losartan-potassium and Inflammation

In patients with heart failure, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to decrease hepcidin and ferritin and increase transferrin receptor protein, changes that are typically indicative of worsening absolute iron deficiency, as would be seen with poor dietary intake or gastrointestinal bleeding, neither of which is provoked by SGLT2 inhibitors. Therefore, 2 alternative conceptual frameworks may explain the observed pattern of changes in iron homeostasis proteins. According to the "cytosolic iron depletion hypothesis," the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor is related to a decline in cytosolic Fe

Topics: Erythropoietin; Ferritins; Heart Failure; Hepcidins; Humans; Inflammation; Iron; Iron Deficiencies; Receptors, Transferrin; Sodium-Glucose Transporter 2 Inhibitors; Transferrin

In recent years, tissue engineering has emerged as a promising approach to address limitations of organ transplantation. The ultimate goal of tissue engineering is to provide scaffolds that closely mimic the physicochemical and biological cues of native tissues' extracellular matrix. In this endeavor, new generation of scaffolds have been designed that utilize the incorporation of signaling molecules in order to improve cell recruitment, enhance angiogenesis, exert healing activities, and increase the engraftment of the scaffolds. Among different signaling molecules, the role of erythropoietin (EPO) in regenerative medicine is increasingly being appreciated. It is a biological macromolecule which can prevent programed cell death, modulate inflammation, induce cell proliferation, and provide tissue protection in different disease models. In this review, we have outlined and critically analyzed different techniques of scaffolds' modification with EPO or EPO-loaded nanoparticles. We have also explored different strategies for the incorporation of EPO into scaffolds. Non-hematopoietic functions of EPO have also been discussed. Finalizing with detailed discussion surrounding the applications, challenges, and future perspectives of EPO-modified scaffolds in regenerative medicine.

Topics: Cell Proliferation; Erythropoietin; Extracellular Matrix; Humans; Inflammation; Regenerative Medicine; Tissue Engineering; Tissue Scaffolds

Spinal cord injury (SCI) is one of the most destructive traumatic diseases in human beings. The balance of inflammation in the microenvironment is crucial to the repair process of spinal cord injury. Inflammatory cytokines are direct mediators of local lesion inflammation and affect the prognosis of spinal cord injury to varying degrees. In spinal cord injury models, some inflammatory cytokines are beneficial for spinal cord repair, while others are harmful. A large number of animal studies have shown that local targeted administration can effectively regulate the secretion and delivery of inflammatory cytokines and promote the repair of spinal cord injury. In addition, many clinical studies have shown that drugs can promote the repair of spinal cord injury by regulating the content of inflammatory cytokines. However, topical administration affects only a small portion of inflammatory cytokines. In addition, different individuals have different inflammatory cytokine profiles during spinal cord injury. Therefore, future research should aim to develop a personalized local delivery therapeutic cocktail strategy to effectively and accurately regulate inflammation and obtain substantial functional recovery from spinal cord injury.

Topics: Animals; Chemokine CXCL12; Cytokines; Disease Models, Animal; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation; Interferon-beta; Interleukin-1; Interleukin-10; Interleukin-33; Mice; Neuroinflammatory Diseases; Neuroprotective Agents; Recovery of Function; Spinal Cord; Spinal Cord Injuries

Erythropoietin (EPO) is a hypoxia-induced hormone produced in adult kidneys with erythropoietic and non-erythropoietic effects. In vivo studies represent an important role to comprehend the efficacy and safety in the early phase of repurposing drugs. The aim is to evaluate the potential anti-inflammatory effect of EPO observed in animal models of disease. Following PRISMA statements, electronic database Medline via PubMed platform was used to search articles with the research expression ((erythropoietin [MeSH Terms]) AND (inflammation [MeSH Terms]) AND (disease models, animal [MeSH Terms])). The inclusion criteria were original articles, studies where EPO was administered, studies where inflammation was studied and/or evaluated, non-clinical studies in vivo with rodents, and articles published in English. Thirty-six articles met the criteria for qualitative analysis. Exogenous EPO was used in models of sepsis, traumatic brain injury, and autoimmune neuritis, with an average of 3000 IU/Kg for single and multiple doses, using mice and rats. Biomarkers such as immune-related effectors, cytokines, reactive oxygen species, prostaglandins, and other biomarkers were assessed. EPO has been recognized as a multifunctional cytokine with anti-inflammatory properties, showing its significant effect both in acute and chronic models of inflammation. Further non-clinical studies are suggested for the enlightenment of anti-inflammatory mechanisms of EPO in lower doses, allowing us to understand the translational data for humans.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Drug Evaluation, Preclinical; Erythropoietin; Humans; Inflammation; Rodentia

Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.

Topics: Acute Kidney Injury; Erythropoiesis; Erythropoietin; Homeostasis; Humans; Inflammation; Iron; Iron-Regulatory Proteins; Kidney; Kidney Tubules, Distal; Kidney Tubules, Proximal; Mitochondria; Nephrons; Oxidative Stress; Renal Insufficiency, Chronic

Anemia is frequently observed in the course of chronic kidney disease (CKD) and it is associated with diminishing the quality of a patient's life. It also enhances morbidity and mortality and hastens the CKD progression rate. Patients with CKD frequently suffer from a chronic inflammatory state which is related to a vast range of underlying factors. The results of studies have demonstrated that persistent inflammation may contribute to the variability in Hb levels and hyporesponsiveness to erythropoietin stimulating agents (ESA), which are frequently observed in CKD patients. The understanding of the impact of inflammatory cytokines on erythropoietin production and hepcidin synthesis will enable one to unravel the net of interactions of multiple factors involved in the pathogenesis of the anemia of chronic disease. It seems that anti-cytokine and anti-oxidative treatment strategies may be the future of pharmacological interventions aiming at the treatment of inflammation-associated hyporesponsiveness to ESA. The discovery of new therapeutic approaches towards the treatment of anemia in CKD patients has become highly awaited. The treatment of anemia with erythropoietin (EPO) was associated with great benefits for some patients but not all.

Topics: Anemia; Animals; Antioxidants; Cytokines; Erythropoietin; Humans; Inflammation; Renal Insufficiency, Chronic

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecu

Topics: Acetylcysteine; Animals; Anticonvulsants; Antioxidants; Atorvastatin; Brain Injuries, Traumatic; Ceftriaxone; Dibenzazepines; Drug Repositioning; Epilepsy; Epilepsy, Post-Traumatic; Erythropoietin; Fingolimod Hydrochloride; GABA Agents; Gabapentin; Humans; Immunologic Factors; Inflammation; Interleukin 1 Receptor Antagonist Protein; Isoflurane; Levetiracetam; Losartan; Neuroprotective Agents; Oxidative Stress; Pregabalin; Pyrrolidinones; Sirolimus; Stroke; Topiramate; Translational Research, Biomedical; Vigabatrin

Berger, Marc Moritz, Peter H. Hackett, and Peter Bärtsch. No relevant analogy between COVID-19 and acute mountain sickness.

Topics: Acute Disease; Altitude Sickness; Angiotensin-Converting Enzyme 2; COVID-19; COVID-19 Drug Treatment; Erythropoietin; Humans; Hypoxia; Inflammation; SARS-CoV-2; Symptom Assessment

The findings of recent clinical trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors produce effects beyond glucose lowering and have demonstrated beneficial cardiovascular effects that have been observed across a broad range of patients with type 2 diabetes mellitus. In particular, the cardiovascular benefit results largely from substantial and early effects of SGLT2 inhibition on cardiovascular death and hospitalization for heart failure. Recent cardiovascular outcomes trials (CVOTs) have also shown that relative risk reductions in cardiovascular outcomes were observed with SGLT2 inhibition both in patients with current and prior heart failure. Since the observed reductions of cardiovascular outcomes with SGLT2 inhibitor therapy were observed much earlier than would be expected by an anti-atherosclerotic effect, these results have led to speculation about the potential underlying pathways. Suggested mechanisms include natriuresis and osmotic diuresis; reductions in inflammation, oxidative stress, and arterial stiffness; reductions in blood pressure and body weight; and possible renoprotective effects. These effects could produce cardiovascular benefits through a range of cardiac effects, including reduction in left ventricular load, attenuation of cardiac fibrosis and inflammation, and improved myocardial energy production. Other possible mechanisms include inhibition of sodium-hydrogen exchange, increases in erythropoietin levels, and reduction in myocardial ischemia or reperfusion injury. It is likely that a range of mechanisms underlie the observed cardiovascular benefits of SGLT2 inhibitors; further elucidation of these mechanisms will be answered by ongoing research.

Topics: Blood Pressure; Body Weight; Cardiovascular Diseases; Cardiovascular System; Diuresis; Erythropoietin; Heart; Humans; Inflammation; Kidney; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Natriuresis; Oxidative Stress; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Hydrogen Exchangers; Vascular Stiffness

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, and intracellular neurofibrillary tangles and extracellular amyloid-beta protein deposits represent the major pathological hallmarks of the disease. Currently available treatments provide some symptomatic relief but fail to modify primary pathological processes that underlie the disease. Erythropoietin (EPO), a hematopoietic growth factor, acts primarily to stimulate erythroid cell production, and is clinically used to treat anemia. EPO has evolved as a therapeutic agent for neurodegeneration and has improved neurological outcomes and AD pathology in rodents. However, penetration of the blood-brain barrier (BBB) and negative hematopoietic effects are the two major challenges for the therapeutic development of EPO for chronic neurodegenerative diseases like AD. The transferrin receptors at the BBB, which are responsible for transporting transferrin-bound iron from the blood into the brain parenchyma, can be used to shuttle therapeutic molecules across the BBB. In this review, we discuss the role of EPO as a potential neurotherapeutic for AD, challenges associated with EPO development for AD, and targeting the BBB transferrin receptor for EPO brain delivery.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cognition; Erythropoietin; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Inflammation; Mice; Microglia; Mitochondria; Models, Neurological; Neuroprotective Agents; Neurotransmitter Agents; Oxidative Stress; Protein Transport; Rats; Receptors, Erythropoietin; Receptors, Transferrin; Transcytosis

Cardiovascular disease and infections are directly or indirectly associated with an altered immune response, which leads to a high incidence of morbidity and mortality, and together, they account for up to 70% of all deaths among patients with chronic kidney dysfunction. Impairment of the normal reaction of the innate and adaptive immune systems in chronic kidney disease predisposes patients to an increased risk of infections, virus-associated cancers, and a diminished vaccine response. On the other hand, an abnormal, exaggerated reaction of the immune systems can also occur in this group of patients, resulting in increased production and decreased clearance of proinflammatory cytokines, which can lead to inflammation and its sequelae (eg, atherosclerotic cardiovascular disease). Epigenetically, modifications in hematopoietic stem cells involving a shift from lymphoid to myeloid cell lineage may underlie uremia-associated immunological senescence, which is not reversed by renal replacement therapy, including kidney transplantation. Measures aimed at attenuating the immune abnormalities in chronic kidney disease/end-stage renal disease should be an area of focused research as this could potentially lead to a better understanding and, thus, development of therapies that could reduce the disastrously high death rate in this patient population. The aim of the present article is to review the characteristics, causes, and mechanisms of the immune dysfunction related to chronic kidney disease.

Topics: Adaptive Immunity; Calcitriol; Calcium; Epigenesis, Genetic; Erythropoietin; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gastrointestinal Microbiome; Hematopoietic Stem Cells; Humans; Immunity, Innate; Immunocompromised Host; Immunosenescence; Infections; Inflammation; Iron; Oxidative Stress; Parathyroid Hormone; Renal Insufficiency, Chronic; Renal Replacement Therapy; Renin; Renin-Angiotensin System; Vitamin D

Recent research has revealed that regulation of the bone-secreted hormone fibroblast growth factor 23 (FGF23) is not limited to classical mineral factors. Specifically, bidirectional relationships have been described between FGF23 production and anemia, iron status, and inflammation. Here, we will review the latest published articles on the crosstalk between FGF23 and the aforementioned nonclassical factors.. It has been recently reported that erythropoietin, iron deficiency, and inflammation increase FGF23 production and metabolism. Moreover, FGF23 promotes anemia and regulates inflammatory responses. These findings are particularly important in the setting of chronic kidney disease which is characterized by elevated FGF23 levels and several associated comorbidities.. Regulation of FGF23 is complex and involves many bone and renal factors. More recently, erythropoietin, iron deficiency, and inflammation have been also shown to affect FGF23 transcription and cleavage. Importantly, FGF23 has emerged as a regulator of erythropoiesis, iron metabolism, and inflammation. These findings provide novel and important insights into the pathophysiologic mechanisms of chronic kidney disease and may present new opportunities for therapeutic clinical interventions.

Topics: Erythropoiesis; Erythropoietin; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Inflammation; Iron; Renal Insufficiency, Chronic

During the past 35 years, recombinant DNA technology has allowed the production of a wide range of hematopoietic and neurotrophic growth factors including erythropoietin (EPO). These have emerged as promising protein drugs in various human diseases. Accumulated evidences have recently demonstrated the neuroprotective effect of EPO in preclinical models of acute and chronic degenerative disorders. Nevertheless, tissue protective effect of EPO could not be translated to the clinical trials because of common lethal thromboembolic events, erythropoiesis and hypertension. Although chemically modified nonerythropoietic analogs of EPO bypass these side effects, high expense, development of antidrug antibodies, and promotion of tumorigenicity are still concern especially in long-term use. As an alternative, nonerythropoietic EPO mimetic peptides can be used as candidate drugs with their high potency and selectivity, easy production, low cost, and immunogenicity properties. Recent experimental studies suggest that these peptides prevent ischemic brain injury and neuroinflammation. The results of clinical trial in patients with neuropathic pain are also promising. Herein, we summarize these studies and review advanced experimental and in silico methods in peptide drug discovery.

Topics: Animals; Erythropoietin; Humans; Inflammation; Neurodegenerative Diseases; Neuroprotective Agents; Peptides

Fetal erythropoietin (EPO), in addition to regulating erythropoiesis, has also tissue-protective properties based on its anti-inflammatory, anti-apoptotic, antioxidant, and neurotrophic effects. Notably, EPO concentrations needed for tissue protection are 100-1000 times higher than concentrations needed for regulating erythropoiesis. This dual effect of EPO is based on EPO-receptor (EPO-R) isoforms, which differ structurally and functionally. We hypothesize in this Integrated Mechanism Review that during severe fetal hypoxia the observed, but poorly understood, marked increases of fetal plasma EPO concentrations occur to protect the brain, heart, and other vital fetal organs. We further hypothesize that the concurrent marked increases of EPO in the amniotic fluid during fetal hypoxia, occur to protect newborn infants from necrotizing enterocolitis. This review presents experimental and clinical evidence in support of these hypotheses and points out unknown or poorly understood functions of EPO in the fetus. If these novel hypotheses are correct, the importance of fetal EPO as an antenatal hypoxia biomarker will become apparent. It will also likely point the way to important diagnostic and therapeutic fetal and neonatal interventions.

Topics: Amniotic Fluid; Animals; Biomarkers; Brain; Enterocolitis, Necrotizing; Erythropoietin; Female; Fetal Blood; Fetal Diseases; Hematopoiesis; Humans; Hypoxia; Infant, Newborn; Inflammation; Intestines; Neuroprotection; Pregnancy; Protein Isoforms; Reactive Oxygen Species

In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control.

Topics: Carbon Monoxide; Erythropoietin; Estrogens; Free Radical Scavengers; Heme Oxygenase-1; Humans; Hydrogen Sulfide; Inflammasomes; Inflammation; Inflammation Mediators; Mitochondria; Mitochondrial Diseases; Mitophagy; Nitric Oxide; Oxidative Phosphorylation; Polyphenols; Thyroid Hormones

Hospital-acquired anemia is common, especially in the most critically ill patients. It may be associated with poor patient outcomes. It may result from increased blood loss, impaired red cell production or reduced red cell life span. Multiple associated factors may contribute simultaneously or sequentially to the decrease in hemoglobin level. Some of them are related to the underlying disease and others are iatrogenic. Clinicians should be aware of the importance and consequences of iatrogenic anemia caused by diagnostic blood sampling. Strategies and measures to minimize iatrogenic blood loss should be prioritized. They may reduce the risk of developing anemia and then red blood cells transfusion requirement.

Topics: Adult; Anemia; Blood Transfusion; Child; Erythrocyte Aging; Erythropoietin; Ferritins; Health Services Needs and Demand; Hematinics; Hemodilution; Humans; Iatrogenic Disease; Inflammation; Iron; Multicenter Studies as Topic; Phlebotomy; Retrospective Studies; Vascular Access Devices

In the adult brain, neural progenitor cells (NPCs) reside in the subventricular zone (SVZ) of the lateral ventricles, the dentate gyrus and the olfactory bulb. Following CNS insult, NPCs from the SVZ can migrate along the rostral migratory stream (RMS), a migration of NPCs that is directed by proinflammatory cytokines. Cells expressing CXCR4 follow a homing signal that ultimately leads to neuronal integration and CNS repair, although such molecules can also promote NPC quiescence. The ligand, SDF1 alpha (or CXCL12) is one of the chemokines secreted at sites of injury that it is known to attract NSC-derived neuroblasts, cells that express CXCR4. In function of its concentration, CXCL12 can induce different responses, promoting NPC migration at low concentrations while favoring cell adhesion via EGF and the alpha 6 integrin at high CXCL12 concentrations. However, the preclinical effectiveness of chemokines and their relationship with NPC mobilization requires further study, particularly with respect to CNS repair. NPC migration may also be affected by the release of cytokines or chemokines induced by local inflammation, through autocrine or paracrine mechanisms, as well as through erythropoietin (EPO) or nitric oxide (NO) release. CXCL12 activity requires G-coupled proteins and the availability of its ligand may be modulated by its binding to CXCR7, for which it shows a stronger affinity than for CXCR4.

Topics: Brain; Cell Adhesion; Cell Differentiation; Cell Movement; Chemokine CXCL12; Dentate Gyrus; Erythropoietin; Humans; Inflammation; Lateral Ventricles; Neural Stem Cells; Neurogenesis; Nitric Oxide; Olfactory Bulb; Protein Binding; Receptors, CXCR; Receptors, CXCR4; Signal Transduction

Iron, an essential nutrient, is required for many diverse biological processes. The absence of a defined pathway to excrete excess iron makes it essential for the body to regulate the amount of iron absorbed; a deficiency could lead to iron deficiency and an excess to iron overload and associated disorders such as anaemia and haemochromatosis respectively. This regulation is mediated by the iron-regulatory hormone hepcidin. Hepcidin binds to the only known iron export protein, ferroportin (FPN), inducing its internalization and degradation, thus limiting the amount of iron released into the blood. The major factors that are implicated in hepcidin regulation include iron stores, hypoxia, inflammation and erythropoiesis. The present review summarizes our present knowledge about the molecular mechanisms and signalling pathways contributing to hepcidin regulation by these factors.

Topics: Animals; Bone Morphogenetic Proteins; Cation Transport Proteins; Cell Hypoxia; Erythropoietin; Hemochromatosis; Hepcidins; Humans; Inflammation; Iron; Mice; Signal Transduction; Smad Proteins; Transferrin

Topics: Aged; Algorithms; Anemia; Anemia, Iron-Deficiency; Cardiovascular Diseases; Cohort Studies; Comorbidity; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Multicenter Studies as Topic; Peptides; Renal Dialysis

Resistance to erythropoiesis-stimulating agents (ESAs) has been observed in a considerable proportion of patients with chronic kidney disease (CKD) and it is reportedly associated with adverse outcomes, such as increased cardiovascular morbidity, faster progression to end-stage renal disease (ESRD) and all-cause mortality. The major causes of ESA resistance include chronic inflammation producing suppressive cytokines of early erythroid progenitor proliferation. In addition, pro-inflammatory cytokines stimulate hepcidin synthesis thus reducing iron availability for late erythropoiesis. Recent studies showing an association in deficiencies of the vitamin D axis with low haemoglobin (Hb) levels and ESA resistance suggest a new pathophysiological co-factor of renal anaemia. The administration of either native or active vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Notably, these effects are not related to parathyroid hormone (PTH) values and seem to be independent on PTH suppression. Another possible explanation may be that calcitriol directly stimulates erythroid progenitors; however, this proliferative effect by extra-renal activation of 1α-hydroxylase enzyme is only a hypothesis. The majority of studies concerning vitamin D deficiency or supplementation, and degree of renal anaemia, point out the prevalent role of inflammation in the mechanism underlying these associations. Immune cells express the vitamin D receptor (VDR) which in turn is involved in the modulation of innate and adaptive immunity. VDR activation inhibits the expression of inflammatory cytokines in stromal and accessory cells and up-regulates the lymphocytic release of interleukin-10 (IL-10) exerting both anti-inflammatory activity and proliferative effects on erythroid progenitors. In CKD patients, vitamin D deficiency may stimulate immune cells within the bone marrow micro-environment to produce cytokines, inducing impaired erythropoiesis. Immune activation involves the reticuloendothelial system, increasing hepcidin synthesis and functional iron deficiency. Consequences of this inflammatory cascade are erythropoietin (EPO) resistance and anaemia. Given the key role of inflammation in the response to EPO, the therapeutic use of agents with anti-cytokines properties, such as vitamin D and paricalcitol, may provide benefit in the prevention/treatment of ESA hyporesponsiveness.

