macrophages, which are primarily accumulating in the spleen under inflammatory conditions. MRI-related iron measurement may help to better characterize actual iron needs and to define better biomarker thresholds in the diagnosis of true ID in patients with AI. It may qualify as a useful diagnostic method to estimate the need for iron supplementation and to guide therapy.


Asunto(s)
Anemia Ferropénica , Anemia , Deficiencias de Hierro , Animales , Hierro/metabolismo , Proyectos Piloto , Estudios Prospectivos , Anemia/etiología , Anemia Ferropénica/complicaciones , Hepcidinas , Ferritinas , Inflamación
2.
Int J Mol Sci ; 23(21)2022 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-36361875

RESUMEN

The sequestration of iron in case of infection, termed nutritional immunity, is an established strategy of host defense. However, the interaction between pathogens and the mammalian iron storage protein ferritin is hitherto not completely understood. To better characterize the function of ferritin in Gram-negative infections, we incubated iron-starved cultures of Salmonella Typhimurium and knockout mutant strains defective for major iron uptake pathways or Escherichia coli with horse spleen ferritin or ionic iron as the sole iron source. Additionally, we added bovine superoxide dismutase and protease inhibitors to the growth medium to assess the effect of superoxide and bacterial proteases, respectively, on Salmonella proliferation and reductive iron release. Compared to free ionic iron, ferritin-bound iron was less available to Salmonella, but was still sufficient to significantly enhance the growth of the bacteria. In the absence of various iron acquisition genes, the availability of ferritin iron further decreased. Supplementation with superoxide dismutase significantly reduced the growth of the ΔentC knockout strain with holoferritin as the sole iron source in comparison with ionic ferrous iron. In contrast, this difference was not observed in the wildtype strain, suggesting that superoxide dismutase undermines bacterial iron uptake from ferritin by siderophore-independent mechanisms. Ferritin seems to diminish iron availability for bacteria in comparison to ionic iron, and its iron sequestering effect could possibly be enhanced by host superoxide dismutase activity.


Asunto(s)
Ferritinas , Hierro , Bovinos , Animales , Caballos , Ferritinas/metabolismo , Hierro/metabolismo , Enterobacteriaceae , Salmonella typhimurium , Superóxido Dismutasa/metabolismo , Escherichia coli/metabolismo , Mamíferos/metabolismo
3.
Nutrients ; 13(11)2021 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-34835988

RESUMEN

Anemia is very common in patients with inflammatory disorders. Its prevalence is associated with severity of the underlying disease, and it negatively affects quality of life and cardio-vascular performance of patients. Anemia of inflammation (AI) is caused by disturbances of iron metabolism resulting in iron retention within macrophages, a reduced erythrocyte half-life, and cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation. AI is mostly mild to moderate, normochromic and normocytic, and characterized by low circulating iron, but normal and increased levels of the storage protein ferritin and the iron hormone hepcidin. The primary therapeutic approach for AI is treatment of the underlying inflammatory disease which mostly results in normalization of hemoglobin levels over time unless other pathologies such as vitamin deficiencies, true iron deficiency on the basis of bleeding episodes, or renal insufficiency are present. If the underlying disease and/or anemia are not resolved, iron supplementation therapy and/or treatment with erythropoietin stimulating agents may be considered whereas blood transfusions are an emergency treatment for life-threatening anemia. New treatments with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors emerge but their therapeutic efficacy for treatment of AI in ill patients needs to be evaluated in clinical trials.


Asunto(s)
Anemia/fisiopatología , Anemia/terapia , Homeostasis , Inflamación/fisiopatología , Inflamación/terapia , Hierro/metabolismo , Anemia/complicaciones , Anemia/diagnóstico , Eritropoyesis , Humanos , Inflamación/complicaciones , Fenómenos Fisiológicos de la Nutrición
4.
EBioMedicine ; 71: 103568, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34488018