Topics: Anemia; Animals; Cytokines; Erythropoietin; Humans; Inflammation; Renal Insufficiency, Chronic; Vitamin D Deficiency

Erythropoietin (EPO) is traditionally described as a hematopoietic cytokine or growth hormone regulating proliferation, differentiation, and survival of erythroid progenitors. The use of EPO in patients with chronic kidney disease (CKD) was a milestone achievement in the treatment of anemia. However, EPO involves some degree of risk, which increases with increasing hemoglobin levels. A growing number of studies have assessed the renoprotective effects of EPO in acute kidney injury (AKI) or CKD. Analysis of the biological effects of erythropoietin and pathophysiology of CKD in these studies suggests that treatment with erythropoiesis-stimulating agents (ESAs) may exert renoprotection by pleiotropic actions on several targets and directly or indirectly slow the progression of CKD. By reducing ischemia and oxidative stress or strengthening anti-apoptotic processes, EPO may prevent the development of interstitial fibrosis and the destruction of tubular cells. Furthermore, it could have a direct protective impact on the integrity of the interstitial capillary network through its effects on endothelial cells and promotion of vascular repair, or modulate inflammation response. Thus, it is biologically plausible to suggest that correcting anemia with ESAs could slow the progression of CKD.                         The aim of this article is to discuss these possible renoprotection mechanisms and provide a comprehensive overview of erythropoietin and its derivatives.

Topics: Apoptosis; Erythropoietin; Humans; Inflammation; Kidney; Oxidative Stress; Protective Agents

Iron Deficiency Anaemia (IDA) has been shown to be the most common cause of anaemia worldwide. It is accepted that people with chronic kidney disease (CKD) develop anaemia as their kidney function declines.. To better understand IDA in CKD, it is necessary to appreciate the normal iron metabolism and utilisation of iron and how these processes can be disordered in patients with CKD. The problems related to infection / inflammation and oxidative stress are examined. Whilst National and international guidelines recommend specific tests for IDA, these and alternative tests are reviewed.. Whilst iron supplementation is necessary for CKD patients with IDA, iron metabolism and utilisation can be affected by factors such as infection or inflammation. Iron is essential element for all life, it can be toxic to cells through the process of oxidative stress. The recommended tests for IDA may be affected by factors such as infection and inflammation. Alternative tests are available, which may be a more accurate indicator of IDA as they are not affected by external factors.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Guideline Adherence; Hepcidins; Humans; Infections; Inflammation; Iron; Kidney Failure, Chronic; Oxidative Stress; Reference Values

Topics: Anemia; Animals; Clinical Trials as Topic; Erythropoietin; Hepcidins; Humans; Inflammation; Iron

Erythropoietin (EPO) is a multi-functional cytokine, which exerts erythropoietic effects but also carries anti-apoptotic and immune-modulatory activities upon binding to two distinct receptors which are expressed on erythroid, parenchymal and immune cells, respectively. Whereas EPO ameliorates hemolytic anemia in malaria or trypanosomiasis and improves the course of autoimmune diseases such as inflammatory bowel disease or autoimmune encephalomyelitis, it deleteriously inhibits macrophage functions in Salmonella infection in animal models. Thus, the specific modulation of extra-erythropoietic EPO activity forms an attractive therapeutic target in infection and inflammation.

Topics: Anemia, Hemolytic; Animals; Cell Hypoxia; Erythropoiesis; Erythropoietin; Genetic Pleiotropy; Host-Pathogen Interactions; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Macrophages; Mice; NF-kappa B; Salmonella; Salmonella Infections; Signal Transduction

The relationships between erythropoietin (EPO), iron, and erythropoiesis and the presence of iron-restricted erythropoiesis have important implications in anemia management. Iron-restricted erythropoiesis occurs in the presence of one or more iron deficiency syndromes: absolute iron deficiency, functional iron deficiency, and/or iron sequestration. Absolute iron deficiency is a common nutritional deficiency in women's health, pediatrics, and the elderly and is therefore an important public health problem. Functional iron deficiency occurs in patients with significant EPO-mediated erythropoiesis or therapy with erythropoiesis-stimulating agents, even when storage iron is present. Iron sequestration mediated by hepcidin is an underappreciated but common cause of iron-restricted erythropoiesis in patients with chronic inflammatory disease. The challenge for treating and laboratory-based physicians is to understand the contributory role(s) of each of these syndromes, so that the potential value of emerging and innovative pharmacologic strategies can be considered as options in patient blood management.

Topics: Aged; Antimicrobial Cationic Peptides; Child; Child, Preschool; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Hepcidins; Humans; Infant; Inflammation; Iron; Iron Deficiencies; Iron Metabolism Disorders; Male; Middle Aged; Syndrome

This systematic review summarizes and critically appraises the literature on the effect of erythropoietin (EPO) in schizophrenia patients and the pathophysiological mechanisms that may explain the potential of its use in this disease. EPO is mainly known for its regulatory activity in the synthesis of erythrocytes and is frequently used in treatment of chronic anemia. This cytokine, however, has many other properties, some of which may improve the symptoms of psychiatric illness. The review follows the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement guidelines. Three databases (Medline, Web of Science, and Cochrane) were searched combining the search terms 'erythropoietin AND (psychotic disorders OR schizophrenia)'. Seventy-eight studies were included in qualitative synthesis, a meta-analytic approach being prohibited. The findings suggest that several EPO cerebral potential properties may be relevant for schizophrenia treatment, such as neurotransmission regulation, neuroprotection, modulation of inflammation, effects on blood-brain barrier permeability, effects on oxidative stress and neurogenesis. Several potentially detrimental side-effects of EPO therapy, such as increased risk of thrombosis, cancer, increased metabolic rate and mean arterial blood pressure leading to cerebral ischemia could severely limit or halt the use of EPO. Overall, because the available data are inconclusive, further efforts in this field are warranted.

Topics: Blood-Brain Barrier; Cognition Disorders; Erythropoietin; Humans; Inflammation; Neurogenesis; Neuroprotective Agents; Oxidative Stress; Schizophrenia

Topics: Anemia; Antibodies, Monoclonal, Humanized; Antimicrobial Cationic Peptides; Arthritis, Rheumatoid; Erythropoiesis; Erythropoietin; Hepcidins; Humans; Inflammation; Interleukin-6; Iron; Vitamin D; Vitamins

The essential biological role of erythropoietin (EPO) in maintaining erythrocyte mass has been well understood for many years. Although EPO is required for the maturation of red cells, it also has strong procoagulant effects on the vascular endothelium and platelets, which limit erythrocyte losses after hemorrhage. Like other members of the type 1 cytokine superfamily, EPO has multiple biological activities. For the past 10 years, multiple investigators have shown that EPO acts as a locally produced antagonist of proinflammatory cytokines that are generated by the innate immune response in response to infection, trauma, or metabolic stress. Specifically, EPO inhibits apoptosis of cells surrounding a locus of injury, reduces the influx of inflammatory cells, and recruits tissue-specific stem cells and endothelial progenitor cells. Available evidence suggests that these multiple, nonerythropoietic effects of EPO are mediated by a tissue protective receptor (TPR) that is distinct from the homodimeric receptor responsible for erythropoiesis. Notably, activation of the TPR requires a higher concentration of EPO than is needed for maximal erythropoiesis. Unfortunately, these higher concentrations of EPO also stimulate hematopoietic and procoagulant pathways, which can cause adverse effects and, therefore, potentially limit the clinical use of EPO for tissue protection. To circumvent these problems, the EPO molecule has been successfully modified in a variety of ways to interact only with the TPR. Early clinical experience has shown that these compounds appear to be safe, and proof of concept trials are ready to begin.

Topics: Animals; Apoptosis; Coagulants; Erythrocytes; Erythropoiesis; Erythropoietin; Hemorrhage; Humans; Hypoxia; Inflammation; Ischemia; Malaria, Cerebral; Neoplasms; Signal Transduction; Stem Cells; Thrombosis

Topics: Angiopoietin-1; Animals; Cell Movement; Diabetic Retinopathy; Erythropoietin; Humans; Hyperglycemia; Inflammation; Mice; Mice, Transgenic; Neovascularization, Pathologic; Neovascularization, Physiologic; Receptor, TIE-2; Retina; Vascular Endothelial Growth Factor A

Topics: Anemia; Anemia, Iron-Deficiency; Avitaminosis; Disease Management; Drug Resistance; Erythropoietin; Ferritins; Hemoglobins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Practice Guidelines as Topic; Reference Values; Renal Dialysis; Time Factors; Transferrin

Anemia is inevitable as chronic kidney disease (CKD) advances. With the advent of erythropoietin-stimulating agents (ESAs), considerable improvement has been achieved in the management of anemia. However, some patients show a reduced response to ESAs.. Many factors affect the response to ESA treatment. CKD is now considered as an inflammatory disorder and this understanding led to the recognition of the central role of inflammation in ESA resistance. Inflammation is related to untoward outcomes, including atherosclerosis and anemia, in the CKD population. Furthermore, recognition of deleterious effects of proinflammatory markers at different levels of erythropoiesis led to a change in the name of 'anemia of chronic disease' to anemia of inflammation.. The discovery of hepcidin as the major controller of iron metabolism in anemia of inflammation answered many questions regarding the interaction of erythropoietin, iron and bone marrow. Hepcidin production in the liver is driven by three major factors: inflammation, iron overload and anemia/hypoxia. Hepcidin levels are increased in patients with CKD due to the interaction of many factors; a comprehensive understanding of these pathways is thus critical in the effort to alleviate anemia of inflammation and ESA resistance.. In this review, we discussed the epidemiology, determinants and consequences of anemia of inflammation in CKD patients with special emphasis on the central role of hepcidin along with molecular pathways driving its production.

Topics: Anemia; Antimicrobial Cationic Peptides; Bone Marrow; Chronic Disease; Erythropoietin; Hepcidins; Humans; Inflammation; Iron; Iron Overload; Kidney Diseases

Despite optimal antimalarial treatment and advances in malaria eradication, the mortality rate associated with severe malaria due to Plasmodium falciparum infection, including cerebral malaria (CM), remains unacceptably high. This suggests that strategies directed solely at parasite eradication may be insufficient to prevent neurological complications and death in all cases of CM. Therefore, there is an urgent need to develop innovative adjunctive therapeutic strategies to effectively reduce CM-associated mortality. CM pathogenesis is believed to be due, in part, to an aberrant host immune response to P. falciparum, resulting in deleterious consequences, including vascular activation and dysfunction. Development of effective and affordable therapeutic strategies that act to modulate the underlying host-mediated immunopathology should be explored to improve outcome. In this article, we summarize immunomodulatory therapies that have been assessed in clinical trials to date, and highlight novel and promising treatment strategies currently being investigated to address this major global health challenge.

Topics: Africa; Antimalarials; Arginine; Clinical Trials as Topic; Dexamethasone; Epidemiologic Studies; Erythropoietin; Humans; Immunomodulation; Inflammation; Levamisole; Malaria, Cerebral; Malaria, Falciparum; Nitric Oxide; Plasmodium falciparum; PPAR gamma; Rosiglitazone; Thiazolidinediones

Despite new therapeutic options and treatment strategies, anemia still remains one of the major complications of chronic kidney disease (CKD), especially in patients undergoing chronic hemodialysis for end-stage renal disease. Successful management of anemia is a central part of patient care that may improve clinical outcomes. Although the National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-DOQI) working group reformulated its recommendations by stating that the hemoglobin target in patients receiving erythropoiesis stimulatory agents (ESA) should generally be 11-12 g/dl, this target value can not be achieved in many of them, despite treatment with high doses of ESA. The aim of the present review is to provide an update of the recent literature on causes and possible management of ESA-resistant anemia in CKD patients.

Topics: Anemia; Anemia, Iron-Deficiency; Drug Resistance; Erythropoiesis; Erythropoietin; Hematinics; Humans; Inflammation; Kidney Failure, Chronic; Patient Compliance; Recombinant Proteins; Renal Dialysis

The 39th Annual meeting of the Society for Neuroscience was held in Chicago, Illinois, USA from 17 to 21 October, 2009. The conference was attended by more than 33,000 delegates from across the globe including scientists from both basic and clinical settings. Co-incidentally, this year, the scientific community is commemorating the 200th anniversary of the birth of the famous English naturalist and biologist, Charles Darwin, who described the theory of natural selection. Keeping its traditions, the congress discussed various new advances in the area of neuroscience. The topics were divided into symposia, mini-symposia, nano-symposia, special lectures and poster sessions. The main areas of discussion were novel discoveries in Alzheimer's, Parkinson's, drug addiction, autism, epilepsy and major depression. According to the WHO, neurological disorders are one of the greatest threats to public health. There are many unknown and challenging facts in the field of neuroscience that needs exploration. It is unfortunate that despite the availability of various drugs for treating these disorders, a sizeable population still do not achieve complete remission. Therefore, organizing such events and addressing the latest developments may open new treatment vistas for patients suffering from these disorders. The present review discusses some of the outcomes of the deliberations in the field of epilepsy and major depression.

Topics: Administration, Inhalation; Adrenergic Uptake Inhibitors; Anti-Inflammatory Agents; Anticonvulsants; Antidepressive Agents; Depressive Disorder, Major; Dopamine Uptake Inhibitors; Epilepsy; Erythropoietin; Glutamates; Humans; Inflammation; Receptors, Cannabinoid; Recombinant Proteins; Selective Serotonin Reuptake Inhibitors; Signal Transduction; Wnt Proteins

Erythropoietin (EPO) is a well-known therapeutic protein employed widely in the treatment of anemia. Over the past decade, abundant evidence has shown that in addition to its systemic role in the regulation of plasma pO(2) by modulating erythrocyte numbers, EPO is also a cytoprotective molecule made locally in response to injury or metabolic stress. Many studies have shown beneficial effects of EPO administration in reducing damage caused by ischemia-reperfusion, trauma, cytotoxicity, infection and inflammation in a variety of organs and tissues. Notably, the receptor mediating the nonerythropoietic effects of EPO differs from the one responsible for hematopoiesis. The tissue-protective receptor exhibits a lower affinity for EPO and is a heteromer consisting of EPO receptor monomers in association with the common receptor that is also employed by granulocyte macrophage colony-stimulating factor, interleukin 3, and interleukin 5. This heteromeric receptor is expressed immediately following injury, whereas EPO production is delayed. Thus, early administration of EPO can dramatically reduce the deleterious components of the local inflammatory cascade. However, a high dose of EPO is required and this also stimulates the bone marrow to produce highly reactive platelets and activates the vascular endothelium into a prothrombotic state. To circumvent these undesirable effects, the EPO molecule has been successfully altered to selectively eliminate erythropoietic and prothrombotic potencies, while preserving tissue-protective activities. Very recently, small peptide mimetics have been developed that recapitulate the tissue-protective activities of EPO. Nonerythropoietic tissue-protective molecules hold high promise in a wide variety of acute and chronic diseases.

Topics: Amino Acid Sequence; Animals; Cytokine Receptor Common beta Subunit; Cytokines; Drug Design; Erythropoietin; Feedback, Physiological; Hematinics; Hematopoiesis; Humans; Inflammation; Inflammation Mediators; Janus Kinase 2; Models, Molecular; Molecular Sequence Data; Protein Conformation; Protein Multimerization; Receptors, Erythropoietin; Recombinant Proteins; Reperfusion Injury; STAT Transcription Factors; Stress, Physiological; Wounds and Injuries

Premature cardiovascular disease (CVD) is a frequent complication in patients with chronic kidney disease (CKD). The traditional (Framingham) risk factors only partly explain the high prevalence of CVD in these patients and nontraditional risk factors/markers such as oxidative stress, persistent inflammation, cardiovascular ossification, endothelial dysfunction and anaemia are prevalent and seem to play an important role in the pathogenesis of CVD in CKD patients. In addition, the so-called reverse epidemiology phenomenon, which occurs in advanced kidney disease, complicates the search for causative mechanisms. Here we review a few recently developed concepts regarding the high incidence of CVD in CKD patients.

Topics: Anemia; Cardiovascular Diseases; Chronobiology Disorders; Endothelium, Vascular; Erythropoietin; Humans; Inflammation; Kidney Failure, Chronic; Netherlands; Ossification, Heterotopic; Oxidative Stress; Prevalence; Risk Assessment; Risk Factors

Perinatal hypoxic-ischemic encephalopathy can be a devastating complication of childbirth. Herein, the authors review the pathophysiology of hypoxic-ischemic encephalopathy and the current status of neuroprotective strategies to ameliorate the injury centering on four themes: (1) monitoring in the perinatal period, (2) rapid identification of affected neonates to allow timely institution of therapy, (3) preconditioning therapy (a therapeutic that reduces the brain vulnerability) before hypoxic-ischemic encephalopathy, and (4) prompt institution of postinsult therapies to ameliorate the evolving injury. Recent clinical trials have demonstrated the significant benefit for hypothermic therapy in the postnatal period; furthermore, there is accumulating preclinical evidence that adjunctive therapies can enhance hypothermic neuroprotection. Advances in the understanding of preconditioning may lead to the administration of neuroprotective agents earlier during childbirth. Although most of these neuroprotective strategies have not yet entered clinical practice, there is a significant hope that further developments will enhance hypothermic neuroprotection.

Topics: Adrenergic alpha-Agonists; Animals; Anti-Inflammatory Agents; Anticonvulsants; Antioxidants; Apoptosis; Erythropoietin; Female; Free Radical Scavengers; Humans; Hyperoxia; Hypocapnia; Hypoxia-Ischemia, Brain; Inflammation; Ischemic Preconditioning; Neuroprotective Agents; Neurotoxins; Pregnancy; Prenatal Diagnosis; Receptors, N-Methyl-D-Aspartate; Seizures

Anemia is highly prevalent in patients with chronic heart failure (CHF) and is associated with poor clinical outcome. Increased prevalence of anemia in CHF has been linked to advanced age, female gender, renal function impairment, severity of symptoms, and clinical settings. Overall, the anemia of CHF shares many common features with the anemia of chronic disease. Both impaired iron metabolism and inflammatory stress appear to be the key mediators of the anemia of CHF.

Topics: Age Factors; Anemia, Iron-Deficiency; Disease Progression; Erythropoietin; Female; Heart Failure; Humans; Inflammation; Iron, Dietary; Kidney Failure, Chronic; Male; Prevalence; Prognosis; Renin-Angiotensin System; Risk Factors; Sex Factors; Stress, Physiological; United States

Type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, dementia and depression constitute a cluster of diseases, which defines 'a diseasome of physical inactivity'. Both physical inactivity and abdominal adiposity, reflecting accumulation of visceral fat mass, are associated with the occurrence of the diseases within the diseasome. Physical inactivity appears to be an independent and strong risk factor for accumulation of visceral fat, which again is a source of systemic inflammation. Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration and tumour growth. Evidence suggests that the protective effect of exercise may to some extent be ascribed to the anti-inflammatory effect of regular exercise, which can be mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise. The finding that muscles produce and release myokines provides a conceptual basis to understand the mechanisms whereby exercise influences metabolism and exerts anti-inflammatory effects. According to our theory, contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specific endocrine effects on visceral fat. Other myokines work locally within the muscle via paracrine mechanisms, exerting their effects on signalling pathways involved in fat oxidation.

Topics: Abdominal Fat; Adipose Tissue; Adiposity; Animals; Brain-Derived Neurotrophic Factor; Chronic Disease; Cytokines; Erythropoietin; Exercise; Humans; Inflammation; Interleukin-15; Interleukin-6; Motor Activity; Muscle, Skeletal; Receptor Cross-Talk

Anemia of cancer and chronic inflammatory diseases is a frequent complication affecting quality of life. For cancer patients it represents a particularly bad prognostic. Low level of erythropoietin is considered as one of the causes of anemia in these pathologies. The deficiency in erythropoietin production results from pro-inflammatory cytokines effect. However, few data is available concerning molecular mechanisms involved in cytokine-mediated anemia. Some recent publications have demonstrated the direct effect of pro-inflammatory cytokines on cell differentiation towards erythroid pathway, without erythropoietin defect. This suggested that pro-inflammatory cytokine-mediated signaling pathways affect erythropoietin activity. They could interfere with erythropoietin-mediated signaling pathways, inducing early apoptosis and perturbing the expression and regulation of specific transcription factors involved in the control of erythroid differentiation. In this review we summarize the effect of tumor necrosis factor (TNF)alpha, TNF-related apoptosis-inducing ligand (TRAIL), and interferon (IFN)-gamma on erythropoiesis with a particular interest for molecular feature.

Topics: Anemia; Apoptosis; Cytokines; Erythropoiesis; Erythropoietin; Humans; In Vitro Techniques; Inflammation; Inflammation Mediators; Interferon-gamma; Models, Biological; Neoplasms; Oxidative Stress; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

Anemia is a common comorbidity in patients with heart failure and is associated with worse long-term outcomes. Although the cause of anemia in heart failure is unclear, the weight of evidence suggests that renal dysfunction, along with neurohormonal and proinflammatory cytokine activation in heart failure, favors the development of anemia of chronic disease, with defective iron utilization, inappropriate erythropoietin production, and depressed bone marrow function. Similarly, the mechanisms by which anemia worsens heart failure outcomes are unknown but may be related to increased myocardial workload. If anemia is a mediator and not just a marker of poor outcomes, correcting anemia could become an important and novel therapeutic target to improve long-term outcomes in such patients. Indeed, several small-sized studies have shown the beneficial effects of empirically treating anemia in heart failure patients with recombinant erythropoietin and intravenous iron. However, the ideal threshold at which therapy should be initiated and the extent of correction considered safe and desirable in the individual patient with heart failure need to be known. These issues become more important because of increasing safety concerns that recombinant erythropoietin therapy for treating anemia may be associated with adverse cardiovascular outcomes in patients with chronic kidney disease and may worsen cancer in patients receiving chemotherapy to treat various types of cancer. Therefore, further prospectively designed studies are required to address some of these questions. Fortunately, 2 large mortality morbidity trials, TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) in patients with chronic kidney disease and RED-HF (Reduction of Events with Darbepoetin alfa in Heart Failure) in heart failure patients, are in progress and are likely to provide definitive answers.

Topics: Anemia; Biomarkers; Bone Marrow; Erythropoietin; Female; Heart Failure; Humans; Inflammation; Iron Compounds; Kidney Failure, Chronic; Male; Receptors, Erythropoietin; Risk Factors

Among the elderly, anemia occurs with increasing frequency with each advancing decade. Unlike when anemia occurs in younger adults, the cause of anemia in the elderly is oftentimes not readily apparent or attributable to a single cause. However, this commonly observed form of anemia in the elderly (termed unexplained anemia [UA]) can generally be dissected to its root causes, which include renal insufficiency, inflammation, testosterone deficiency, and stem cell proliferative decline. Myelodysplasia (MDS) occurs commonly in this age group but can and should, for both diagnostic and therapeutic considerations, be distinguished from UA.

Topics: Adult; Aged; Aging; Androgens; Anemia; Cellular Senescence; Cytokines; Erythropoietin; Hematopoietic Stem Cells; Humans; Inflammation; Recombinant Proteins; Renal Insufficiency

Parenteral ascorbic acid has been frequently used to overcome problems of vitamin C deficiency in haemodialysis patients. The benefits of vitamin C supplementation in clinical studies have been controversial and did not consider toxicological aspects. The review summarizes recent findings of the effects of parenteral ascorbic acid and discusses toxicological effects.. Vitamin C deficiency in haemodialysis patients, which has been frequently described, cannot be improved with oral supplementation due to limited absorption of high dosages. To avoid consequences of vitamin C deficiency, parenteral vitamin C solutions should be administered because this intervention is the only way to guarantee a sufficient supply to the cells. A beneficial consequence of parenteral vitamin C on the recombinant human erythropoietin resistance is an additional therapeutic effect, which contributes to the prevention of iron deficiency anaemia in haemodialysis patients. Thus, large amount of supplemental vitamin C are required for extended periods of time (up to 500 mg 3 times a week). To avoid hyperoxaluria, plasma oxalate levels should be monitored on a regular basis, for example, once a week.. Parenteral administration of ascorbic acid may be an approach that can overcome problems of vitamin C deficiency in haemodialysis patients - in particular problems of iron overload, erythropoetin resistance, and chronic inflammation.

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; Drug Resistance; Erythropoietin; Hemosiderosis; Humans; Inflammation; Infusions, Parenteral; Renal Dialysis

Spinal cord injury leads to a devastating cascade of secondary complications that eventually results in the formation of scar tissue many times the size of the original insult. Inflammation plays a very important role towards the development of such scar, but paradoxically, at the same time it has neuroprotective properties. Only recently have we understood enough about the relevant events to make the repair of injured spinal cords a reachable goal. Over the past decade, researchers have designed and tested numerous innovative therapeutic strategies, and many of such involve manipulation of the immune response. Interestingly, both immuno-stimulatory and immuno-suppressive interventions have shown positive results, which include the prevention of further tissue damage, prevention of secondary cell death and axonal degeneration, promotion of remyelination, stimulation of axonal regeneration, and facilitation of sensorimotor function recovery.

Topics: Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lymphocyte Activation; Macrophage Activation; Minocycline; Neutrophils; Peptides; rho-Associated Kinases; Spinal Cord Injuries; T-Lymphocytes

Global use of erythropoietin (EPO) continues to increase as a proven agent for the treatment of anemia. Yet, EPO is no longer believed to have exclusive biological activity in the hematopoietic system and is now considered applicable for a variety of disorders such as diabetes, Alzheimer's disease, and cardiovascular disease. Treatment with EPO is considered to be robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. On the converse side, observations that EPO administration is not without risk have fueled controversy. Here we present recent advances that have elucidated a number of novel cellular pathways governed by EPO to open new therapeutic avenues for this agent and avert its potential deleterious effects.

Topics: Animals; Apoptosis; Diabetes Mellitus; Erythropoietin; Gene Expression Regulation; Hematopoiesis; Humans; Inflammation; Models, Biological; Neovascularization, Pathologic; Neurodegenerative Diseases; Oxidative Stress; Signal Transduction

Anemia of chronic disease (ACD) is a mild to moderate anemia seen with many infections and inflammatory disorders. These patients have low serum iron, but high serum ferritin levels. As for the pathogenesis of ACD, previous studies have reported several abnormalities, such as insufficient EPO production, impaired growth response of erythroid progenitors to EPO, and shortened survival of erythrocytes, due to the inflammatory cytokines. However, recent analyses have clearly shown that hepcidin, of which expression is induced by inflammatory cytokines such as IL-1beta and IL-6, suppresses the expression of the iron transporter, ferroportin-1, thereby inhibiting the absorption of iron from the duodenum, the release of iron from the reticulo-endothelial system. So, the abnormal expression of hepcidin alone may be able to explain the unique iron metabolism in ACD.

Topics: Anemia; Antimicrobial Cationic Peptides; Cation Transport Proteins; Chronic Disease; Cytokines; Duodenum; Erythroid Precursor Cells; Erythropoietin; Ferritins; Hepcidins; Humans; Infections; Inflammation; Inflammation Mediators; Intestinal Absorption; Iron; Iron Deficiencies

The biology of iron in relation to anemia is best understood by a review of the iron cycle, since the majority of iron for erythropoiesis is provided by iron recovered from senescent erythrocytes. In iron-deficiency anemia, storage iron declines until iron delivery to the bone marrow is insufficient for erythropoiesis. This can be monitored with clinical indicators, beginning with low plasma ferritin, followed by decreased plasma iron and transferrin saturation, and culminating in red blood cells with low-Hb content. When adequate dietary iron is provided, these markers show return to normal, indicating a response to the dietary supplement. Anemia of inflammation (also known as anemia of chronic disease, or ACD) follows a different course, because in this form of anemia storage iron is often abundant but not available for erythropoiesis. The diagnosis of ACD is more difficult than the diagnosis of iron-deficiency anemia, and often the first identified symptom is the failure to show a response to a dietary iron supplement. Confirmation of ACD is best obtained from elevated markers of inflammation. The treatment of ACD, which typically employs erythropoietin (EPO) supplements and intravenous iron (i.v.-iron), is empirical and often falls shorts of therapeutic goals. Dialysis patients show a complex pattern of anemia, which results from inadequate EPO production by the kidney, inflammation, changes in nutrition, and blood losses during treatment. EPO and i.v.-iron are the mainstays of treatment. Patients with heart failure can be anemic, with incidence as high as 50%. The causes are multifactorial; inflammation now appears to be the primary cause of this form of anemia, with contributions from increased plasma volume, effects of drug therapy, and other complications of heart disease. Discerning the mechanisms of anemia for the heart failure patient may aid rational therapy in each case.

Topics: Anemia; Anemia, Iron-Deficiency; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Heart Diseases; Hematinics; Humans; Inflammation; Iron; Kidney Diseases; Male; Recombinant Proteins

Two hematopoietic cytokines are currently gaining increasing attention within neurological research. Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) have long been known for their ability to induce the proliferation of certain populations of hematopoietic lineage cells. However, it has recently been found that EPO, G-CSF, and their respective receptors are also expressed in the human central nervous system (CNS) and may be an important part of the brain's endogenous system of protection. Both hematopoietic cytokines have been shown to have neuroprotective potential in a variety of animal disease models both in vitro and in vivo, through the inhibition of apoptosis, induction of angiogenesis, exertion of anti-inflammatory and neurotrophic effects, as well as by the enhancement of neurogenesis. EPO and G-CSF have been extensively studied in the context of hematological disorders and have recently been successfully applied in the first clinical trials in stroke patients. Intravenous high-dose EPO therapy was associated with an improvement in the clinical outcome and preclinical studies with intravenous high-dose G-CSF therapy have clearly shown that it has considerable neuroprotective potential in the acute, as well as in the chronic phase of stroke. In this review, the current knowledge of the neuroprotective mechanisms of EPO and G-CSF is summarized with regard to in vitro and in vivo data. Focus is placed on the role of EPO in neurological disease models with an emphasis on its influence on functional outcome. New experimental results are assessed in detail and correlated with the findings of recent clinical studies.

Topics: Animals; Apoptosis; Brain; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; In Vitro Techniques; Inflammation; Models, Neurological; Neovascularization, Physiologic; Nervous System Diseases; Neurology; Neuroprotective Agents; Parkinson Disease; Research Design; Signal Transduction; Stroke

Neurocognitive dysfunction is a common postoperative complication exacerbated by cardiopulmonary bypass triggering a systemic inflammatory response. This clinical column focuses on the up-regulation of endogenous erythropoietin related to neurological inflammation and the use of recombinant erythropoietin as a neuroprotective pharmacotherapeutic agent.

Topics: Cardiac Surgical Procedures; Cognition Disorders; Erythropoietin; Hematinics; Humans; Hypoxia; Inflammation; Recombinant Proteins

Approximately 5-10% of patients with chronic kidney disease demonstrate hyporesponsiveness to erythropoiesis-stimulating agents (ESA), defined as a continued need for greater than 300 IU/kg per week erythropoietin or 1.5 mug/kg per week darbepoetin administered by the subcutaneous route. Such hyporesponsiveness contributes significantly to morbidity, mortality and health-care economic burden in chronic kidney disease and represents an important diagnostic and management challenge. The commonest causes of ESA resistance are non-compliance, absolute or functional iron deficiency and inflammation. It is widely accepted that maintaining adequate iron stores, ideally by administering iron parenterally, is the most important strategy for reducing the requirements for, and enhancing the efficacy of ESA. There have been recent epidemiologic studies linking parenteral iron therapy to an increased risk of infection and atherosclerosis, although other investigations have refuted this. Inflammatory ESA hyporesponsiveness has been reported to be improved by a number of interventions, including the use of biocompatible membranes, ultrapure dialysate, transplant nephrectomy, ascorbic acid therapy, vitamin E supplementation, statins and oxpentifylline administration. Other variably well-established causes of ESA hyporesponsiveness include inadequate dialysis, hyperparathyroidism, nutrient deficiencies (vitamin B12, folate, vitamin C, carnitine), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aluminium overload, antibody-mediated pure red cell aplasia, primary bone marrow disorders, myelosuppressive agents, haemoglobinopathies, haemolysis and hypersplenism. This paper reviews the causes of ESA hyporesponsiveness and the clinical evidence for proposed therapeutic interventions. A practical algorithm for approaching the investigation and management of patients with ESA hyporesponsiveness is also provided.

Topics: Algorithms; Darbepoetin alfa; Decision Trees; Erythropoiesis; Erythropoietin; Hematinics; Humans; Inflammation; Iron Deficiencies

Nephrogenic systemic fibrosis is a new disorder reported almost exclusively in patients who have renal insufficiency and are exposed to contrast media formulated with gadolinium. High morbidity and mortality are associated with this severely disabling and painful condition. The acute phase begins upon exposure to gadolinium contrast media, characterized by a systemic inflammatory response involving iron mobilization, and then as a progressive, chronic phase in which fibrosis develops. Proposed is a unifying model of cumulative risk factors in which the interplay of systemic inflammation and stimulated hematopoietic environment associated with hyperparathyroidism and erythropoietin may tie to a common pathogenic mechanism of fibrogenesis. Because there are no uniformly effective interventions to treat nephrogenic systemic fibrosis other than successful renal transplantation, prevention by avoiding gadolinium contrast media in patients with chronic kidney disease is vital. On the basis of suspected pathogenesis, it is also reasonable to limit erythropoietin and iron therapy to dosages ensuring recommended targets and adequately control hyperparathyroidism. Herein is reviewed what is currently known about this subject.

Topics: Blood Vessels; Erythropoietin; Fibrosis; Gadolinium; Humans; Inflammation; Iron; Renal Insufficiency

Renal ischemia-reperfusion (I-R) contributes to the development of ischemic acute renal failure (ARF). Multi-factorial processes are involved in the development and progression of renal I-R injury with the generation of reactive oxygen species, nitric oxide and peroxynitrite, and the decline of antioxidant protection playing major roles, leading to dysfunction, injury, and death of the cells of the kidney. Renal inflammation, involving cytokine/adhesion molecule cascades with recruitment, activation, and diapedesis of circulating leukocytes is also implicated. Clinically, renal I-R occurs in a variety of medical and surgical settings and is responsible for the development of acute tubular necrosis (a characteristic feature of ischemic ARF), e.g., in renal transplantation where I-R of the kidney directly influences graft and patient survival. The cellular mechanisms involved in the development of renal I-R injury have been targeted by several pharmacological interventions. However, although showing promise in experimental models of renal I-R injury and ischemic ARF, they have not proved successful in the clinical setting (e.g., atrial natriuretic peptide, low-dose dopamine). This review highlights recent pharmacological developments, which have shown particular promise against experimental renal I-R injury and ischemic ARF, including novel antioxidants and antioxidant enzyme mimetics, nitric oxide and nitric oxide synthase inhibitors, erythropoietin, peroxisome-proliferator-activated receptor agonists, inhibitors of poly(ADP-ribose) polymerase, carbon monoxide-releasing molecules, statins, and adenosine. Novel approaches such as recent research involving combination therapies and the potential of non-pharmacological strategies are also considered.

Topics: Acute Kidney Injury; Animals; Antioxidants; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Kidney; Kidney Diseases; Nitric Oxide; Nitric Oxide Synthase; Peroxisome Proliferator-Activated Receptors; Poly(ADP-ribose) Polymerase Inhibitors; Purinergic P1 Receptor Agonists; Reactive Nitrogen Species; Reactive Oxygen Species; Receptors, Lysosphingolipid; Recombinant Proteins; Reperfusion Injury

To review of the prevalence, pathogenesis, diagnosis, and management of iron (Fe)-related anemias in critical illness.. A MEDLINE/PubMed search from 1966 to October 2005 was conducted. References from relevant articles were manually cross-referenced with additional original articles, review articles, correspondence, and chapters from selected textbooks.. Both Fe metabolism and erythropoiesis are affected by the inflammatory response that accompanies critical illness. As a result, many critically ill patients develop the anemia of inflammation, which may be compounded by an underlying Fe deficiency. Most commonly available markers of total body Fe detect Fe deficiency unreliably in the setting of inflammation. Among these tests, the serum transferrin receptor assay is relatively accurate in reflecting total body Fe, regardless of inflammation. Treatment options for Fe-related anemias in critical illness include Fe replacement and recombinant human erythropoietin therapy. The decision to implement these therapies is complex and centers on a critical evaluation of ability to affect anemia, morbidity, and mortality in critical illness and on the potential risks of therapy.. Fe deficiency anemia and the anemia of inflammation may co-exist in critical illness. Diagnosis of and differentiation between these two anemias involves careful interpretation of multiple markers of total body Fe stores. The utility of treatment with both Fe and recombinant human erythropoietin for these disorders during critical illness requires further investigation.

Topics: Anemia, Iron-Deficiency; Critical Illness; Erythropoietin; Humans; Inflammation; Iron; Recombinant Proteins; Transferrin

Despite the proven benefits of intravenous (i.v.) iron therapy in anemia management, it remains underutilized in the hemodialysis population. Although overall i.v. iron usage continues to increase slowly, monthly usage statistics compiled by the US Renal Data System suggest that clinicians are not implementing continued dosing regimens following repletion of iron stores. Continued therapy with i.v. iron represents a key opportunity to improve patient outcomes and increase the efficiency of anemia treatment. Regular administration of low doses of i.v. iron prevents the recurrence of iron deficiency, enhances response to recombinant human erythropoietin therapy, minimizes fluctuation of hemoglobin levels, hematocrit levels, and iron stores, and may reduce overall costs of care. This article reviews the importance of i.v. iron dosing on a regular basis in the hemodialysis patient with iron-deficiency anemia and explores reasons why some clinicians may still be reluctant to employ these protocols in the hemodialysis setting.

Topics: Anemia, Iron-Deficiency; Dose-Response Relationship, Drug; Drug Resistance; Erythropoiesis; Erythropoietin; Ferric Compounds; Ferritins; Hematocrit; Hemoglobins; Humans; Inflammation; Injections, Intravenous; Iron; Practice Guidelines as Topic; Recombinant Proteins; Renal Dialysis; Risk Assessment; Treatment Outcome

Intravenous (i.v.) iron and recombinant human erythropoietin (EPO), like all other medications, are associated with the risk of adverse events. Historically, the primary concern with iron therapy has been the possibility of iron overload, which exposes the individual to the effects associated with nontransferrin-bound iron. Experience with EPO use has demonstrated an association with hypertension and with the upregulation of a number of markers of inflammation. The impact of these potential adverse effects merits careful analysis, given that both i.v. iron and EPO are designed for long-term use in a patient population at high risk for infection and cardiovascular disease. However, the incidence of iron overload and the risks associated with nontransferrin-bound iron have dramatically been reduced since the introduction of EPO therapy, and no data exist that demonstrate a definitive association between i.v. iron and an increased risk of morbidity related to infection or cardiovascular disease. On the other hand, EPO use is associated with hypertension, endothelial dysfunction, and prothrombotic and inflammatory states in hemodialysis patients. Risks associated with hypertension can be minimized by using the lowest effective EPO dose, which may be achieved through the regular use of i.v. iron. Judicious use of both i.v. iron and EPO may optimize cardiovascular outcomes.