RESUMEN

BACKGROUND: Iron deficiency anaemia (IDA) is a major health concern. However, preventive iron supplementation in regions with high burden of infectious diseases resulted in an increase of infection related morbidity and mortality. METHODS: We fed male C57BL/6N mice with either an iron deficient or an iron adequate diet. Next, they received oral iron supplementation or placebo followed by intraperitoneal infection with Salmonella Typhimurium (S.Tm). FINDINGS: We found that mice with IDA had a poorer clinical outcome than mice on an iron adequate diet. Interestingly, iron supplementation of IDA mice resulted in higher bacterial burden in organs and shortened survival. Increased transferrin saturation and non-transferrin bound iron in the circulation together with low expression of ferroportin facilitated the access of the pathogen to iron and promoted bacterial growth. Anaemia, independent of iron supplementation, was correlated with reduced neutrophil counts and cytotoxic T cells. With iron supplementation, anaemia additionally correlated with increased splenic levels of the cytokine IL-10, which is suggestive for a weakened immune control to S.Tm infection. INTERPRETATION: Supplementing iron to anaemic mice worsens the clinical course of bacterial infection. This can be traced back to increased iron delivery to bacteria along with an impaired anti-microbial immune response. Our findings may have important implications for iron supplementation strategies in areas with high endemic burden of infections, putting those individuals, who potentially profit most from iron supplementation for anaemia, at the highest risk for infections. FUNDING: Financial support by the Christian Doppler Laboratory for Iron Metabolism and Anemia Research.


Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Bacteriemia/complicaciones , Hierro/sangre , Infecciones por Salmonella/complicaciones , Anemia Ferropénica/sangre , Anemia Ferropénica/complicaciones , Animales , Bacteriemia/sangre , Bacteriemia/patología , Carga Bacteriana , Hierro/administración & dosificación , Hierro/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Infecciones por Salmonella/sangre , Infecciones por Salmonella/patología
5.
Front Immunol ; 12: 637809, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34108960

RESUMEN

Iron plays an important role in host-pathogen interactions, in being an essential element for both pathogen and host metabolism, but also by impacting immune cell differentiation and anti-microbial effector pathways. Iron has been implicated to affect the differentiation of T lymphocytes during inflammation, however, so far the underlying mechanism remained elusive. In order to study the role of iron in T cell differentiation we here investigated how dietary iron supplementation affects T cell function and outcome in a model of chronic infection with the intracellular bacterium Salmonella enterica serovar typhimurium (S. Typhimurium). Iron loading prior to infection fostered bacterial burden and, unexpectedly, reduced differentiation of CD4+ T helper cells type 1 (Th1) and expression of interferon-gamma (IFNγ), a key cytokine to control infections with intracellular pathogens. This effect could be traced back to iron-mediated induction of the negative immune checkpoint regulator T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), expressed on the surface of this T cell subset. In vitro experiments demonstrated that iron supplementation specifically upregulated mRNA and protein expression of TIM-3 in naïve Th cells in a dose-depdendent manner and hindered priming of those T cells towards Th1 differentiation. Importantly, administration of TIM-3 blocking antibodies to iron-loaded mice infected with S. Typhimurium virtually restored Th1 cell differentiation and significantly improved bacterial control. Our data uncover a novel mechanism by which iron modulates CD4+ cell differentiation and functionality and hence impacts infection control with intracellular pathogens. Specifically, iron inhibits the differentiation of naive CD4+ T cells to protective IFNγ producing Th1 lymphocytes via stimulation of TIM-3 expression. Finally, TIM-3 may serve as a novel drug target for the treatment of chronic infections with intracellular pathogens, specifically in iron loading diseases.


Asunto(s)
Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Hierro/metabolismo , Salmonella typhi/fisiología , Células TH1/inmunología , Fiebre Tifoidea/inmunología , Animales , Diferenciación Celular , Células Cultivadas , Suplementos Dietéticos , Modelos Animales de Enfermedad , Receptor 2 Celular del Virus de la Hepatitis A/genética , Humanos , Interferón gamma/metabolismo , Activación de Linfocitos , Ratones , Regulación hacia Arriba
6.
Lancet Respir Med ; 9(8): 863-872, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34126053

RESUMEN

BACKGROUND: SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19. METHODS: ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUCSOFA), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596. FINDINGS: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUCSOFA (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group. INTERPRETATION: Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options. FUNDING: Austrian Science Fund and German Center for Cardiovascular Research.