Topics: Anemia, Iron-Deficiency; Blood Pressure; Cardiovascular Diseases; Comorbidity; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Ferritins; Hemoglobins; Hemosiderosis; Humans; Hypertension; Inflammation; Injections, Intravenous; Iron; Patient Care Planning; Recombinant Proteins; Renal Dialysis; Risk Assessment

Anemia is a common complication of chronic kidney disease. Although mechanisms involved in the pathogenesis of renal anemia include chronic inflammation, iron deficiency, and shortened half-life of erythrocytes, the primary cause is deficiency of erythropoietin (EPO). Serum EPO levels in patients with chronic kidney disease are usually within the normal range and thus fail to show an appropriate increase with decreasing hemoglobin levels, as found in nonrenal anemias. Studies elucidating the regulation of EPO expression led to the identification of the hypoxia inducible factor-hypoxia responsive element system. However, despite much progress in understanding the molecular mechanisms through which cells can sense oxygen availability and translate this information into altered gene expression, the reason why EPO production is inappropriately low in diseased kidneys remains incompletely understood. Both alterations in the function of EPO-producing cells and perturbations of the oxygen-sensing mechanism in the kidney may contribute. As with other anemias, the consequences of renal anemia are a moderate decrease in tissue oxygen tensions and counterregulatory mechanisms that maintain total oxygen consumption, including a persistent increase in cardiac output.

Topics: Anemia; Animals; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Hypoxia-Inducible Factor 1; Inflammation; Iron Deficiencies; Kidney; Kidney Failure, Chronic; Receptors, Erythropoietin; Uremia

Discovery that the hormone erythropoietin (EPO) and its receptor play a significant biological role in tissues outside of the hematopoietic system has fueled significant interest in EPO as a novel cytoprotective agent in both neuronal and vascular systems. Erythropoietin is now considered to have applicability in a variety of disorders that include cerebral ischemia, myocardial infarction, and chronic congestive heart failure. Erythropoietin modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. As a result, cellular protection by EPO is robust and EPO inhibits the apoptotic mechanisms of injury, including the preservation of cellular membrane asymmetry to prevent inflammation. As the investigation into clinical applications for EPO that maximize efficacy and minimize toxicity progresses, a deeper appreciation for the novel roles that EPO plays in the brain and heart and throughout the entire body should be acquired.

Topics: Animals; Apoptosis; Cytoprotection; Erythropoietin; Humans; Inflammation; Neovascularization, Physiologic; Receptors, Erythropoietin

The absolute majority of maintenance hemodialysis (MHD) patients die within 5 years of commencing dialysis treatment, mostly because of cardiovascular (CV) disease. The strongest and most common correlates of death in MHD patients are not conventional CV risk factors, but markers of protein-energy malnutrition and inflammation, together also known as malnutrition-inflammation complex syndrome (MICS). Paradoxically, classic risk factors such as obesity and hypercholesterolemia are associated with better survival in MHD patients. It has been hypothesized that this so-called reverse epidemiology is caused by the overwhelming prevalence and dominating effect of MICS in MHD patients. Hence, the key to improving survival and quality of life in MHD patients may be a better understanding of MICS and its interactions with CV disease and outcome. The Nutritional and Inflammatory Evaluation in Dialysis Patients (NIED) study is a longitudinal multicenter cohort study that aims to examine these hypotheses. At any given semiannual round, approximately 360 MHD patients from 8 DaVita dialysis facilities in the Los Angeles area are examined; 900 MHD patients will be cumulatively studied by the end of this 5-year prospective study (October 2001 to September 2006). Repeated measures of markers of nutritional status and inflammation are performed by 10 to 12 dialysis unit dietitians while patients attend their routine HD treatment in their dialysis facilities. All-cause and CV mortality, hospitalization, and quality of life are studied as outcome measures. The collaborating dietitians are the main evaluators and play crucial roles in all aspects of the study. This article reviews the design and infrastructure of the NIED study and reports preliminary findings of the first 12 to 30 months of the study.

Topics: Body Composition; Cholesterol, LDL; Dietary Proteins; Dietetics; Erythropoietin; Homocysteine; Hospitalization; Humans; Inflammation; Kidney Failure, Chronic; Malnutrition; Nutrition Assessment; Nutritional Status; Quality of Life; Renal Dialysis

Resistance to erythropoiesis-stimulating agents (ESA) in patients with chronic kidney disease (CKD) can be associated with evidence of enhanced systemic inflammatory responses. This review considers the inflammatory mechanisms thought to be involved in the development and aetiology of anaemia of CKD that may help our understanding and management of patients with ESA resistance. The potential role of nutritional support and of anti-inflammatory therapies in managing resistance to ESA therapy is discussed and explored.

Topics: Anemia; Anti-Inflammatory Agents; Antioxidants; Chronic Disease; Drug Resistance; Erythropoiesis; Erythropoietin; Ferritins; Humans; Inflammation; Iron; Kidney Diseases; Nitric Oxide; Nutritional Support; Reactive Oxygen Species; Recombinant Proteins

The anaemia associated with chronic renal failure is multi-factorial. Although a relative erythropoietin deficiency is a major factor, it has also been recognized in recent times that uraemia is a chronic inflammatory state, and thus patients with renal failure also develop anaemia due to mechanisms associated with chronic inflammation. Thus, patients with chronic renal failure have activation of various immune cells, both monocytes and T-cells. These mononuclear cells have also been shown to release pro-inflammatory cytokines such as IL-1, IL-6, TNF-alfa and interferon gamma. These cytokines, particularly TNF-alfa and interferon gamma, are known to cause significant suppression of erythropoiesis. The exact molecular mechanism for this effect is not yet clear, but interferon gamma is an important stimulator of apoptosis in various cell types, including erythroid progenitor cells. This effect may be potentiated by other cytokines such as TNF-alfa, and this might then antagonise the anti-apoptotic action of erythropoietin on erythroid progenitors cells, thus reducing responsiveness to exogenous erythropoietic therapy. Chronic renal failure is also associated with increased hepcidin production which may also exacerbate the anaemia by inducing a functional iron deficiency in such patients.

Topics: Anemia; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Humans; Inflammation; Renal Insufficiency

A neurohumoral link between kidneys and the heart has been established, particularly in the context of hypertension and cardiomyopathy. Beyond this neuro-endocrine pathway, another connecting system theoretically recruits growth factors that are selectively produced by the kidneys and have the ability to promote a distant reaction at the level of bone marrow. This reaction differentiates and circulates vascular progenitor cells capable of repairing the injured cardiovascular system. Reducing injuries (prevention) stabilizes disease processes by reducing tissue damage and destruction but the gradual degradation of the body's natural repair mechanisms eventually allows progressive reactivation of disease processes. In this light, a focus on tissue repair rather than injury prevention may hold the key to controlling chronic heart diseases. This article examines the medical therapies, including recombinant human erythropoietin, that have been shown to improve the function and survival of endothelial progenitor cells and promote the healing of damaged tissue.

Topics: Endothelium, Vascular; Erythropoietin; Growth Substances; Heart Diseases; Homeostasis; Humans; Inflammation; Kidney Failure, Chronic; Stem Cells

The anemia of critical illness is a distinct clinical entity with characteristics similar to that of chronic disease anemia. Several solutions to the processes of anemia, such as blunted erythropoietin production and erythropoietin response and abnormalities in iron metabolism have been developed. The transfusion of RBCs provides immediate correction of low hemoglobin levels, which may be of value in patients with life-threatening anemia. Avoidance of RBC and blood component transfusion, however, is becoming increasingly important as data of adverse clinical outcomes in critically ill patients become clearer. Although the optimal hemoglobin in critically ill patients is not determined, this organ system has a generous reserve. Short-term compensated anemia is tolerated well, while exogenous erythropoietin allows patients to achieve higher hemoglobin concentrations without exposure to transfused blood/blood components. A recent randomized trial enrolled over 1300 critically ill patients to receive either 40,000 units of exogenous erythropoietin or placebo. These authors found that patients randomized to erythropoietin received significantly less allogeneic RBC transfusions and had significantly greater increases in hemoglobin. Although no differences were found between groups in gross clinical outcomes (ie, death, renal failure, myocardial infarction), this study did not have the power to identify small differences in outcomes. This and other studies of exogenous erythropoietin therapy in critically ill patients clearly demonstrate that the bone marrow in many of these patients will respond to the administration of erythropoietin despite their illness, suggesting a blunted production of erythropoietin rather than a blunted response to erythropoietin. Exogenous erythropoietin therefore represents a therapeutic option for treating anemia in critical illness. Acute events in medicine and surgery often lead to many patients becoming anemic. Solutions to this process of anemia should be focused on preventing such events. Anemia after surgery represents an area for prevention. Blood conservation strategies can be performed with adequate results. Monk et al randomized 79 patients undergoing radical prostatectomy to preoperative autologous donation (PAD), preoperative exogenous erythropoietin therapy plus ANH immediately following induction of general anesthesia, and ANH alone. This study concluded that all three techniques resulted in similar hemostasis outcomes

Topics: Anemia; Blood Loss, Surgical; Critical Illness; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Humans; Inflammation; United States

Erythropoietin (EPO) increases the number of circulating erythrocytes primarily by preventing apoptosis of erythroid progenitors. In addition to this proerythroid action, results of recent studies show that systemically administered EPO is protective in vivo, in several animal models of neuronal injury. In vitro, EPO prevents neuronal apoptosis induced by a variety of stimuli. This review summarizes the neuroprotective actions of EPO and discusses the underlying mechanisms in terms of signal transduction pathways involved. The understanding of these mechanisms will help differentiate the neuroprotective actions of EPO from its role in the bone marrow.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cytokines; Cytoprotection; DNA-Binding Proteins; Endothelial Cells; Epithelial Cells; Erythropoietin; Hematopoiesis; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Kidney Tubules; Models, Biological; Myocardial Ischemia; Neurons; Neuroprotective Agents; Nuclear Proteins; Signal Transduction; Transcription Factors; Trauma, Nervous System

Topics: Aluminum; Anemia; Angiotensin-Converting Enzyme Inhibitors; Carnitine; Chronic Disease; Drug Resistance; Erythropoietin; Humans; Hyperparathyroidism, Secondary; Inflammation; Iron Deficiencies; Kidney Failure, Chronic; Malnutrition; Recombinant Proteins; Renal Dialysis

Mortality in dialysis patients is greater than that in the general population across all age groups. The disparity in mortality is greatest among patients aged under 35 years. Chronic kidney disease (CKD) is associated with the malnutrition, inflammation and atherosclerosis (MIA) syndrome, which helps to explain the high mortality rates among patients with CKD. Paradoxically, CKD patients exhibit signs of immune suppression as well as immune system activation. Chronic inflammation and immune system activation are not only integral to the MIA syndrome, but also may underlie resistance to erythropoietin treatment in patients with anaemia. Chronic immune system activation is reflected by abnormally raised T-lymphocyte and monocyte expression of both pro- and anti-inflammatory cytokines. Patients who respond well to erythropoietin treatment exhibit fairly normal expression of these cytokines. Patients who persistently fail to respond, however, express abnormally raised levels of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), which are also known to inhibit erythropoiesis. Paradoxically, these patients also express abnormally high levels of the anti-inflammatory cytokines interleukin (IL)-10 and IL-13. Although anti-inflammatory in nature, these cytokines might also affect erythropoiesis. One strategy to overcome the problem of chronic inflammation in anaemic patients with CKD may be treatment with the phosphodiesterase inhibitor, pentoxifylline. Preliminary results suggest that once-daily treatment with 400 mg of pentoxifylline orally not only can reduce T-cell expression of TNF-alpha and IFN-gamma, but can also restore the response to erythropoietin and improve haemoglobin levels. Ongoing studies will investigate further the use of pentoxifylline in erythropoietin resistance.

Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Epoetin Alfa; Erythropoietin; Humans; Inflammation; Interferon-gamma; Interleukins; Kidney Failure, Chronic; Pentoxifylline; Phosphodiesterase Inhibitors; Recombinant Proteins; Renal Dialysis; Treatment Outcome; Tumor Necrosis Factor-alpha

Anaemia is a common problem in critically ill patients admitted to intensive care units. Many factors can be involved in its development, including rapid alterations of iron metabolism. Maintenance of iron homeostasis is a prerequisite for many essential biological processes and a central element for the development of erythroid precursors and mature red blood cells. With the inflammatory process, iron distribution is disturbed, with decreased serum iron levels and increased iron stores. Little information is available on the precise role of alterations of iron metabolism in the development of iron anaemia in critically ill patients.

Topics: Anemia; Critical Illness; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Homeostasis; Humans; Inflammation; Intensive Care Units; Iron

Erythropoiesis usually fails during severe illness because of a blunting of the kidney-erythropoietin (EPO)-bone marrow axis. In this setting, clinical studies have shown that recombinant human erythropoietin (rhEPO), administered in pharmacological amounts, significantly reduces the need for blood transfusions. In addition to the kidney, however, EPO is also produced locally by other tissues in a paracrine-autocrine manner. Here, similar to its role in the bone marrow, EPO rescues cells from apoptosis. Additionally, EPO reduces inflammatory responses, restores vascular autoregulation, and promotes healing. The results of many studies (including a phase II clinical trial in ischemic stroke) demonstrate that rhEPO protects the brain, spinal cord, retina, heart, and kidney from ischemic and other types of injury. Although rhEPO is efficacious in the treatment of EPO-deficient anemia during illness, inadequate effort has been devoted to determining whether direct tissue protection might also result from its administration. Here, we speculate on the potential utility of EPO as a protective cytokine in the context of acute critical illness and suggest key parameters required for a proof-of-concept clinical study.

Topics: Apoptosis; Blood Cell Count; Bone Marrow; Critical Care; Critical Illness; Cytokines; Erythropoietin; Humans; Inflammation; Recombinant Proteins

Critically ill patients frequently develop anemia due to several factors. Iron-withholding mechanisms caused by inflammation contribute to this anemia. The iron metabolism imbalances described or reported in all intensive care studies are similar to the values observed in anemia of inflammation. The administration of iron could be useful in the optimization of recombinant human erythropoietin activity, but this could be at the expense of bacterial proliferation. Since there is a lack of evidence to support either oral or intravenous iron administration in intensive care patients, further studies are necessary to determine the efficacy and safety of iron supplementation in conjunction with recombinant human erythropoietin in critically ill patients. We review the mechanisms leading to iron sequestration in the presence of inflammation. The present article also reviews the literature describing the iron status in critically ill patients and explores the role of iron supplementation in this setting.

Topics: Anemia; Critical Care; Critical Illness; Dietary Supplements; Erythropoiesis; Erythropoietin; Ferritins; Humans; Inflammation; Intensive Care Units; Iron; Recombinant Proteins

Protein-energy malnutrition (PEM) and inflammation are common and usually concurrent in maintenance dialysis patients. Many factors that appear to lead to these 2 conditions overlap, as do assessment tools and such criteria for detecting them as hypoalbuminemia. Both these conditions are related to poor dialysis outcome. Low appetite and a hypercatabolic state are among common features. PEM in dialysis patients has been suggested to be secondary to inflammation; however, the evidence is not conclusive, and an equicausal status or even opposite causal direction is possible. Hence, malnutrition-inflammation complex syndrome (MICS) is an appropriate term. Possible causes of MICS include comorbid illnesses, oxidative and carbonyl stress, nutrient loss through dialysis, anorexia and low nutrient intake, uremic toxins, decreased clearance of inflammatory cytokines, volume overload, and dialysis-related factors. MICS is believed to be the main cause of erythropoietin hyporesponsiveness, high rate of cardiovascular atherosclerotic disease, decreased quality of life, and increased mortality and hospitalization in dialysis patients. Because MICS leads to a low body mass index, hypocholesterolemia, hypocreatininemia, and hypohomocysteinemia, a "reverse epidemiology" of cardiovascular risks can occur in dialysis patients. Therefore, obesity, hypercholesterolemia, and increased blood levels of creatinine and homocysteine appear to be protective and paradoxically associated with a better outcome. There is no consensus about how to determine the degree of severity of MICS or how to manage it. Several diagnostic tools and treatment modalities are discussed. Successful management of MICS may ameliorate the cardiovascular epidemic and poor outcome in dialysis patients. Clinical trials focusing on MICS and its possible causes and consequences are urgently required to improve poor clinical outcome in dialysis patients.

Topics: Acute-Phase Reaction; Anemia; Chronic Disease; Erythropoietin; Humans; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Protein-Energy Malnutrition; Quality of Life; Recombinant Proteins; Renal Dialysis; Syndrome; Wasting Syndrome

End-stage renal disease (ESRD) is characterized by a high mortality rate, which is mainly caused by cardiovascular disease. In patients with ESRD, high levels of pro-inflammatory cytokines and increased oxidative stress are common features and may contribute to the development of malnutrition, anaemia, resistance to recombinant human erythropoietin (epoetin) and atherosclerosis. The onset of inflammation is multi-factorial and is a predictor of poor outcome in ESRD. Although the inflammation may reflect the underlying cardiovascular disease, the acute-phase response may also contribute to both oxidative stress and progressive vascular injury. The acute-phase response in these patients may be influenced by a number of factors, and possibly the dialysis procedure itself. Inflammation and the acute-phase response interact with the haematopoietic system at several levels, resulting in reduced erythropoiesis, accelerated destruction of erythrocytes and blunting of the reactive increase in erythropoietin in response to reduced haemoglobin levels. In patients with ESRD, epoetin resistance has been linked with inflammation, which is often associated with a state of functional iron deficiency. Patients with ESRD are thought to have a reduced capacity in their control of oxidative stress and there is evidence that suggests that a relationship may exist between inflammation, oxidative stress and the treatment of anaemia with epoetin. Controlled trials are needed before evidence-based recommendations for the management of inflammation-induced anaemia and resistance to epoetin can be defined.

Topics: Anemia; Arteriosclerosis; Cytokines; Dialysis; Drug Resistance; Erythropoietin; Hematinics; Humans; Inflammation; Kidney Failure, Chronic; Malnutrition; Oxidative Stress

Up to 10% of patients with renal disease receiving recombinant human erythropoietin (rHuEPO) therapy show poor responsiveness to the drug. Even in patients who do respond to rHuEPO, there is a marked variability in drug sensitivity. Several factors have been recognized as causing resistance to rHuEPO, notably iron deficiency, infection/inflammation, and under dialysis. However, when these factors are excluded, the wide variation in responsiveness to rHuEPO persists. The mechanism of this effect needs to be fully elucidated. One hypothesis is that patients with uraemia showing resistance to rHuEPO may have enhanced levels of immune activation, causing increased release of pro-inflammatory cytokines in the bone marrow. Uraemia is known to be a chronic inflammatory state, with some patients showing considerably increased laboratory markers of inflammation and immune activation. Chronic inflammation can modify the process of erythropoiesis, probably mediated via pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). The concept that rHuEPO resistance is due to enhanced levels of immune activity has been investigated by studying T-cell phenotypes using flow cytometry, as well as cytokine release from T cells and monocytes in 'good' and 'poor' responders to rHuEPO. Poor responders had significantly reduced CD28 expression on both CD4+ and CD8+ cells, enhanced IL-10 generation from peripheral blood mononuclear cells (PBMCs), higher plasma IL-12 levels, and increased TNF-alpha and IFN-gamma release from PBMCs. Anti-cytokine antibodies may be useful for studying inflammatory cytokine secretion from T cells in patients with renal failure. Strategies utilizing anti-cytokine therapy may prove to be a useful adjuvant in optimizing the response to rHuEPO therapy.

Topics: Anemia; Cytokines; Drug Resistance; Erythropoietin; Humans; Inflammation; Kidney Diseases; Recombinant Proteins; Treatment Outcome

Patients receiving epoetin therapy show wide variability in their responsiveness to the drug. Many factors may be responsible for this, particularly iron deficiency, acute infection and under-dialysis. Even after excluding factors known to cause resistance to epoetin, the marked variability in sensitivity to epoetin remains. The exact mechanism of this effect is unclear. It is, however, recognized that uraemia is a chronic inflammatory state, with some patients showing quite significantly increased laboratory markers of inflammation and immune activation. It is also known that chronic inflammation can modify the process of erythropoiesis, and this is probably mediated via pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). It is hypothesized, therefore, that some patients showing resistance to epoetin may have enhanced levels of immune activation, causing increased release of pro-inflammatory cytokines in the bone marrow. This has been investigated by studying T-cell phenotypes by flow cytometry, along with cytokine release from T cells and monocytes in 'good' and 'poor' responders to epoetin. Poor responders were found to have significantly reduced CD28 expression on both CD4(+) and CD8(+) cells, enhanced IL-10 generation from peripheral blood mononuclear cells (PBMCs), higher plasma IL-12 levels and enhanced TNF-alpha release from PBMCs. The patients in this study, who were followed-up for the subsequent 24 months, had a considerably lower survival if they were poor responders (54% vs 88% for good responders; P<0.05). Further work in this area is required to confirm or contest the hypothesis that epoetin resistance is due to enhanced levels of immune activation.

Topics: Drug Resistance; Erythropoiesis; Erythropoietin; Humans; Inflammation; Models, Biological; Recombinant Proteins; Uremia

End-stage renal disease (ESRD) is characterized by a high mortality rate, derived largely from cardiovascular disease (CVD). In patients with ESRD, high levels of pro-inflammatory cytokines and increased oxidative stress are common features that may contribute to malnutrition, anaemia, recombinant human erythropoietin (rHuEPO) resistance, and atherosclerosis. Inflammation predicts poor outcome in ESRD. It is multifactorial in cause and, while it may reflect the underlying CVD, the acute-phase response may also contribute to both oxidative stress and progressive vascular injury. In patients with ESRD, the acute-phase response may be influenced by a number of factors unrelated to dialysis and perhaps by the dialysis procedure itself. Inflammation and the acute-phase response interact with the haematopoietic system at several levels resulting in reduced erythropoiesis, accelerated destruction of erythrocytes, and blunting of the reactive increase in erythropoietin in response to reduced haemoglobin levels. In patients with ESRD, rHuEPO resistance has been linked with inflammation, the latter of which is often associated with a state of functional iron deficiency. Patients with ESRD are thought to have a reduced capacity to handle oxidative stress. There is recent evidence that a relationship may exist between inflammation and oxidative stress and treatment of anaemia with rHuEPO. However, iron may also generate oxidative stress. Controlled trials are needed before evidence-based recommendations for the management of inflammation-induced anaemia and resistance to rHuEPO can be defined.

Topics: Anemia; Cardiovascular Diseases; Cytokines; Drug Resistance; Erythropoietin; Humans; Inflammation; Kidney Failure, Chronic; Oxidative Stress; Recombinant Proteins; Treatment Failure

Topics: Anemia; C-Reactive Protein; Drug Resistance; Erythropoietin; Humans; Inflammation; Kidney Failure, Chronic

Serum ferritin concentration is most informative in estimating the amount of storage iron available for a particular individual. The serum transferrin receptor concentration, in contrast to serum ferritin, provides direct information about any deficit in the adequacy of iron supply to the erythropoiesis. The combination of serum transferrin receptor and serum ferritin provides complete information about storage and functional iron compartments. Using this combination along with the hemoglobin concentration, it is possible to define the iron nutritional status completely. Inflammatory conditions as well as parenteral iron administration interfere, however, with the direct and quantitative ferritin to storage iron relationship and, therefore, have to be considered carefully with respect to diagnostic purposes. The diagnostic use of the serum transferrin receptor is presently limited because of limitations in methodology and definition (standardization) of reference ranges.

Topics: Anemia, Iron-Deficiency; Erythrocytes; Erythropoietin; Ferritins; Humans; Inflammation; Iron; Iron Deficiencies; Iron, Dietary; Receptors, Transferrin; Reference Values

Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 microg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporesponsiveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1+/-0.9% to 31+/-1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 microg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin sa

Topics: Aluminum; Anemia; Erythropoietin; Hemoglobinopathies; Hemolysis; Humans; Infections; Inflammation; Iron; Iron Deficiencies; Iron Overload; Kidney Failure, Chronic; Recombinant Proteins; Thalassemia

The anemia found in patients with chronic infectious, inflammatory, and neoplastic disorders, known as the anemia of chronic disease (ACD), is one of the most common syndromes in medicine. A characteristic finding of the disorders associated with ACD is increased production of the cytokines that mediate the immune or inflammatory response, such as tumor necrosis factor, interleukin-1, and the interferons. All the processes involved in the development of ACD can be attributed to these cytokines, including shortened red cell survival, blunted erythropoietin response to anemia, impaired erythroid colony formation in response to erythropoietin, and abnormal mobilization of reticuloendothelial iron stores. In this review, advances in the understanding of the diagnostic, pathophysiologic, and therapeutic aspects of this syndrome are summarized.

Topics: Anemia; Cell Survival; Chronic Disease; Cytokines; Diagnosis, Differential; Erythrocytes; Erythropoietin; Humans; Inflammation; Syndrome

The plasma level of erythropoietin (Epo) in anemic patients suffering from inflammation is often low in relation to the blood hemoglobin concentration. Various proinflammatory cytokines have been tested for their action on the synthesis of Epo. Interleukin 1 (IL-1) and tumor necrosis factor-alpha(TNF-alpha) suppress Epo gene expression in isolated perfused rat kidneys and in human hepatoma cell cultures. IL-6 inhibits in the kidney, and conflicting results have been reported for its effect on Epo synthesis in hepatic cells. Several other cytokines tested were without effect. Thus, mainly IL-1 and TNF-alpha seem to be responsible for the defect in Epo production in severe systemic and renal inflammatory diseases.

Topics: Animals; Carcinoma, Hepatocellular; Cytokines; Erythropoietin; Humans; Inflammation; Kidney; Liver Neoplasms; Tumor Cells, Cultured

Infectious and inflammatory disorders cause a disturbance in iron metabolism that leads to a sequestration of iron in the reticuloendothelial (R-E) system and a sometimes sharp and sudden decline in red blood cell indices. Underlying inflammatory conditions can decrease responsiveness to Epoetin alfa in dialysis patients and complicate anemia management. Understanding the possible infectious and inflammatory etiologies that can affect enemia management is essential to enhancing the nursing care of dialysis patients. Nurses caring for patients receiving Epoetin alfa must be aware of the possible effects of these conditions and know how to assess, detect, intervene, and evaluate factors that detract from an optimal erythropoietic response.

Topics: Aged; Anemia; Erythropoietin; Humans; Infections; Inflammation; Kidney Failure, Chronic; Male; Nursing Assessment; Renal Dialysis

Pediatricians should understand that the anemia of inflammation is second only to iron deficiency in overall incidence. When evaluating a child for mild to moderate anemia, one should always consider hemolytic anemia, both immune and congenital, and blood loss. Careful scrutiny of the peripheral blood smear is always helpful and can assist in minimizing expensive and unnecessary evaluations. When the anemia of inflammation is suggested by history or physical examination and the CBC reveals a normocytic, or possibly microcytic, mild to moderate anemia with a normal peripheral blood smear, it is prudent to not embark on an extensive evaluation for the anemia but instead wait for the inflammation to resolve. This may take as many as 3 months, depending on the degree of inflammation. Because the anemia resolves with subsiding inflammation, it is best to avoid treatment with iron or RBC transfusions. More studies need to be performed concerning the pathogenesis of the anemia of acute inflammation in children and the best course of treatment, if needed. The role of erythropoietin in the treatment of this form of anemia, though promising in some adult models of inflammation, awaits exploration in pediatric patients.

Topics: Adult; Anemia; Anemia, Hemolytic; Cytokines; Diagnosis, Differential; Erythropoietin; Humans; Infant; Infections; Inflammation

Erythropoietin (EPO) plays a central role in the regulation of red blood cell (RBC) production. Since iron is an essential element for erythropoiesis and hemoglobin (Hb) synthesis, its importance is heightened in patients treated with epoetin alfa. Stimulation of erythropoiesis following the administration of epoetin alfa is associated with several changes in iron metabolism; indeed, plasma ferritin levels fall as a result of increased utilization of iron by the expanding erythroid marrow. The administration of epoetin alfa can therefore lead to a state of relative iron deficiency. Thus, iron supplementation is essential to maximize the effect of epoetin alfa-induced erythropoiesis.

Topics: Adult; Anemia, Hypochromic; Bone Marrow; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Inflammation; Iron; Iron Deficiencies; Iron Overload; Male; Middle Aged; Recombinant Proteins

Topics: Acute-Phase Proteins; Acute-Phase Reaction; Anemia; Animals; Blood Platelets; Cytokines; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Granulocytes; Hematopoiesis; Hematopoietic Stem Cells; Hematopoietic System; Humans; Inflammation; Iron; Liver; Megakaryocytes; Models, Biological

The anemia associated with chronic infectious, inflammatory, and malignant diseases is characterized by a blunted erythropoietin response; for any given decrease in hemoglobin or hematocrit, the increase in serum or plasma erythropoietin is less than would be found in an equally anemic patient with iron deficiency. This observation provides a rationale for the use of recombinant human erythropoietin in the treatment of the anemia in these diseases. During the past year, new information has been reported on the pathophysiology of erythropoiesis in chronic infectious, inflammatory, and neoplastic diseases, and on the use of recombinant human erythropoietin for this anemia. This article reviews these developments.

Topics: Anemia; Chronic Disease; Clinical Trials as Topic; Erythropoietin; Humans; Infections; Inflammation; Neoplasms; Recombinant Proteins

We review data concerning site and regulation of erythropoietin (EPO) production, its effects on target tissue, routes of administration and clinical applications. In the anaemia of chronic renal failure (ACRF) treatment with recombinant human erythropoietin (r-Hu-EPO) has been shown to be effective in both improvement of the anaemia and increase in quality of life. In the anaemia of chronic disease (ACD), associated with various malignant, infectious and inflammatory disorders, many investigators have demonstrated an inappropriately low EPO response to anaemia. Therapeutic trials in patients with ACD mostly lacked sufficient numbers of patients for evaluation of the effects. The results obtained from some studies in AIDS and rheumatoid arthritis and the effect on the number of units of autologous blood obtained from patients planned for elective surgery are encouraging, however. Adverse reactions of r-Hu-EPO treatment are mainly confined to the ACRF population and include hypertension, shunt thrombosis and pain at the injection site. The exact mechanism of action of EPO is not yet fully understood. Large scale clinical trials are required to establish its effects on both the anaemia and quality of life in anaemias other than ACRF.

Topics: Anemia; Chronic Disease; Clinical Protocols; Clinical Trials as Topic; Drug Administration Schedule; Erythropoietin; Humans; Infections; Inflammation; Kidney Failure, Chronic; Neoplasms

The absence of any response to the administration of recombinant human erythropoietin (rHuEpo) is exceptional in uremic patients with anemia. Initial "nonresponders" generally respond to higher doses of the hormone. However, a small number of patients may remain unresponsive. The most common cause of limited response is mild to moderate iron deficiency, either at the start of treatment or secondary to enhanced iron utilization by newly formed erythrocytes. Another common cause of resistance is the presence of an overt or, more often, an unrecognized inflammatory state, including acute or chronic infection. Marked aluminum overload and severe hyperparathyroidism also have been shown to induce resistance in at least some patients. Other factors may contribute to the severity of anemia and hence increase rHuEpo requirements, such as acute or chronic hemolytic conditions or blood loss, folate deficiency, hemoglobinopathies, and still poorly defined uremic toxins. In patients who show a resistance to the effect of the recombinant hormone, these should be sought and eliminated, if possible.

Topics: Anemia; Drug Resistance; Erythropoietin; Hematopoiesis; Humans; Hyperparathyroidism; Inflammation; Kidney Failure, Chronic; Recombinant Proteins

The currently available radioimmunoassay for erythropoietin (Epo) using recombinant reagents is an accurate, reproducible, sensitive and specific assay which can be used to identify whether lack of Epo is contributing to anemia and, by extension, whether therapy with recombinant Epo might be appropriate. Elevation of the serum Epo level with anemia suggests that a marrow abnormality is the cause of the anemia, while a "high" Epo level in a non-anemic or plethoric patient suggests the presence of hypoxia or autonomous Epo production. Liver disease can elevate the serum Epo level, while modest degrees of anemia do not affect it appreciably. The lowest Epo levels occur in polycythemia vera, but in a particular patient this finding is not completely diagnostic.

Topics: Anemia, Hemolytic; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Infections; Inflammation; Neoplasms; Polycythemia; Pregnancy; Radioimmunoassay

The anemia of chronic renal failure can now be effectively treated with recombinant human erythropoietin when given in adequate doses. This hormone replacement therapy is associated with significant clinical benefits but it requires adequate iron stores for maximal effectiveness, it may result in elevation in diastolic blood pressure, and the response may be blunted by the presence of infection or inflammation.

Topics: Anemia; Erythropoietin; Humans; Inflammation; Iron; Kidney Failure, Chronic; Recombinant Proteins

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Blood Transfusion, Autologous; Erythropoietin; Humans; Hypertension; Inflammation; Iron; Kidney Failure, Chronic; Recombinant Proteins; Vascular Resistance

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Inflammation; Iron

The present study aimed to explore the efficacy and safety of roxadustat in patients with renal anemia and erythropoietin (EPO) hyporesponsive who are receiving continuous ambulatory peritoneal dialysis (CAPD).. This is a single center, before and after treatment, self-controlled study; 55 CAPD patients with renal anemia and EPO hyporesponsiveness were enrolled. The main follow-up parameters included routine blood, liver and kidney function, electrolyte, blood lipid, high-sensitivity C-reactive protein, and iron tests. Serum samples were used to determine interleukin-6 and tumor necrosis factor-α levels via enzyme linked immunosorbent assay. The Modified Quantitative Subjective Global Assessment Score and Malnutrition-Inflammation Score before and after treatment, and adverse events during treatment were recorded. The follow-up observation time was 12 weeks. Preliminary data 12-24 weeks before the enrollment as well as post-follow-up data at 36 weeks were also collected.. Fifty patients completed the 12-week follow-up. The hemoglobin levels were 8.0 ± 1.2 g/dL at baseline and 11.2 ± 2.0 g/dL after 12 weeks of roxadustat treatment. The hemoglobin increases at all measured time points and was statistically significant compared with the baseline value (P < .05). The overall hemoglobin response rate (hemoglobin increase ≥ 1.0 g/dL) was 80%, and 50% of the patients reached the hemoglobin target (hemoglobin ≥ 11.0 g/dL) at 12 weeks. Transferrin was higher at 12 weeks (2.2 ± 0.5 g/L) than at baseline (1.7 ± 0.5 g/L) (P < .05), while serum ferritin levels slightly decreased compared with the baseline value (P > .05). The median high-sensitivity C-reactive protein level and other inflammation-related indicators, such as white blood cell counts, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, interleukin-6, and tumor necrosis factor-α, were not significantly different from their baseline values. Nutrition-related biochemical indices such as albumin, creatinine, and blood lipids were also not significantly changed. The Modified Quantitative Subjective Global Assessment Score and Malnutrition-Inflammation Score were slightly lower at 12 weeks than at baseline. No serious adverse events were observed during the follow-up period. Post-follow-up data revealed a maintained hemoglobin level in patients who remained on roxadustat treatment while those switched back to EPO treatment after 12 weeks resulted in a decreased hemoglobin at 36 weeks.. In patients with EPO hyporesponsiveness on CAPD, roxadustat can efficiently and safely improve anemia and nutritional status without promoting inflammation.

Topics: Anemia; C-Reactive Protein; Erythropoietin; Glycine; Hemoglobins; Humans; Inflammation; Interleukin-6; Isoquinolines; Malnutrition; Peritoneal Dialysis; Pilot Projects; Prospective Studies; Renal Dialysis; Tumor Necrosis Factor-alpha

Topics: Aged; Erythropoietin; Ferritins; Ferrous Compounds; Hemoglobins; Hepcidins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Middle Aged; Resistance Training

The response to erythropoiesis stimulating agents (ESAs) is affected by inflammation linked to middle molecules in hemodialysis (HD) patients. We evaluated the effect of a medium cut-off (MCO) dialyzer on ESA resistance in maintenance HD patients. Forty-nine patients who underwent high-flux HD were randomly allocated to the MCO or high-flux group. The primary outcome was the changes of erythropoietin resistance index (ERI; U/kg/wk/g/dL) between baseline and 12 weeks. The MCO group showed significant decrease in the ESA dose, weight-adjusted ESA dose, and ERI compared to the high-flux group at 12 weeks (p < 0.05). The generalized estimating equation models revealed significant interactions between groups and time for the ESA dose, weight-adjusted ESA dose, and ERI (p < 0.05). Serum iron and transferrin saturation were higher in the MCO group at 12 weeks (p < 0.05). The MCO group showed a greater reduction in TNF-α and lower serum TNF-α level at 12 weeks compared to the high-flux group (p < 0.05), whereas no differences were found in the reduction ratio of hepcidin and serum levels of erythropoietin, erythroferrone, soluble transferrin receptor and hepcidin between groups. HD with MCO dialyzer improves ESA resistance over time compared to high-flux HD in maintenance HD patients. The MCO dialyzer provides superior removal of the inflammatory cytokine and thus improves iron metabolism in a hepcidin-independent manner.

Topics: Aged; Anemia; C-Reactive Protein; Erythropoiesis; Erythropoietin; Female; Hematinics; Hepcidins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Male; Middle Aged; Receptors, Transferrin; Renal Dialysis; Tumor Necrosis Factor-alpha

Inadequate response to Erythropoietin Stimulating Agents (ESA) despite using relatively larger doses regimen represents a potential risk factor of Cardiovascular (CV) related mortality in addition to health-care economic problems in anemic patients with Chronic Kidney Disease (CKD). Erythropoietin (EPO) hyporesponsiveness related to inflammation has been increased progressively. Melatonin is well known as a potent anti-inflammatory agent. Therefore, the current study was designed to evaluate whether melatonin could improve anemic patients response to EPO.. This single controlled clinical study was carried out in 41 CKD patients with hemoglobin (Hb) levels less than 11g/dl divided randomly in a 1:1 ratio into 2 groups; treatment group who received 5mg melatonin plus their regular treatments and control group who received their regular treatments only. Hematological and iron status parameters include Hb level, serum iron (S. iron), Transferrin Saturation Ratio (TSAT) and serum ferritin (S. ferritin) in addition to inflammatory parameters that include tissue necrotic factor alfa (TNF-α), interleukin-1beta (IL-1β) and interleukin-6 (IL-6) determined before and after 12 weeks of treatment.. Melatonin remarkably increases the Hb level with a significant increase in S. iron and TSAT compared to baseline. The elevation of S. iron and TSAT was significantly higher in the melatonin group. Additionally, all inflammatory markers estimated were reduced significantly by melatonin compared to base line and control group.. The results of the current study showed that melatonin has an advantageous effect on improving EPO response in anemic patients with CKD.

Topics: Anemia; Antioxidants; Biomarkers; Erythropoietin; Female; Hematinics; Humans; Inflammation; Male; Melatonin; Middle Aged; Renal Insufficiency, Chronic

This study investigated the effect of repeated infusions of recombinant human erythropoietin (EPO) on markers of inflammation in patients with affective disorders and whether any changes in inflammatory markers were associated with improvements on verbal memory.. In total, 83 patients were recruited: 40 currently depressed patients with treatment-resistant depression (TRD) (Hamilton Depression Rating Scale-17 items (HDRS-17) score >17) (sub-study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS)⩽14) (sub-study 2). In both sub-studies, patients were randomised in a double-blind, parallel-group design to receive eight weekly intravenous infusions of EPO (Eprex; 40,000IU/ml) or saline (0.9% NaCl). Plasma concentrations of interleukin 6 (IL-6), interleukin 18 (IL-18) and high sensitive c-reactive protein (hsCRP) were measured at week 1 (baseline) and weeks 5, 9 and 14. HDRS-17 and neuropsychological function was assessed at weeks 1, 9 and 14 using a test battery including the RAVLT Auditory Verbal Learning Test (primary depression and primary cognition outcomes in the original trial).. EPO had no cumulative effect on plasma levels of IL-6 or IL-18 but increased hsCRP levels in patients with TRD (mean±SD change in ng/L: EPO: 0.43±1.64; Saline: -0.90±2.43; F(1,39)=4.78, p=0.04). EPO had no effects on inflammatory markers in BD. There was no correlation between change in inflammatory markers and change in verbal memory.. Repeated EPO infusions had no effect on IL-6 and IL-18 levels but produced a modest increase in hsCRP levels in patients with TRD. Changes over time in inflammatory markers were not correlated with changes in cognition suggesting that modulation of the inflammatory pathway is not a putative mechanism of the EPO-associated improvement of cognition in affective disorders.

Topics: Adult; Bipolar Disorder; C-Reactive Protein; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Erythropoietin; Female; Humans; Inflammation; Interleukin-18; Interleukin-6; Male; Middle Aged; Outcome Assessment, Health Care; Recombinant Proteins

Previous studies have suggested that erythropoietin (Epo) levels may be inappropriately low in patients with sickle cell disease compared to the extent of the related anemia they demonstrate. Here, we evaluate Epo level vs. renal function, oxygenation, and markers of inflammation for patients treated for sickle cell disease at our institution. Blood was drawn from 54 patients with sickle cell disease during routine visits to the outpatient hematology office and analyzed for hemoglobin (Hb) level, Epo, markers of inflammation, oxygenation, and renal function. Erythropoietin levels were lower than expected for patients with sickle cell disease, compared to the degree of anemia demonstrated in these patients. In addition, a correlation between Hb level and Epo was not consistently observed. Higher Epo levels were seen in patients receiving hydroxyurea (HU), but no correlation with oxygenation, hemolysis, renal function, or inflammation was observed.