Asunto(s)
Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , COVID-19 , Hipertensión , Sistema Renina-Angiotensina , SARS-CoV-2 , Antagonistas de Receptores de Angiotensina/administración & dosificación , Antagonistas de Receptores de Angiotensina/efectos adversos , Enzima Convertidora de Angiotensina 2/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Área Bajo la Curva , COVID-19/epidemiología , COVID-19/metabolismo , COVID-19/terapia , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Evaluación de Procesos y Resultados en Atención de Salud , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Ajuste de Riesgo/métodos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Privación de Tratamiento/estadística & datos numéricos
7.
Front Oncol ; 10: 584477, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33344239

RESUMEN

Iron is both, an essential compound for many metabolic processes, and iron deficiency can impact on the proliferation of cells including lymphocytes but also tumor cells. On the other hand, excess iron-catalyzed radical formation can induce cellular toxicity which has been previously demonstrated for T cells in hereditary iron overload. Despite these interconnections, little is known on the effects of clinically approved intravenous iron supplements for curing cancer-related anemia, on T cell differentiation, tumor proliferation, anti-tumor T cell responses and, of clinical importance, on efficacy of cancer immunotherapies. Herein, we analyzed the effects of intravenous iron supplementation on T cell function and on the effectiveness of anti-cancer chemotherapy with IL-2/doxorubicin or immunotherapy with checkpoint-inhibitor anti-PD-L1 in C57Bl/6N female mice with implanted E0771 mammary carcinomas. We found that iron application resulted to an increased availability of iron in the tumor microenvironment and stimulation of tumor growth. In parallel, iron application inhibited the activation, expansion and survival of cytotoxic CD8+ T cells and of CD4+ T helper cells type 1 and significantly reduced the efficacy of the investigated anti-cancer treatments. Our results indicate that iron administration has a tumor growth promoting effect and impairs anti-cancer responses of tumor infiltrating T lymphocytes along with a reduced efficacy of anti-cancer therapies. Iron supplementation in cancer patients, especially in those treated with immunotherapies in a curative setting, may be thus used cautiously and prospective studies have to clarify the impact of such intervention on the outcome of patients.

8.
Nutrients ; 12(9)2020 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-32932831

RESUMEN

The novel Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a global health concern. Vitamin D (VITD) deficiency has been suggested to alter SARS-CoV-2 susceptibility and the course of disease. Thus, we aimed to investigate associations of VITD status to disease presentation within the CovILD registry. This prospective, multicenter, observational study on long-term sequelae includes patients with COVID-19 after hospitalization or outpatients with persistent symptoms. Eight weeks after PCR confirmed diagnosis, a detailed questionnaire, a clinical examination, and laboratory testing, including VITD status, were evaluated. Furthermore, available laboratory specimens close to hospital admission were used to retrospectively analyze 25-hydroxyvitamin D levels at disease onset. A total of 109 patients were included in the analysis (60% males, 40% females), aged 58 ± 14 years. Eight weeks after the onset of COVID-19, a high proportion of patients presented with impaired VITD metabolism and elevated parathyroid hormone (PTH) levels. PTH concentrations were increased in patients who needed intensive care unit (ICU) treatment, while VITD levels were not significantly different between disease severity groups. Low VITD levels at disease onset or at eight-week follow-up were not related to persistent symptom burden, lung function impairment, ongoing inflammation, or more severe CT abnormalities. VITD deficiency is frequent among COVID-19 patients but not associated with disease outcomes. However, individuals with severe disease display a disturbed parathyroid-vitamin-D axis within their recovery phase. The proposed significance of VITD supplementation in the clinical management of COVID-19 remains elusive.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/sangre , Neumonía Viral/sangre , Deficiencia de Vitamina D/virología , Vitamina D/análogos & derivados , Anciano , COVID-19 , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estado Nutricional , Pandemias , Hormona Paratiroidea/sangre , Neumonía Viral/complicaciones , Neumonía Viral/virología , Estudios Prospectivos , Sistema de Registros , Factores de Riesgo , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Vitamina D/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/epidemiología
9.
Nat Commun ; 11(1): 1775, 2020 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-32286299

RESUMEN

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.