Topics: Adult; Aged; Anemia, Sickle Cell; Antisickling Agents; Biomarkers; Erythropoietin; Female; Hemoglobins; Hemolysis; Humans; Hydroxyurea; Inflammation; Kidney Function Tests; Male; Middle Aged

Vasoprotective effects of erythropoietin in animal models are mediated by endothelium-derived NO and/or mobilization of EPCs (endothelial progenitor cells) and may be enhanced by ischaemia: whether they are present in humans is unknown. We examined whether the erythropoietin analogue darbepoetin improves FMD (flow-mediated dilatation), a measure of endothelium-derived NO, and whether this is influenced by preceding I/R (ischaemia/reperfusion). A total of 36 patients (50-75 years) with stable coronary artery disease were randomized to receive a single dose of darbepoetin (300 μg) or saline placebo. FMD was measured at the brachial artery using high-resolution ultrasound. CD133⁺/CD34⁺/VEGFR2⁺ (vascular endothelial growth factor receptor 2) circulating EPCs were enumerated by flow cytometry. Measurements were made immediately before darbepoetin/placebo and at 24 h, 72 h and 7 days. At 24 h, FMD was repeated after 20 min of I/R of the upper limb. A further group of 11 patients was studied according to the same protocol, all receiving darbepoetin, with omission of forearm I/R at 24 h. Immunoreactive erythropoietin peaked at 24 h and remained elevated at approximately 50-fold of baseline at 72 h. FMD did not differ significantly between groups at 24 h (before I/R). At 72 h (48 h after I/R), FMD was greater (by 2.3±0.5% in the darbepoetin compared with the placebo group, a 66% increase over baseline; P<0.001) and greater than FMD at the same time point without preceding I/R (P<0.01). Increases in CD133⁺/CD34⁺/VEGFR2⁺ cells after darbepoetin did not differ according to the presence or absence of preceding I/R. Preceding I/R is required for darbepoetin to enhance endothelial function, possibly by increasing expression of the erythropoietin receptor and by a mechanism likely to involve Akt/NO rather than circulating EPCs.

Topics: Aged; Biomarkers; Blood Pressure; Coronary Artery Disease; Cytokines; Darbepoetin alfa; Endothelial Cells; Endothelium; Erythropoietin; Female; Humans; Inflammation; Male; Middle Aged; Myocardial Reperfusion Injury; Platelet Activation; Stem Cells; Vasomotor System

Erythropoietin improves myocardial function and enhances re-endothelialisation. Aim of this study was to analyse progenitor cell mobilisation and restenosis in patients from the Regeneration of Vital Myocardium in ST-Segment Elevation Myocardial Infarction by Erythropoietin (REVIVAL-3) study. Patients with STEMI undergoing percutaneous coronary intervention (PCI) were randomly assigned to Epoetin beta (EPO) (n=68) or placebo (n=70). Drug-eluting stents (DES) were utilised in 93% of patients receiving EPO and in 95% of patients receiving placebo (p=0.83). Serial venous blood samples were drawn; CD133+ progenitor cells were quantified by four-colour flow cytometry and cytokines interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumour necrosis factor (TNF) alpha were analysed by cytometric bead array. Forty-eight hours after PCI a significant increase in CD133+ progenitor cells was observed in the EPO group. Yet, no differences in plasma cytokines were found. Quantitative coronary angiography after six months revealed an increase in segment diameter stenosis in the EPO group (32 ± 19% vs. 26 ± 14%, p=0.046). However, this increase in neointima generation was not associated with progenitor cell mobilisation. EPO in patients with STEMI treated with PCI is associated with an increase in diameter stenosis that is not associated with circulating progenitor cells.

Topics: Angiography; Cytokines; Drug-Eluting Stents; Erythropoietin; Flow Cytometry; Hematopoietic Stem Cell Mobilization; Humans; Inflammation; Interleukins; Myocardial Infarction; Placebos; Recombinant Proteins; Stem Cells; Time Factors; Treatment Outcome

Experimentally, erythropoietin (EPO) has nephroprotective as well as immunomodulatory properties when administered after ischemic renal injury. We tested the hypothesis that different doses of recombinant human EPO administered to patients after cardiac surgery would minimize kidney lesions and the systemic inflammatory response, thereby decreasing acute kidney injury (AKI) incidence.. In this double-blinded randomized control study, 80 patients admitted to the ICU post-cardiac surgery were randomized by computer to receive intravenously isotonic saline (n = 40) versus α-Epoetin (n = 40): either 40000 IU (n = 20) or 20000 IU (n = 20). The study lasted one year. The primary outcome was the change in urinary NGAL concentration from baseline and 48 h after EPO injection. Creatinine, cystatine C and urinary NGAL levels were measured on the day of randomization and 2-4 days after EPO injection. To assess acute inflammatory response, serum cytokines (IL6 and IL8) were measured at randomization and four days after r-HuEPO injection. Patients and care-takers were blinded for the assignment.. No patient was excluded after randomization. Patient groups did not differ in terms of age, gender, comorbidities and renal function at randomization. The rate of AKI assessed by AKIN criteria was 22.5% in our population. EPO treatment did not significantly modify the difference in uNGAl between 48 hours and randomization compared to placebo [2.5 ng/ml (-17.3; 22.5) vs 0.7 ng/ml (-31.77; 25.15), p = 0.77] and the incidence of AKI was similar. Inflammatory cytokines levels were not influenced by EPO treatment. Mortality and hospital stays were similar between the groups and no adverse event was recorded.. In this randomized-controlled trial, α-Epoetin administrated after cardiac surgery, although safe, demonstrated neither nephroprotective nor anti-inflammatory properties.. NCT00676234.

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiac Surgical Procedures; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Humans; Inflammation; Inflammation Mediators; Kidney; Male; Middle Aged; Pilot Projects; Postoperative Complications; Recombinant Proteins; Treatment Outcome

French and international clinical practice guidelines recommend a minimum hemoglobin level of 11 g/dl in patients with chronic kidney disease. Previous studies implemented between 1996 and 2003 showed that only 35 to 55% the patients reach this target. Dialysis NeoRecormon Epidemiology (DiaNE) is a one-year French multicentric observational study designed to follow a cohort of 1200 patients with ESRD treated with epoetin beta to assess the management of anemia in routine nephrologic practice. From December 2003 to September 2004, 1241 hemodialysis patients were recruited by 229 centers. At baseline, 64.4% of patients had hemoglobin levels greater than 11 g/dl. The proportion of patients with hemoglobin levels greater than 11 g/dl at the end of the study was 71.6%. These results could be partly explained by iron deficiency: 46% of patients had a serum ferritin between 200 and 500 microg/l and about one third of patients had a transferrin-iron saturation percentage greater or equal to 30% at baseline and at the end of the study. Epoetin beta was administrated by subcutaneous route in 65.5% of patients with similar efficacy and with less mean doses than intravenous route (114.6+/-81.5 IU/kg versus 146.5+/-124.3 IU/kg at the end of the study). In conclusion, the management of anemia in hemodialysis patients is not optimal but is slightly better than the management observed between 1996 and 2003. Iron and inflammatory status should be taken into account to improve the efficacy of anemia therapy using erythropoietin-stimulating agents.

Topics: Aged; Anemia; Anemia, Iron-Deficiency; Biomarkers; Comorbidity; Disease Management; Erythropoietin; Female; Follow-Up Studies; France; Humans; Inflammation; Injections, Intravenous; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

The FX class of haemodialysers features a new class of high-flux polysulfone membrane which has been suggested to induce less inflammation.. This was a randomized, cross-over study performed on 33 haemodialysis patients. Patients were randomized to FX60 or HF80 dialysers for 3 months and then changed to the other dialyser. Interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) were measured at baseline, and every 3 months. The Kidney Disease Quality of Life Short Form was also administered.. The mean of the difference in the IL-6 level between dialysers was 1.4 +/- 8.0 pg/ml (95% CI -1.8, 4.5 pg/ml). There was no significant difference in TNF-alpha (95% CI -0.35, 0.18 pg/ml) or CRP levels (95% CI -2.67, 6.20 mg/l). The quality of social interaction and role limitations caused by physical health problems were significantly higher with the FX60, p = 0.04 and 0.047, respectively.. The FX dialysers do not result in a significant difference in the level of systemic inflammation compared to the HF80.

Topics: Adult; Aged; C-Reactive Protein; Cross-Over Studies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Quality of Life; Recombinant Proteins; Renal Dialysis; Tumor Necrosis Factor-alpha

Recent studies have shown that erythropoietin (EPO) offers protection against ischemia, hemorrhagic shock and systemic inflammation in many tissues and it has been suggested that EPO has anti-inflammatory effects. With the aim of investigating the potential acute anti-inflammatory effects of EPO in a human in vivo model of acute systemic low-grade inflammation, we measured circulating inflammatory mediators after intravenous administration of Escherichia coli endotoxin (LPS) bolus injection (0.1 ng/kg of body weight) in young healthy male subjects. The subjects were divided into three groups receiving either (1) LPS alone, (2) EPO alone (15,000 IE of rHuEPO) or (3) EPO and LPS. Endotoxin administration alone induced a 3-, 12- and 5-fold increase in plasma concentrations of TNF-alpha, IL-6 and IL-10, respectively, 3h after LPS challenge. When EPO was given prior to a bolus injection with endotoxin, the levels of TNF-alpha and IL-6 were enhanced by 5- and 40-fold, respectively, whereas the endotoxin-induced increase in IL-10 response was not influenced by EPO. In contrast to our hypothesis, we find that EPO augments the acute inflammatory effect.

Topics: Adult; Cytokines; Endotoxins; Erythropoietin; Humans; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-6; Lymphocyte Count; Male; Neutrophils; Recombinant Proteins; Tumor Necrosis Factor-alpha

To help identify factors contributing to intra-patient Hb variability, pooled records were analyzed from 5,592 patients undergoing hemodialysis (HD) in European, multicenter, open-label, single-arm Phase 3b trials.. Patients previously treated with recombinant human erythropoietin (rHuEPO) were switched to darbepoietin-alpha administered once a week (QW) or once every 2 weeks (Q2W), maintaining the same dosing schedule and route of ESA administration (intravenous or subcutaneous) up to and through the evaluation period. Patients were treated with darbepoietin-alpha to maintain Hb levels between 10 and 13 g/dl. Intrapatient variability was calculated using the SD model, taking all of an individual patient's Hb values during the evaluation period (Weeks 21 - 24 after conversion) and calculating the SD of these Hb values. Adverse events (AE) of infection or inflammation were recorded.. Smaller variability was seen for patients 65 years of age or older compared with younger patients (p = 0.0044) and greater variability for patients less than 40 years of age compared with older patients (p < 0.01). Little difference in variability was seen in relation to sex overall or to the presence or absence of diabetes. Intra-patient Hb variability was greater in the presence of intercurrent conditions, including infection or inflammation (p = 0.0032), blood transfusion (p < 0.0001), hospitalization (p < 0.0001), or hospitalization for cardiovascular (CV) causes (p = 0.0012), than in their absence. Iron status differences had little detectable effect on intra-patient Hb variability. A larger number of changes made to the ESA dose during the evaluation period was also associated with greater Hb variability compared with fewer dose changes, but this association could not be proved as being causative. Although p values were calculated for some comparisons, statistical significance might not indicate clinical significance because of the large sample size. Multivariable analysis to assess the association between AE status and intra-patient Hb variability, adjusting for age, sex, diabetes status, number of dose changes and iron status showed that AE status was significantly associated with Hb variability.. Additional studies would be needed to further investigate causes and effects of Hb variability and intercurrent events.

Topics: Adult; Age Factors; Aged; Anemia; Blood Transfusion; Comorbidity; Dose-Response Relationship, Drug; Erythropoietin; Europe; Female; Hemoglobins; Hospitalization; Humans; Inflammation; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Pilot Projects; Recombinant Proteins; Renal Dialysis; Risk Factors

Inflammatory cytokines are important predictors of cardiovascular mortality especially in patients with chronic kidney disease. Here we explored the relationship of anemia and epoetin treatment to inflammatory cytokine levels in patients with chronic kidney disease. One hundred non-dialysis patients with chronic kidney disease over 18 years of age were evenly split into anemic and non-anemic cohorts. Of the 50 anemic patients, 23 were receiving erythropoiesis stimulating agents treatments. Levels of tumor necrosis factor (TNF)-alpha were found to be significantly higher and serum albumin was significantly lower with trends towards higher interleukin (IL)-6 and IL-8 in anemic compared to non-anemic patients. Further analysis by multiple logistic regression found that anemic patients treated with erythropoiesis stimulating agents had significantly higher odds for the upper two quartiles for IL-6, IL-8 and TNF-alpha compared to non-anemic patients. Our study found that the anemia of chronic kidney disease was associated with up regulation of TNF-alpha, and possibly IL-6 and IL-8 along with increased levels of these proinflammatory cytokines in patients treated with epoetin.

Topics: Aged; Anemia; Biomarkers; Case-Control Studies; Chronic Disease; Cytokines; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Inflammation; Interleukin-6; Interleukin-8; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Tumor Necrosis Factor-alpha; Up-Regulation

In hemodialysis patients, the hematological response to erythropoietin (epo) is variable and clinical factors that explain this variability are incompletely understood. We tested the hypothesis that the variability in hemoglobin (Hgb) response (epo sensitivity) is determined by key nutritional, inflammation, and oxidative stress markers.. Eighty-two consecutive patients on hemodialysis had 3 consecutive monthly predialysis evaluations of Hgb, total white blood cell (WBC) count, serum albumin, malondialdehyde (MDA), and monocyte chemoattractant protein-1 (MCP1). We analyzed the time course of Hgb in relationship to serum albumin, WBC, MDA, MCP1, epo and iron administration, and tests of iron sufficiency in a linear growth curve model.. Subjects with higher Hgb had a fall in Hgb and vice versa, regressing to a mean Hgb (SD) of 11.8 g/dl (1.8 g/dl). Whereas the average slope of Hgb was flat, the SD of slopes was 0.63 g/dl, which explained 39% of the variance in Hgb. Nonuse of epo was associated with a mean Hgb change of -0.18 g/dl (95% confidence interval [CI] -0.26 to -0.10) per 10,000 IU epo/mo (P < 0.05). Epo use was associated with steeper rate of change at 0.04 g/dl per mo per 10,000 IU (95% CI 0.01 to 0.07) (P < 0.01). Hgb at baseline was 0.73 g/dl higher for each 1-g/dl increase in albumin, and the rate of change increased by 0.49 g/dl per mo for each 1-g/dl increase in albumin concentration. WBC, MDA, or MCP1 had no role in predicting the baseline Hgb or its change over time.. Serum albumin concentration is an important predictor of both baseline Hgb and epo sensitivity in chronic hemodialysis patients. Factors that improve serum albumin may also improve Hgb in hemodialysis patients.

Topics: Adult; Aged; Anemia; Biomarkers; Chemokine CCL2; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Kidney Failure, Chronic; Leukocyte Count; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Predictive Value of Tests; Prospective Studies; Renal Dialysis; Serum Albumin; Treatment Outcome

Experimental studies have demonstrated interleukin-6 and iron load induce expression of hepcidin (an iron regulatory peptide), whereas anemia and erythropoietin (EPO) suppress its expression. We are the first to explore the relationships of plasma prohepcidin (the pro-hormone of hepcidin) in patients undergoing chronic hemodialysis (HD).. We enrolled 71 chronic HD patients. During the preceding 3 months before enrollment, they all had steady weekly levels of haematocrit (Hct) and fixed subcutaneous doses of recombinant human EPO. Plasma levels of prohepcidin, proinflammatory cytokines, and EPO were determined by ELISA kits.. Of the patients, prohepcidin levels correlated positively with Hct, and negatively with interleukin-6 and EPO. Examined by a multivariate lineal regression method, we found Hct was the only significant predictor of plasma prohepcidin level. However, prohepcidin had no significant correlation with iron profiles.. Our findings suggest prohepcidin expression in chronic HD patients might be positively regulated by Hct.

Topics: Adult; Aged; Aged, 80 and over; Antimicrobial Cationic Peptides; Chronic Disease; Cytokines; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Hematocrit; Hepcidins; Humans; Inflammation; Injections, Subcutaneous; Interleukin-6; Iron; Male; Middle Aged; Predictive Value of Tests; Protein Precursors; Recombinant Proteins; Renal Dialysis

Dialysate quality has been suggested to influence inflammation status in patients subject to haemodialysis (HD). The aim of this study was to compare ultrapure dialysate (UPD) vs conventional dialysate (CD) with respect to darbepoetin requirements and other inflammation markers.. A controlled prospective randomized study was carried out on 78 patients from two HD units who were treated with low-flux polyamide dialysers. Patients were assigned to two groups by using different sized blocks per unit and dialysis session. One group received CD treatment while the other was treated with UPD over 12 months. From the groups, 37 patients started treatment with CD and 41 with UPD while 31 patients ended with CD and 30 with UPD. The main variables analysed were haemoglobin (Hb) and darbepoetin dose; other variables studied were C-reactive protein (CRP), albumin, interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1Ra).. No significant differences were observed between the two groups for the variables analysed. At the beginning of the study the following values of CD and UPD were assessed: Hb 11.3 and 11.3 (g/dl); darbepoetin dose: 0.49 and 0.44 (microg/kg/week); CRP: 13 and 24 (mg/l); albumin: 3.8 and 3.7 (g/dl); IL-6: 5.94 and 4.18; and IL-1Ra: 345 and 420 (ng/l), respectively. At the end of the study the values of CD and UPD were: Hb 12 and 11.9 (g/dl); darbepoetin dose: 0.47 and 0.48 (microg/kg/week); CRP: 14 and 14 (mg/l); albumin: 3.8 and 3.7 (g/dl); IL-6: 14.03 and 12.93 and IL-1Ra: 322 and 340 (ng/l).. UPD does not improve the inflammatory status evaluated by darbepoetin requirements in conventional HD patients treated with low-flux polyamide dialyser. Further controlled studies are required to evaluate the clinical influence of UPD in HD with other low- and high-flux membranes.

Topics: Aged; Aged, 80 and over; C-Reactive Protein; Darbepoetin alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemodialysis Solutions; Hemoglobins; Humans; Inflammation; Interleukin-6; Kidney; Male; Middle Aged; Renal Dialysis; Serum Albumin; Time Factors

In a prospective observational study, we examined the temporal relationships between serum erythropoietin (EPO) levels, haemoglobin concentration and the inflammatory response in critically ill patients with and without acute renal failure (ARF).. Twenty-five critically ill patients, from general and cardiac intensive care units (ICUs) in a university hospital, were studied. Eight had ARF and 17 had normal or mildly impaired renal function. The comparator group included 82 nonhospitalized patients with normal renal function and varying haemoglobin concentrations. In the patients, levels of haemoglobin, serum EPO, C-reactive protein, IL-1beta, IL-6, serum iron, ferritin, vitamin B12 and folate were measured, and Coombs test was performed from ICU admission until discharge or death. Concurrent EPO and haemoglobin levels were measured in the comparator group.. EPO levels were initially high in patients with ARF, falling to normal or low levels by day 3. Thereafter, almost all ICU patients demonstrated normal or low EPO levels despite progressive anaemia. IL-6 exhibited a similar initial pattern, but levels remained elevated during the chronic phase of critical illness. IL-1beta was undetectable. Critically ill patients could not be distinguished from nonhospitalized anaemic patients on the basis of EPO levels.. EPO levels are markedly elevated in the initial phase of critical illness with ARF. In the chronic phase of critical illness, EPO levels are the same for patients with and those without ARF, and cannot be distinguished from noncritically ill patients with varying haemoglobin concentrations. Exogenous EPO therapy is unlikely to be effective in the first few days of critical illness.