Asunto(s)
Enfermedad de Crohn/metabolismo , Grasas de la Dieta/efectos adversos , Enteritis/metabolismo , Ácidos Grasos Insaturados/metabolismo , Inflamación/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Adulto , Animales , Muerte Celular/genética , Muerte Celular/fisiología , Enfermedad de Crohn/genética , Enteritis/etiología , Enteritis/genética , Ácidos Grasos Insaturados/genética , Femenino , Glutatión Peroxidasa/metabolismo , Humanos , Inflamación/genética , Peroxidación de Lípido/genética , Peroxidación de Lípido/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética
10.
Intern Emerg Med ; 15(4): 573-585, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32040829

RESUMEN

Anaemia is a highly prevalent condition, which negatively impacts on patients' cardiovascular performance and quality of life. Anaemia is mainly caused by disturbances of iron homeostasis. While absolute iron deficiency mostly as a consequence of chronic blood loss or insufficient dietary iron absorption results in the emergence of iron deficiency anaemia, inflammation-driven iron retention in innate immune cells and blockade of iron absorption leads to the development of anaemia of chronic disease. Both, iron deficiency and anaemia have been linked to the clinical course of pulmonary hypertension. Various mechanistic links between iron homeostasis, anaemia, and pulmonary hypertension have been described and current treatment guidelines suggest regular iron status assessment and the implementation of iron supplementation strategies in these patients. The pathophysiology, diagnostic assessment as well as current and future treatment options concerning iron deficiency with or without anaemia in individuals suffering from pulmonary hypertension are discussed within this review.


Asunto(s)
Anemia Ferropénica/diagnóstico , Anemia Ferropénica/fisiopatología , Hipertensión Pulmonar/fisiopatología , Deficiencias de Hierro , Enfermedad Crónica , Homeostasis , Humanos
11.
Microb Cell ; 6(12): 531-543, 2019 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-31832425

RESUMEN

Iron is an essential nutrient for immune cells and microbes, therefore the control of its homeostasis plays a decisive role for infections. Moreover, iron affects metabolic pathways by modulating the translational expression of the key tricarboxylic acid cycle (TCA) enzyme mitochondrial aconitase and the energy formation by mitochondria. Recent data provide evidence for metabolic re-programming of immune cells including macrophages during infection which is centrally controlled by mTOR. We herein studied the effects of iron perturbations on metabolic profiles in macrophages upon infection with the intracellular bacterium Salmonella enterica serovar Typhimurium and analysed for a link to the mTOR pathway. Infection of the murine macrophage cell line RAW264.7 with Salmonella resulted in the induction of mTOR activity, anaerobic glycolysis and inhibition of the TCA activity as reflected by reduced pyruvate and increased lactate levels. In contrast, iron supplementation to macrophages not only affected the mRNA expression of TCA and glycolytic enzymes but also resulted in metabolic reprogramming with increased pyruvate accumulation and reduced lactate levels apart from modulating the concentrations of several other metabolites. While mTOR slightly affected cellular iron homeostasis in infected macrophages, mTOR inhibition by rapamycin resulted in a significant growth promotion of bacteria. Importantly, iron further increased bacterial numbers in rapamycin treated macrophages, however, the metabolic profiles induced by iron in the presence or absence of mTOR activity differed in several aspects. Our data indicate, that iron not only serves as a bacterial nutrient but also acts as a metabolic modulator of the TCA cycle, partly reversing the Warburg effect and resulting in a pathogen friendly nutritional environment.

12.
Pharmaceuticals (Basel) ; 11(4)2018 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-30544952

RESUMEN

Inflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia of inflammation (AI). Iron deficiency, regardless of anemia, has a detrimental impact on quality of life so that treatment is warranted. Therapeutic strategies include (1) resolution of the underlying disease, (2) iron supplementation, and (3) iron redistribution strategies. Deeper insights into the pathophysiology of AI has led to the development of new therapeutics targeting inflammatory cytokines and the introduction of new iron formulations. Moreover, the discovery that the hormone, hepcidin, plays a key regulatory role in AI has stimulated the development of several therapeutic approaches targeting the function of this peptide. Hence, inflammation-driven hepcidin elevation causes iron retention in cells and tissues. Besides pathophysiological concepts and diagnostic approaches for AI, this review discusses current guidelines for iron replacement therapies with special emphasis on benefits, limitations, and unresolved questions concerning oral versus parenteral iron supplementation in chronic inflammatory diseases. Furthermore, the review explores how therapies aiming at curing the disease underlying AI can also affect anemia and discusses emerging hepcidin antagonizing drugs, which are currently under preclinical or clinical investigation.

13.
Front Oncol ; 8: 549, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30534534

RESUMEN

Iron metabolism and tumor biology are intimately linked. Iron facilitates the production of oxygen radicals, which may either result in iron-induced cell death, ferroptosis, or contribute to mutagenicity and malignant transformation. Once transformed, malignant cells require high amounts of iron for proliferation. In addition, iron has multiple regulatory effects on the immune system, thus affecting tumor surveillance by immune cells. For these reasons, inconsiderate iron supplementation in cancer patients has the potential of worsening disease course and outcome. On the other hand, chronic immune activation in the setting of malignancy alters systemic iron homeostasis and directs iron fluxes into myeloid cells. While this response aims at withdrawing iron from tumor cells, it may impair the effector functions of tumor-associated macrophages and will result in iron-restricted erythropoiesis and the development of anemia, subsequently. This review summarizes our current knowledge of the interconnections of iron homeostasis with cancer biology, discusses current clinical controversies in the treatment of anemia of cancer and focuses on the potential roles of iron in the solid tumor microenvironment, also speculating on yet unknown molecular mechanisms.

14.
PLoS One ; 13(8): e0203396, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30161261

RESUMEN

Imbalances of iron homeostasis are associated with an adverse clinical outcome of pulmonary hypertension (PH). Herein, we aimed to analyze the impact of iron deficiency (ID) in a real-life PH patient cohort according to different currently used ID definitions. In a retrospective study including 153 precapillary PH patients followed over a mean period of five years, iron deficiency was assessed according to five clinical definitions used in previous trials. The impact of ID on clinical, hematological and hemodynamic parameters was investigated. Depending on the different cutoff levels for serum ferritin and transferrin saturation, currently used ID definitions indicated a prevalence of either true or functional ID in 11 to 75 percent of PH patients. A good diagnostic accuracy was achieved by using the sTFRF/log ferritin (sTFRF) index, which identified 33 to 42 percent of PH patients as being iron deficient. The sTFRF index had the best prediction for the association between ID and clinical outcome. Iron deficient patients with precapillary PH had a significantly higher mortality as compared to non-iron deficiency subjects, which was true for both, PH patients with and without anemia. Although levels of the iron hormone hepcidin were rather affected by ID than by inflammation, they were not associated with the clinical course or mortality of PH subjects. To conclude, ID had a significant impact on the clinical course of precapillary PH patients. The appropriate use of robust biomarkers to define ID is a prerequisite to further evaluate the role of ID and the potential benefit of iron supplementation in precapillary PH patients.


Asunto(s)
Anemia Ferropénica/complicaciones , Hipertensión Pulmonar/etiología , Adulto , Anciano , Anciano de 80 o más Años , Anemia Ferropénica/diagnóstico , Femenino , Humanos , Deficiencias de Hierro , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto Joven
15.
Med Sci Monit ; 24: 4009-4019, 2018 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-29895816

RESUMEN

Tissue hypoxia contributes to the pathogenesis of several acute and chronic diseases. Hyperbaric oxygen therapy (HBO) and whole-body warming using low-temperature infrared technology (LIT) are techniques that might improve hypoxemia. Combining HBO and LIT as hyperbaric oxygen therapy combined with low-temperature infrared radiation (HBOIR) might be an approach that results in positive synergistic effects on oxygenation. LIT increases blood flow and could reduce HBO-induced vasoconstriction, and hyperoxia could compensate for the increased metabolic oxygen requirements mediated by LIT. Both LIT and HBO increase the oxygen diffusion distance in the tissues. HBOIR at 0.5 bar has been shown to be safe and feasible. However, physiological responses and the safety of HBOIR at an increased oxygen (O2) partial pressure of 1.4 bar or 2.4 atmospheres absolute (ATA) still need to be determined. The hope is that should HBOIR at an increased oxygen partial pressure of 1.4 bar be safe, future studies to examine its efficacy in patients with clinical conditions, which include peripheral arterial disease (PAD) or wound healing disorders, will follow. The results of pilot studies have shown that HBOIR at an overload pressure is safe and well tolerated in healthy participants but can generate moderate cardiovascular changes and an increase in body temperature. From the findings of this pilot study, due to its potential synergistic effects, HBOIR could be a promising tool for the treatment of human diseases associated with hypoxemia.