Topics: Acute Kidney Injury; Acute-Phase Reaction; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Transfusion; Critical Illness; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Outpatients; Prospective Studies; Reference Values; Time

Topics: Acute Kidney Injury; Aged; Drug Resistance; Erythropoietin; Female; Humans; Inflammation; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Treatment with recombinant human erythropoietin (rHuEPO) in dialysis patients has been associated with improvement of nutritional and immune status through an increase of cytokine production [such as tumor necrosis factor alpha (TNF alpha)]. The high cytokine production can be a double-edged sword owing to the relationship of cytokines with the systemic inflammatory process, which has been associated with many complications of uremic status. Our aim was to analyze the medium-long term effects of rHuEPO treatment on uremic inflammatory markers. We studied 45 peritoneal dialysis (PD) patients divided in two groups: a rHuEPO group (40-70 subcutaneous units/kg weekly) and a control group (no rHuEPO). The treated group was analyzed in four periods. Period 1 (rHuEPO-1) included 24 patients who had been using rHuEPO at long-term. Period 2 (rHuEPO-2; n = 21) looked at the patients 2 months after rHuEPO withdrawal. Period 3 (rHuEPO-3; n = 19) looked at the patients after 2 months under rHuEPO therapy. Period 4 (rHuEPO-4; n = 17) looked at the patients after 4 months on rHuEPO treatment. With the reintroduction of rHuEPO, we observed a progressive, statistically significant (p < 0.05), and temporary increase in TNF alpha plasma levels, from 44 +/- 24 pg/mL (rHuEPO-2) to 76.8 +/- 25 pg/mL (rHuEPO-3), and then to 83 +/- 27 pg/mL (rHuEPO-4). But in the long term, TNF alpha decreased [33.5 +/- 10 pg/mL (rHuEPO-1)]. Similarly, albumin increased in the short term (3.73 +/- 0.5 g/dL to 4 +/- 0.5 g/dL, and then to 4 +/- 0.43 g/dL), and then decreased (3.8 +/- 0.44 g/dL). The normalized protein catabolic rate (nPCR) increased from 1 +/- 0.2 g/kg daily to 1.12 +/- 0.3 g/kg daily (rHuEPO-4). Long term, nPCR decreased to 1.06 +/- 0.3 g/kg daily. Leptin initially increased (60.1 +/- 48 ng/mL to 42.8 +/- 22 ng/mL, and then to 38 +/- 18.2 ng/mL); it also increased in the long term (62 +/- 50.9, p < 0.05). At baseline, we found a significant positive linear correlation (p < 0.05) between TNF alpha and leptin (r = 0.52), TNF alpha and C-reactive protein [(CRP) r = 0.4], CRP and leptin (r = 0.49), fibrinogen and CRP (r = 0.78, p < 0.01), fibrinogen and leptin (r = 0.37), and leptin and body mass index [(BMI) r = 0.67]. In conclusion, rHuEPO induces a temporary, non inflammatory immune hyperactivity mediated by TNF alpha, without the adverse effects associated with that cytokine. By decreasing leptin, rHuEPO could increase food intake and improve the nutritional status of PD patients

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; C-Reactive Protein; Erythropoietin; Female; Humans; Inflammation; Leptin; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Proteins; Recombinant Proteins; Serum Albumin; Tumor Necrosis Factor-alpha

The effect of erythropoietin (EPO) on the oxidative stress and inflammation caused by polymorphonuclear leukocytes (PMNLs) in chronic hemodialysis (HD) patients was investigated in vivo and in vitro. The studies were performed on isolated PMNLs from peripheral blood of healthy controls and HD patients before and following 6 weeks of EPO treatment. The oxidative stress was expressed by the rate of superoxide release from phorbol 12-myristate 13-acetate stimulated PMNLs, and the inflammatory state was evaluated by in vitro PMNL survival, in addition to white blood cell and PMNL counts of the enrolled subjects. Following 6 weeks of EPO treatment, in HD patients, the rate of superoxide release from PMNLs as well as WBC and PMNL counts fell significantly when compared with the pretreatment values. PMNLs from HD patients and healthy controls incubated in vitro with increasing amounts of EPO displayed a significant reduction in their rates of superoxide release and a significant improvement in survival. We have concluded that EPO interacts with PMNLs, attenuating their primed state in HD patients, thus reducing oxidative stress and the extent of inflammation. To the best of our knowledge, this attenuation of the primed state of PMNLs by EPO is a new finding.

Topics: Cell Survival; Erythropoietin; Female; Humans; Inflammation; Kinetics; Leukocyte Count; Male; Middle Aged; Neutrophils; Oxidative Stress; Recombinant Proteins; Renal Dialysis; Superoxides; Time Factors

Forty-six patients with rheumatoid arthritis (RA) and documented anemia of chronic disease (Hb < 100/110 g/l) were randomized to receive either human recombinant erythropoietin (r-HuEPO, n = 36, 300 U/kg body weight) or placebo (n = 10) for 12 weeks in a multicenter study. An adequate response was defined as elevation of Hb > or = 120 g/l. Relevant clinical and laboratory assessments were made to evaluate efficacy and secure safety. A significant elevation in Hb from week 10 onwards was noted in twenty-six patients (five drop-outs) out of nine patients receiving placebo (one drop-out) (12 +/- 1.2 g/l vs 4 +/- 0.5 g/l; Hb elevation from 95 g/l to 107 g/l vs 93 g/l to 97 g/l, P < 0.05). Only 14.6%, however, were considered responders according to preset criteria. In the responders a lower initial CRP, a significant reduction in ESR but not in CRP was seen compared to the remaining r-HuEPO group. A significant elevation of energy level was noted in the r-HuEPO group; otherwise, no differences in clinical variables were seen. No serious adverse effects were noted. When analyzing patients receiving oral iron in combination with r-HuEPO and adding five additional, openly selected patients receiving both adequate iron supplementation and r-HuEPO, there was a significant weekly elevation of Hb from week 8 onwards in favor of combination therapy over the ones only receiving r-HuEPO (18 +/- 1.1 g/l vs 7 +/- 1.1 g/l, P < 0.05). The initial six responders had now reached ten of whom seven belonged to the combination therapy group. Response to r-HuEPO in RA patients appears to be dependent on availability of iron and on the degree of inflammation. If r-HuEPO treatment is considered, iron deficiency should always be corrected and strenuous efforts should have been made to control the disease itself.

Topics: Adult; Aged; Anemia; Arthritis, Rheumatoid; Chronic Disease; Erythropoietin; Female; Humans; Inflammation; Iron; Male; Middle Aged; Recombinant Proteins

Acute kidney injury (AKI) is one of frequent complications of sepsis with high mortality. Mitochondria is the center of energy metabolism participating in the pathogenesis of sepsis-associated AKI, and SIRT1/PGC1-α signaling pathway plays a crucial role in the modulation of energy metabolism. Erythropoietin (EPO) exerts protective functions on chronic kidney disease. We aimed to assess the effects of EPO on cell damage and energy metabolism in a cell model of septic AKI. Renal tubular epithelial cells HK-2 were treated with LPS and human recombinant erythropoietin (rhEPO). Cell viability was detected by CCK-8 and mitochondrial membrane potential was determined using JC-1 fluorescent probe. Then the content of ATP, ADP and NADPH, as well as lactic acid, were measured for the assessment of energy metabolism. Oxidative stress was evaluated by detecting the levels of ROS, MDA, SOD and GSH. Pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, were measured with ELISA. Moreover, qRT-PCR and western blot were performed to detect mRNA and protein expressions. shSIRT1 was used to knockdown SIRT1, while EX527 and SR-18292 were applied to inhibit SIRT1 and PGC1-α, respectively, to investigate the regulatory mechanism of rhEPO on inflammatory injury and energy metabolism. In LPS-exposed HK-2 cells, rhEPO attenuated cell damage, inflammation and abnormal energy metabolism, as indicated by the elevated cell viability, the inhibited oxidative stress, cell apoptosis and inflammation, as well as the increased mitochondrial membrane potential and energy metabolism. However, these protective effects induced by rhEPO were reversed after SIRT1 or PGC1-α inhibition. EPO activated SIRT1/PGC1-α pathway to alleviate LPS-induced abnormal energy metabolism and cell damage in HK-2 cells. Our study suggested that rhEPO played a renoprotective role through SIRT1/PGC1-α pathway, which supported its therapeutic potential in septic AKI.

Topics: Acute Kidney Injury; Apoptosis; Energy Metabolism; Erythropoietin; Humans; Inflammation; Kidney; Lipopolysaccharides; Sepsis; Sirtuin 1

ARA 290, an 11-amino acid linear nonhematopoietic peptide derived from the three-dimensional structure of helix B of the erythropoietin (EPO), interacts selectively with the innate repair receptor (IRR) that arbitrates tissue protection. The aim of this study was to investigate the protective effects of ARA290 against cisplatin-induced nephrotoxicity. For this purpose, HEK-293 and ACHN cells were treated with ARA290 (50-400 nM) and cisplatin (2.5 μM) in pretreatment condition. Then, cytotoxicity, genotoxicity, oxidative stress parameters (ROS, GPx, SOD, and MDA), and inflammatory markers (TNFα, IL6, and IL1β) were evaluated. Furthermore, apoptotic cell death was assessed via caspase-3 activity and tunnel assay. To determine the molecular mechanisms of the possible nephroprotective effects of ARA290, gene and protein expressions of TNFα, IL1β, IL6, Caspase-3, Bax, and Bcl2 were evaluated by real-time PCR and western blot assay, respectively. The findings indicated that ARA290 significantly reduced the DNA damage parameters of comet assay and the frequency of micronuclei induced by cisplatin. Besides, ARA290 improved cisplatin-induced oxidative stress by reducing MDA/ROS levels and enhancing antioxidant enzyme levels. In addition, reduced levels of pro-inflammatory cytokines indicated that cisplatin-induced renal inflammation was mitigated upon the treatment with ARA290. Besides, ARA290 ameliorates cisplatin-induced cell injury by antagonizing apoptosis. Furthermore, the molecular findings indicated that gene and protein levels of TNFα, IL1β, IL6, Caspase-3, and Bax were significantly decreased and gene and protein levels of Bcl2 significantly increased in the ARA290 plus cisplatin group compared with the cisplatin group. These findings revealed that ARA290 as a potent chemo-preventive agent exerted a protective effect on cisplatin-induced nephrotoxicity mostly through its anti-apoptotic, anti-inflammatory, and antioxidant potentials and also suggested that ARA290 might be a new therapeutic approach for patients with acute kidney injury.

Topics: Antioxidants; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cisplatin; Erythropoietin; HEK293 Cells; Humans; Inflammation; Interleukin-6; Kidney; Ligands; Oxidative Stress; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Adalimumab (ADM), a humanized antibody against tumour necrosis factor (TNF), is widely applied in treating inflammatory and autoimmune diseases, but its usage in spinal cord injury (SCI) is rarely reported. Hence, this study aimed to explore the effect of ADM with or without erythropoietin (EPO) on microglial polarization, neuroinflammation, neural apoptosis, and functional recovery in SCI.. Primary microglia were stimulated with lipopolysaccharide (LPS) and then treated with ADM, EPO, or ADM combined with EPO. Then, primary neurons were incubated in the microglial culture medium. SCI rats were established and then treated with ADM, EPO or ADM combined with EPO.. ADM suppressed LPS-induced microglial M1 polarization, as reflected by downregulated iNOS and CD86 expression, and neuroinflammation, as reflected by decreased TNF-α, IL-1β, and IL-6 expression, in a dose-dependent manner. Moreover, ADM inhibited microglia-induced neural apoptosis, as reflected by TUNEL assay results and the expression of apoptotic markers (C-Caspase3 and Bcl2), in a dose-dependent manner. EPO monotherapy displayed an effect similar to that of ADM monotherapy. Furthermore, ADM combined with EPO therapy exhibited greater effects than either monotherapy in terms of inhibiting microglial M1 polarization, neuroinflammation, and neural apoptosis. In vivo experiments confirmed the findings of the in vitro experiments and showed that ADM combined with EPO improved SCI functional recovery and neural injury compared with monotherapy.. ADM combined with EPO improves recovery from SCI by suppressing microglial M1 polarization-mediated neural inflammation and apoptosis.

Topics: Adalimumab; Animals; Apoptosis; Erythropoietin; Inflammation; Lipopolysaccharides; Microglia; Neuroinflammatory Diseases; Rats; Spinal Cord; Spinal Cord Injuries; Tumor Necrosis Factor-alpha

Anemia is a common complication of systemic inflammation. Proinflammatory cytokines both decrease erythroblast sensitivity to erythropoietin (EPO) and increase the levels of the hepatic hormone hepcidin, sequestering iron in stores and causing functional iron deficiency. Anemia of chronic kidney disease (CKD) is a peculiar form of anemia of inflammation, characterized by impaired EPO production paralleling progressive kidney damage. Traditional therapy based on increased EPO (often in combination with iron) may have off-target effects due to EPO interaction with its non-erythroid receptors. Transferrin Receptor 2 (Tfr2) is a mediator of the iron-erythropoiesis crosstalk. Its deletion in the liver hampers hepcidin production, increasing iron absorption, whereas its deletion in the hematopoietic compartment increases erythroid EPO sensitivity and red blood cell production. Here, we show that selective hematopoietic Tfr2 deletion ameliorates anemia in mice with sterile inflammation in the presence of normal kidney function, promoting EPO responsiveness and erythropoiesis without increasing serum EPO levels. In mice with CKD, characterized by absolute rather than functional iron deficiency, Tfr2 hematopoietic deletion had a similar effect on erythropoiesis but anemia improvement was transient because of limited iron availability. Also, increasing iron levels by downregulating only hepatic Tfr2 had a minor effect on anemia. However, simultaneous deletion of hematopoietic and hepatic Tfr2, stimulating erythropoiesis and increased iron supply, was sufficient to ameliorate anemia for the entire protocol. Thus, our results suggest that combined targeting of hematopoietic and hepatic Tfr2 may be a therapeutic option to balance erythropoiesis stimulation and iron increase, without affecting EPO levels.

Topics: Anemia; Animals; Disease Models, Animal; Erythropoiesis; Erythropoietin; Hepcidins; Inflammation; Iron; Iron Deficiencies; Mice; Receptors, Transferrin; Renal Insufficiency, Chronic

Anemia, which is a manifestation of the deterioration of patients' health and performance, is a common concomitant condition in diseases with signs of inflammation activation. This anemia - anemia of inflammation, is caused by disturbances of iron metabolism that lead to iron retention within macrophages, cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation, and a reduced erytrocyte half-life. Anemia is usually mild to moderate, normocytic and normochromic. It is characterized by low iron circulation, but normal to increased levels of stored ferritin and the hormone hepcidin. The primary therapeutic approach is the treatment of the underlying inflammatory disease. In case of failure, iron supplementation and / or treatment with erythropoietin stimulating agents may be used. Blood transfusions are just an emergency treatment for life-threatening anemia. A new treatment modalities with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors is emerging. However, their therapeutic efficacy needs to be verified and evaluated in clinical trials.

Topics: Anemia; Erythropoietin; Hepcidins; Humans; Inflammation; Iron

Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. We investigated the toxicopathological role of IS in renal fibrosis using

Topics: Animals; Disease Models, Animal; Erythropoietin; Fibrosis; Humans; Indican; Inflammation; Kidney; Mice; Mice, Inbred C57BL; Renal Insufficiency, Chronic; Sulfotransferases; Ureteral Obstruction

Iron is usually administered in hemodialysis patients by parenteral route, as oral absorption is poor due to high hepcidin levels. However, administrations of intravenous iron and iron overload are associated with high oxidative stress and systemic inflammation that can affect patient survival. With this study, we evaluated an alternative type of oral iron for the treatment of anemia in hemodialysis patients. The formulation consists in ferric pyrophosphate covered by phospholipids plus sucrose ester of fatty acid matrix, named sucrosomial iron, whose absorption is not influenced by hepcidin.. Twenty-four (24) patients undergoing chronic hemodialysis switched iron supplementation from intravenous (ferric gluconate 62.5 mg weekly) to oral (sucrosomial iron, 90 mg weekly in 3 administrations of 30 mg) route for 3 months. Classical anemia, iron metabolism, inflammation and nutritional biomarkers were monitored, as well as biomarkers of oxidative stress, such as protein-bound di-tyrosines, protein carbonylation, advanced oxidation protein products and protein thiols.. Over the 3 months, hemoglobin values remained stable, as the values of hematocrit and mean corpuscular volume. In parallel, other anemia parameters dropped, including ferritin, transferrin saturation and serum iron. On the other side, nutritional biomarkers, such as total proteins and transferrin, increased significantly during the time frame. We also observed a significant decrease in white blood cells as well as a non-significant reduction in C-reactive protein and some oxidative stress biomarkers, such as protein carbonyls and di-tyrosines.. Our study demonstrates that a therapy with sucrosomial iron in hemodialysis patients is safe and can maintain stable hemoglobin levels in a three-month period with a possible beneficial effect on oxidative stress parameters. However, the reduction of ferritin and transferrin saturation suggests that a weekly dosage of 90 mg is not sufficient in hemodialysis patients in the long time to maintain hemoglobin.

Topics: Anemia; Biomarkers; Erythropoietin; Ferric Compounds; Ferritins; Hemoglobins; Hepcidins; Humans; Inflammation; Iron; Oxidative Stress; Renal Dialysis; Transferrin

Anemia of inflammation, also known as anemia of chronic disease, is refractory to erythropoietin (EPO) treatment, but the mechanisms underlying the EPO refractory state are unclear. Here, we demonstrate that high mobility group box-1 protein (HMGB1), a damage-associated molecular pattern molecule recently implicated in anemia development during sepsis, leads to reduced expansion and increased death of EPO-sensitive erythroid precursors in human models of erythropoiesis. HMGB1 significantly attenuates EPO-mediated phosphorylation of the Janus kinase 2/STAT5 and mTOR signaling pathways. Genetic ablation of receptor for advanced glycation end products, the only known HMGB1 receptor expressed by erythroid precursors, does not rescue the deleterious effects of HMGB1 on EPO signaling, either in human or murine precursors. Furthermore, surface plasmon resonance studies highlight the ability of HMGB1 to interfere with the binding between EPO and the EPOR. Administration of a monoclonal anti-HMGB1 antibody after sepsis onset in mice partially restores EPO signaling in vivo. Thus, HMGB1-mediated restriction of EPO signaling contributes to the chronic phase of anemia of inflammation.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; HMGB1 Protein; Inflammation; Mice; Receptors, Erythropoietin; Sepsis

The current research aimed to verify the effects of erythropoietin (EPO) on vascular calcification under inflammatory conditions and the molecular regulator of vascular calcification induced by EPO. To induce vascular calcification and systemic chronic inflammation in SD rats, EPO was administered intraperitoneally, and 10% casein was injected subcutaneously. The administration period lasted for 20 consecutive weeks. Blood samples were subsequently collected to detect inflammatory factors and vascular calcification. Additionally, high-dose EPOs were applied to stimulate primary vascular smooth muscle cells (VSMCs), and vascular calcification was measured using alizarin red staining, alkaline phosphatase (ALP) activity, and calcium salt quantification. The probe 2',7'-dichlorofluorescein diacetate (DCFH-DA) was employed to detect cellular reactive oxygen species (ROS) levels. The expressions of bone formation-related protein and anti-calcification protein matrix gla protein (MGP) were determined via Western blot. Compared with the control group, calcium deposits and vascular calcification were increased in the EPO group, tumor necrosis factor-alpha (TNF-α) group and TNF-α+ EPO group, whereas MGP was significantly reduced. Moreover, under the stimulation of TNF-α and EPO+TNF-α, pp38/p38 was increased substantially, the addition of p38 inhibitor SB203580 could significantly reduce calcium deposits and vascular calcification. In vivo experiment, compared with the EPO group, calcium salt deposition and vascular calcification were elevated in the EPO+casein group. The present results revealed that high-dose EPO could cause calcification of the abdominal aorta in rats. The inflammatory response aggravated the vascular calcification induced by EPO via activating p38 and ROS levels.