Asunto(s)
Oxigenoterapia Hiperbárica/métodos , Hipoxia/terapia , Rayos Infrarrojos/uso terapéutico , Adulto , Monitoreo de Gas Sanguíneo Transcutáneo/métodos , Presión Sanguínea/fisiología , Regulación de la Temperatura Corporal/fisiología , Femenino , Voluntarios Sanos , Humanos , Oxigenoterapia Hiperbárica/efectos adversos , Hiperoxia/fisiopatología , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Presión Parcial , Proyectos Piloto
16.
Nutrients ; 10(1)2018 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-29342861

RESUMEN

Anaemia is the most frequent, though often neglected, comorbidity of inflammatory bowel disease (IBD). Here we want to briefly present (1) the burden of anaemia in IBD, (2) its pathophysiology, which mostly arises from bleeding-associated iron deficiency, followed by (3) diagnostic evaluation of anaemia, (4) a balanced overview of the different modes of iron replacement therapy, (5) evidence for their therapeutic efficacy and subsequently, (6) an updated recommendation for the practical management of anaemia in IBD. Following the introduction of various intravenous iron preparations over the last decade, questions persist about when to use these preparations as opposed to traditional and other novel oral iron therapeutic agents. At present, oral iron therapy is generally preferred for patients with quiescent IBD and mild iron-deficiency anaemia. However, in patients with flaring IBD that hampers intestinal iron absorption and in those with inadequate responses to or side effects with oral preparations, intravenous iron supplementation is the therapy of choice, although information on the efficacy of intravenous iron in patients with active IBD and anaemia is scare. Importantly, anaemia in IBD is often multifactorial and a careful diagnostic workup is mandatory for optimized treatment. Nevertheless, limited information is available on optimal therapeutic start and end points for treatment of anaemia. Of note, neither oral nor intravenous therapies seem to exacerbate the clinical course of IBD. However, additional prospective studies are still warranted to determine the optimal therapy in complex conditions such as IBD.


Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Manejo de la Enfermedad , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Administración Intravenosa , Administración Oral , Anemia Ferropénica/complicaciones , Anemia Ferropénica/diagnóstico , Enfermedad Crónica , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Ferritinas/sangre , Hepcidinas/sangre , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/diagnóstico , Hierro/administración & dosificación , Hierro/sangre , Peso Molecular , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Transferrina/sangre , Transferrina/metabolismo
17.
Kidney Int ; 89(1): 28-39, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26759045

RESUMEN

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.


Asunto(s)
Hipersensibilidad/etiología , Infecciones , Sobrecarga de Hierro , Hierro/administración & dosificación , Hierro/efectos adversos , Estrés Oxidativo , Insuficiencia Renal Crónica/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Ferritinas/sangre , Hematínicos/uso terapéutico , Hemoglobinas/metabolismo , Hepcidinas/sangre , Humanos , Infecciones/sangre , Hierro/sangre , Deficiencias de Hierro , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/inducido químicamente , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia
18.
Medicine (Baltimore) ; 94(23): e963, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26061331

RESUMEN

Anemia is the most frequent complication of inflammatory bowel disease (IBD), but anemia, mostly due to iron deficiency, has long been neglected in these patients. The aim was to briefly present the pathophysiology, followed by a balanced overview of the different forms of iron replacement available, and subsequently, to perform a systematic review of studies performed in the last decade on the treatment of iron-deficiency anemia in IBD. Given that intravenous therapies have been introduced in the last decade, a systematic review performed in PubMed, EMBASE, the Cochrane Library, and the websites of WHO, FDA, and EMA covered prospective trials investigating the management of iron-deficiency anemia in IBD published since 2004. A total of 632 articles were reviewed, and 13 articles (2906 patients) with unique content were included. In general, oral supplementation in iron-deficiency anemia should be administered with a target to restore/replenish the iron stores and the hemoglobin level in a suitable way. However, in patients with IBD flares and inadequate responses to or side effects with oral preparations, intravenous iron supplementation is the therapy of choice. Neither oral nor intravenous therapy seems to exacerbate the clinical course of IBD, and intravenous iron therapy can be administered even in active disease stages and concomitantly with biologics. In conclusion, because many physicians are in doubt as to how to manage anemia and iron deficiency in IBD, there is a clear need for the implementation of evidence-based recommendations on this matter. Based on the data presented, oral iron therapy should be preferred for patients with quiescent disease stages and trivial iron deficiency anemia unless such patients are intolerant or have an inadequate response, whereas intravenous iron supplementation may be of advantage in patients with aggravated anemia or flares of IBD because inflammation hampers intestinal absorption of iron.


Asunto(s)
Anemia Ferropénica/complicaciones , Anemia Ferropénica/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/complicaciones , Anemia Ferropénica/fisiopatología , Humanos , Hierro/uso terapéutico
19.
Metallomics ; 7(6): 1036-45, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25869778

RESUMEN

Due to its multiple roles for the proliferation and pathogenicity of many microbes on the one hand and via modulation of immune effector functions on the other hand the control over iron homeostasis is thought to play a decisive role in the course of infections. Diversion of cellular iron traffic is considered as an important defense mechanism of macrophages to reduce metal availability for intracellular bacteria residing in the phagosome. However, evidence is lacking whether such alterations of iron homeostasis also become evident upon infection with bacteria gaining access to the cytosol like Listeria monocytogenes. Here we show that infection of macrophages with L. monocytogenes triggers the expression of the major cellular iron exporter ferroportin1 and induces cellular iron egress. As the growth of Listeria within macrophages is promoted by iron, stimulation of ferroportin1 functionality limits the availability of the metal for Listeria residing in the cytoplasm, whereas ferroportin1 degradation upon hepcidin treatment increases intracellular bacterial growth. In parallel to an increase of ferroportin1 expression, infected macrophages induce anti-microbial immune effector mechanisms such as TNFα formation or NO expression which are aggravated upon iron deficiency. These adaptive changes of iron homeostasis and immune response pathways are only found in macrophages infected with Listeria which express listeriolysin O and are therefore able to escape from the phagosome to the cytoplasm. Listeriolysin O deficient Listeria which are restricted to the phagosome are even killed by excess iron which may be based on "iron intoxification" via macrophage radical formation, because iron supplementation in that setting is paralleled by increased ROS formation. Our results indicate that ferroportin1 mediated iron export is a nutritional immune effector pathway to control infection with Listeria residing in the cytoplasm, whereas a different strategy is observed in mutant Listeria restricted to the phagosome, where iron remains in the macrophages likewise contributing to ROS mediated intoxification of bacteria.


Asunto(s)
Homeostasis/efectos de los fármacos , Hierro/farmacología , Listeria monocytogenes/fisiología , Listeriosis/metabolismo , Listeriosis/microbiología , Macrófagos/metabolismo , Macrófagos/microbiología , Animales , Proteínas de Transporte de Catión/metabolismo , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Genes Bacterianos , Inmunomodulación/genética , Espacio Intracelular/microbiología , Quelantes del Hierro/farmacología , Listeria monocytogenes/efectos de los fármacos , Listeria monocytogenes/genética , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Viabilidad Microbiana/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Factores de Tiempo
20.
Kidney Int ; 87(1): 10-2, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25549119

RESUMEN

In this issue of Kidney International, the Dialysis Outcomes and Practice Patterns Study reports that hemodialysis patients with monthly intravenous iron supplementation of 300-399 mg or ⩾400 mg had a 13 or 18% higher risk of dying, respectively, compared with those receiving 100-199 mg per month, with no obvious differences in cause-specific mortalities. This study supports that randomized controlled trials are urgently needed to identify optimized iron supplementation strategies for anemic dialysis patients.


Asunto(s)
Hierro/administración & dosificación , Hierro/efectos adversos , Diálisis Renal/mortalidad , Femenino , Humanos , Masculino
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