Topics: Animals; Calcium; Caseins; Cells, Cultured; Erythropoietin; Inflammation; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Tumor Necrosis Factor-alpha; Vascular Calcification

Anemia of cancer (AoC) with its multifactorial etiology and complex pathology is a poor prognostic indicator for cancer patients. One of the main causes of AoC is cancer-associated inflammation that activates mechanisms, commonly observed in anemia of inflammation, whereby functional iron deficiency and iron-restricted erythropoiesis are induced by increased hepcidin levels in response to raised levels of interleukin-6. So far only a few AoC mouse models have been described, and most of them did not fully recapitulate the interplay of anemia, increased hepcidin levels and functional iron deficiency in human patients. To test if the selection and the complexity of AoC mouse models dictates the pathology or if AoC in mice per se develops independently of iron deficiency, we characterized AoC in Trp53floxWapCre mice that spontaneously develop breast cancer. These mice developed AoC associated with high levels of interleukin-6 and iron deficiency. However, hepcidin levels were not increased and hypoferremia coincided with anemia rather than causing it. Instead, an early shift in the commitment of common myeloid progenitors from the erythroid to the myeloid lineage resulted in increased myelopoiesis and in the excessive production of neutrophils that accumulate in necrotic tumor regions. This process could not be prevented by either iron or erythropoietin treatment. Trp53floxWapCre mice are the first mouse model in which erythropoietin-resistant anemia is described and may serve as a disease model to test therapeutic approaches for a subpopulation of human cancer patients with normal or corrected iron levels who do not respond to erythropoietin.

Topics: Anemia; Animals; Breast Neoplasms; Erythropoiesis; Erythropoietin; Female; Hepcidins; Humans; Inflammation; Interleukin-6; Iron; Iron Deficiencies; Mice

Hypoxia-inducible factor prolyl hydroxylase inhibitors improve anemia in CKD and dialysis patients and were approved for anemia treatment with these populations in Japan. An 89 year-old man with anemia and on maintenance hemodialysis was successfully treated with a dose-up of darbepoetin alfa from 10 to 20 μg per week, and the dose was gradually tapered to 5 μg. Later, serum hemoglobin levels decreased with the newly occurring sustained inflammation and left pleural effusion of an unknown cause, and the darbepoetin alfa dose was increased again to 20 μg per week, which was not effective. Darbepoetin alfa was switched to 4 mg of daprodustat daily, which was fairly effective under sustained inflammation, with serum hemoglobin levels maintained at 11-12 g/dL. The increase in hemoglobin levels was ascribed to the increase in the number of red blood cells, not the mean corpuscular hemoglobin level. During the inflammatory state, despite the contrasting effect on anemia by the 20 μg of darbepoetin alfa weekly and 4 mg of daprodustat daily, the reticulocyte counts were equivalent. The serum erythropoietin levels during daprodustat administration were within the physiological range (8.5-18.8 mIU/mL). For anemia treatment in hemodialysis patients, daprodustat is less influenced by the inflammatory status than darbepoetin alfa, and one of the possible reasons for this includes the extended red blood cell lifespan.

Topics: Aged, 80 and over; Anemia; Darbepoetin alfa; Erythropoietin; Hemoglobins; Humans; Inflammation; Male; Renal Dialysis; Treatment Outcome

Each patient undergoing maintenance haemodialysis (MHD) has a different response to erythropoiesis-stimulating agents (ESAs). Haemodilution due to fluid overload has been shown to contribute to anaemia. Body mass index (BMI) has been shown to influence ESA response in dialysis patients; however, BMI calculation does not distinguish between fat and lean tissue. The association between lean muscle mass and erythropoietin hyporesponsiveness is still not well-known among MHD patients. We designed a cross-sectional study and used bioimpedance spectroscopy (BIS) to analyse the relationship between body composition, haemoglobin level, and erythropoietin resistance index (ERI) in MHD patients. Seventy-seven patients were enrolled in the study group. Compared with patients with haemoglobin ≥ 10 g/dL, those with haemoglobin < 10 g/dL had higher serum ferritin levels, malnutrition−inflammation scores (MIS), relative overhydration, ESA doses, and ERIs. In multivariate logistic regression, higher ferritin levels and MIS were the only predictors of lower haemoglobin levels. The ERI was significantly positively correlated with age, Kt/V, ferritin levels, and MIS and negatively correlated with albumin levels, BMI, and lean tissue index (LTI). Multivariate linear regression analysis revealed that ferritin levels, BMI, and LTI were the most important predictors of ERI. In MHD patients, using BIS to measure body composition can facilitate the development of early interventions that aim to prevent sarcopenia, support ESA responsiveness, and, consequently, improve anaemia management.

Topics: Anemia; Cross-Sectional Studies; Erythropoietin; Ferritins; Hemoglobins; Humans; Inflammation; Kidney Failure, Chronic; Muscles; Muscular Diseases; Renal Dialysis

This study aimed to evaluate the effect of direct pulp capping on the expression of erythropoietin (Epo) and Epo-receptor (Epor) genes in relation to the expression of inflammatory and osteogenic genes in rat pulp. Dental pulps of the first maxillary molars of Wistar Albino rats were exposed and capped with either calcium hydroxide or mineral trioxide aggregate, or were left untreated. After 4 wk, animals were euthanized, and maxillae were prepared for histological and real-time polymerase chain reaction analysis. Histological scores of pulp inflammation and mineralization, and relative expressions of Epo, Epor, inflammatory cytokines, and pulp osteogenic genes were evaluated. The capped pulps showed higher expressions of Epo, while the untreated pulps had the highest expression of Epor. Both calcium hydroxide and mineral trioxide aggregate downregulated the expression of tumor necrosis factor alpha compared to untreated controls, and upregulated transforming growth factor beta compared to healthy controls. Alkaline phosphatase expression was significantly higher in experimental groups. Relative expression of Epo negatively correlated with pulp inflammation, and positively correlated with pulp mineralization. Pulp exposure promoted expression of Epor and pro-inflammatory cytokines, while pulp capping promoted expression of Epo, alkaline phosphatase, and downregulated Epor and pro-inflammatory cytokines.

Topics: Alkaline Phosphatase; Aluminum Compounds; Animals; Calcium Hydroxide; Dental Pulp; Dental Pulp Capping; Drug Combinations; Erythropoietin; Inflammation; Oxides; Rats; Rats, Wistar; Receptors, Erythropoietin; Silicates; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis.

Topics: Anemia; COVID-19; Erythropoiesis; Erythropoietin; Hepcidins; Humans; Hypoxia; Inflammation; Iron

While elevated hepcidin levels with inflammation have been postulated as a putative mechanism hindering effective erythropoiesis after intravenous (IV) iron therapy in anemic patients undergoing surgery, little is known about the concomitant changes in other major regulators affecting erythropoiesis. This study investigated the activities of relevant regulators after iron replenishment in a rat model of iron deficiency anemia with inflammation.. Inflammation was induced by administration of complete Freund's adjuvant (CFA) in male Sprague-Dawley rats. After 2 weeks of CFA treatment, the rats received IV iron (CFA‑iron) or saline (CFA-saline). The control group received saline instead of CFA and iron (saline-saline). At 1, 3, and 10 days after iron or saline treatment, inflammatory cytokines, oxidative markers, iron profiles, hepcidin, erythropoietin (EPO), erythroferrone (ERFE), fibroblast growth factor 23 (FGF 23), and expression of mRNA and proteins in the liver involved in hepcidin signaling pathways were measured.. CFA treatment and iron restriction decreased hemoglobin and serum iron levels, significantly increasing inflammatory and oxidative markers. Iron supplementation did not restore hemoglobin levels despite improved iron profiles. CFA injections increased hepcidin and FGF 23 levels and decreased EPO and ERFE levels, which further intensified after iron supplementation with concomitantly elevated levels of oxidative stress and inflammatory markers.. Under inflammatory conditions, IV iron administration exacerbated inflammatory and oxidative stress and did not resolve anemia, even under iron deficiency conditions. Iron therapy exerted adverse influences on the changes in key regulators toward impeding erythropoiesis that was already impeded by inflammation.

Topics: Anemia; Anemia, Iron-Deficiency; Animals; Biomarkers; Dietary Supplements; Erythropoiesis; Erythropoietin; Hemoglobins; Hepcidins; Inflammation; Iron; Iron Deficiencies; Male; Rats; Rats, Sprague-Dawley

Hemodialyzed patients with poor erythropoietin response tend to have low volume of visceral adipose tissue and score high on malnutrition-inflammation score. This study investigates in-depth the role of leptin and chosen cytokines in the development of malnutrition-inflammation syndrome (MIS) and erythropoietin resistance.. Eighty-one hemodialyzed patients with erythropoietin-treated anemia were enrolled in the study. Their body composition was measured. Erythropoietin resistance index was calculated. Blood samples for leptin, IL-6, IL-18, TNF-alpha, and IL-1-alpha serum levels were drawn.. Leptin showed negative correlation with erythropoietin resistance index (ERI), whilst IL-6 showed the opposite. IL-6 seemed to be linked more to HD parameters and vintage, while TNF-alpha and leptin were more dependent on body composition. IL-18 and IL-1-alpha did not affect nutritional parameters nor ERI.. Modulation of adipokine- and cytokine-related signaling is a promising target in tempering malnutrition in hemodialyzed, and thus achieving better outcomes in anemia treatment. Large clinical studies that target the inflammatory response in hemodialysis, especially regarding IL-6, TNF-alpha, and leptin, would be of great worth.

Topics: Anemia; Erythropoietin; Humans; Inflammation; Interleukin-1; Interleukin-18; Interleukin-6; Kidney Failure, Chronic; Leptin; Malnutrition; Renal Dialysis; Tumor Necrosis Factor-alpha

In the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (<28 weeks' gestation) infants.. Plasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III).. Elevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years.. Elevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice.. PENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).

Topics: Adult; Biomarkers; Cerebral Palsy; Cognition; Erythropoietin; Female; Gestational Age; Humans; Hypoxia; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-6; Male; Neuroprotection

The blood hormone erythropoietin (EPO), upon binding to its receptor (EpoR), modulates high-fat diet-induced (HFD-induced) obesity in mice, improves glucose tolerance, and prevents white adipose tissue inflammation. Transgenic mice with constitutive overexpression of human EPO solely in the brain (Tg21) were used to assess the neuroendocrine EPO effect without increasing the hematocrit. Male Tg21 mice resisted HFD-induced weight gain; showed lower serum adrenocorticotropic hormone, corticosterone, and C-reactive protein levels; and prevented myeloid cell recruitment to the hypothalamus compared with WT male mice. HFD-induced hypothalamic inflammation (HI) and microglial activation were higher in male mice, and Tg21 male mice exhibited a lower increase in HI than WT male mice. Physiological EPO function in the brain also showed sexual dimorphism in regulating HFD response. Female estrogen production blocked reduced weight gain and HI. Targeted deletion of EpoR gene expression in neuronal cells worsened HFD-induced glucose intolerance in both male and female mice but increased weight gain and HI in the hypothalamus in male mice only. Both male and female Tg21 mice kept on normal chow and HFD showed significantly improved glycemic control. Our data indicate that cerebral EPO regulates weight gain and HI in a sex-dependent response, distinct from EPO regulation of glycemic control, and independent of erythropoietic EPO response.

Topics: Animals; Blood Glucose; Brain; Erythropoietin; Feeding Behavior; Female; Hypothalamus; Inflammation; Insulin Resistance; Male; Mice; Mice, Transgenic; Receptors, Erythropoietin; Sex Factors

Topics: Animals; Cyclosporine; Cytokines; Erythropoietin; Fibrosis; Inflammation; Kidney; Male; PPAR gamma; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Toll-Like Receptor 4; Transforming Growth Factor beta1

During human pregnancy, iron requirements gradually increase, leading to higher amounts of erythropoietin (EPO) and reticulocytes, and changes in erythrocyte size and density. Women with pregestational obesity experience "obesity hypoferremia" during pregnancy, which alters iron homeostasis. In this study we aimed to describe the relationship between EPO and iron nutrition status during nonanemic pregnancy, and to explore whether obesity and inflammation influence erythropoiesis and red cell indices. We conducted a secondary analysis of a cohort followed throughout pregnancy. Participants were nonanemic women assigned to two study groups based on pregestational body mass index (pgBMI): adequate weight (AW, n = 53) or obesity (Ob, n = 40). All received a multivitamin supplement. At gestational ages (GA) 13, 21, 28 and 34, we measured hemoglobin and red cell indices with an ACT-5DIFF hematology counter, and reticulocyte percentage by manual cell counting. EPO, interleukin (IL-6) and markers of iron status, i.e., hepcidin, serum transferrin receptor (sTfr) and ferritin, were measured by ELISA. Bivariate correlations showed that EPO was positively associated with pgBMI, GA, sTfr and IL-6, but negatively associated with hepcidin, ferritin and hemoglobin, and unrelated to iron intake. Generalized linear models adjusted for confounding factors showed that EPO and erythrocyte concentrations were significantly higher in women in the Ob group, while mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and red cell distribution width (RDW) were lower; reticulocytes and mean corpuscular hemoglobin concentration (MCHC) were not different. Differences were not altered when controlling for inflammation (IL-6). These changes suggest that, in addition to altering iron metabolism, a larger maternal body size during pregnancy results in higher erythropoiesis without increasing hemoglobin, which is exhibited in the latter being distributed among more and smaller erythrocytes.

Topics: Adult; Body Size; Erythrocyte Indices; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Iron; Maternal Nutritional Physiological Phenomena; Obesity, Maternal; Pregnancy; Young Adult

The proliferation and migration of endothelial cells are vascular events of inflammation, a process which can also potentiate the effects of promigratory factors. With the aim of investigating possible modifications in the activity of erythropoietin (Epo) in an inflammatory environment, we found that Epo at a non-promigratory concentration was capable of stimulating EA.hy926 endothelial cell migration when TNF-α was present. VCAM-1 and ICAM-1 expression, as well as adhesion of monocytic THP-1 cells to endothelial layers were also increased. Structurally modified Epo (carbamylation or N-homocysteinylation) did not exhibit these effects. The sensitizing effect of TNF-α on Epo activity was mediated by the Epo receptor. Inhibition assays targeting the PI3K/mTOR/NF-κB pathway, shared by Epo and TNF-α, show a cross-talk between both cytokines. As observed in assays using antioxidants, cell migration elicited by TNF-α + Epo depended on TNF-α-generated reactive oxygen species (ROS). ROS-mediated inactivation of protein tyrosine phosphatase 1B (PTP1B), involved in Epo signaling termination, could explain the synergistic effect of these cytokines. Our results suggest that ROS generated by inflammation inactivate PTP1B, causing the Epo signal to last longer. This mechanism, along with the cross-talk between both cytokines, could explain the sensitizing action of TNF-α on the migratory effect of Epo.

Topics: Cell Adhesion; Cell Movement; Cells, Cultured; Erythropoietin; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Protein Tyrosine Phosphatase, Non-Receptor Type 1

An important comorbidity of chronic inflammation is anemia, which may be related to dysregulated activity of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM). Among HSPCs, we found that the receptor for IL-33, ST2, is expressed preferentially and highly on erythroid progenitors. Induction of inflammatory spondyloarthritis in mice increased IL-33 in BM plasma, and IL-33 was required for inflammation-dependent suppression of erythropoiesis in BM. Conversely, administration of IL-33 in healthy mice suppressed erythropoiesis, decreased hemoglobin expression, and caused anemia. Using purified erythroid progenitors in vitro, we show that IL-33 directly inhibited terminal maturation. This effect was dependent on NF-κB activation and associated with altered signaling events downstream of the erythropoietin receptor. Accordingly, IL-33 also suppressed erythropoietin-accelerated erythropoiesis in vivo. These results reveal a role for IL-33 in pathogenesis of anemia during inflammatory disease and define a new target for its treatment.

Topics: Anemia; Animals; Annexin A5; beta-Glucans; Bone Marrow; Cell Differentiation; Chronic Disease; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Hematopoiesis; Inflammation; Injections; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Ki-67 Antigen; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Biological; Myelopoiesis; NF-kappa B; Phosphorylation; Receptors, Erythropoietin; Signal Transduction; Spondylarthritis

The objective of this study was to explore the neuroprotective molecular mechanisms of erythropoietin (EPO) in rats following spinal cord injury (SCI). First, a standard SCI model was established. After drug or saline treatment was administered, locomotor function was evaluated in rats using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. H&E, Nissl, and TUNEL staining were performed to assess the ratio of cavities, number of motor neurons, and apoptotic cells in the damaged area. The relative protein and mRNA expressions were examined using western blot and qRT-PCR analyses, and the inflammatory markers, axon special protein, and neuromuscular junctions (NMJs) were detected by immunofluorescence. Both doses of EPO notably improved locomotor function, but high-dose EPO was more effective than low-dose EPO. Moreover, EPO reduced the cavity ratio, cell apoptosis, and motor neuron loss in the damaged area, but enhanced the autophagy level and extracellular-regulated protein kinase (ERK) activity. Treatment with an ERK inhibitor significantly prevented the effect of EPO on SCI, and an activator mimicked the benefits of EPO. Further investigation revealed that EPO promoted SCI-induced autophagy via the ERK signaling pathway. EPO activates autophagy to promote locomotor function recovery in rats with SCI via the ERK signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Autophagy; Cell Survival; Down-Regulation; Erythropoietin; Inflammation; MAP Kinase Signaling System; Motor Neurons; Neuroprotective Agents; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord; Spinal Cord Injuries; TOR Serine-Threonine Kinases; Up-Regulation

Topics: Aged; Biomarkers; C-Reactive Protein; Erythropoietin; Female; Humans; Inflammation; Ischemic Attack, Transient; Male; Middle Aged; Peroxiredoxins; Recurrence; Sensitivity and Specificity; Stroke, Lacunar

We aimed to evaluate the effects of EPO in the lipopolysaccharide (LPS) induced rat model of autism in terms of social deficits, learning and memory impairments, as well as their neurochemical correlates. Sixteen female Sprague Dawley rats randomly distributed into two equel groups, then were caged with fertile males for mating. At the 10th day of pregnancy, 0.5 ml %0,9 NaCl saline was given to first group, 100 μg/kg LPS was given to second group to induce autism. On postnatal 21th day, forty-eight littermates were divided into four groups as; 8 male, 8 female controls, 16 male and 16 female LPS-exposed. Then, LPS groups were also divided in to two groups as saline (1 mg/kg/day) and EPO 600 U/kg/day groups, and animals were treated 45 days. At 50th day, after behavioral evaluations, brain levels of TNF-α, nerve growth factor (NGF) were measured. Histologically, hippocampal neuronal density and GFAP expression were assessed. Three-chamber sociability and social novelty test, passive avoidance learning test were revealed significant differences among the EPO and control groups. Histologically, hippocampal CA1 & CA3 regions displayed significant alterations regarding gliosis (GFAP-positive cells) and regarding frontal cortical thickness in EPO groups compare to controls. Biochemical measurements of the brain levels of TNF-α and NGF levels showed significant differences between controls and EPO groups. According to our findings EPO treatment has beneficial effects on ASD-like symptoms, learning and memory processes, neuronal loss and neuroinflammation in the LPS induced rat model of autism, with some gender differences through inflammatory and neurotrophic pathways.

Topics: Animals; Autistic Disorder; Avoidance Learning; Behavior, Animal; Disease Models, Animal; Erythropoietin; Female; Hippocampus; Inflammation; Lipopolysaccharides; Male; Memory; Memory Disorders; Neurons; Rats; Rats, Sprague-Dawley; Social Behavior; Tumor Necrosis Factor-alpha

Dendritic cells (DC) play a key role in the adaptive immune response due to their ability to present antigens and stimulate naïve T cells. Many bacteria and viruses can efficiently target DC, resulting in impairment of their immunostimulatory function or elimination. Hence, the DC compartment requires replenishment following infection to ensure continued operational readiness of the adaptive immune system. Here, we investigated the molecular and cellular mechanisms of inflammation-induced DC generation. We found that infection with viral and bacterial pathogens as well as Toll-like receptor 9 (TLR9) ligation with CpG-oligodeoxynucleotide (CpG-ODN) expanded an erythropoietin (EPO)-dependent TER119

Topics: Animals; Biomarkers; Blood Group Antigens; CD11c Antigen; Cell Differentiation; Cytokines; Dendritic Cells; Disease Models, Animal; Erythropoietin; Female; Hematopoiesis, Extramedullary; Immunity, Innate; Immunophenotyping; Infections; Inflammation; Mice; Mice, Transgenic; Oligodeoxyribonucleotides; Spleen

Topics: Cell Line; Erythroid Precursor Cells; Erythropoietin; Humans; Inflammation; Interferon-gamma; Protein Binding; Receptors, Erythropoietin

Inflammation is a physiological process that primarily occurs as a way to help protect the host against tissue damage and invasion by pathogens. During inflammation, erythropoiesis is suppressed and, if it lasts, anemia develops. The mechanisms underlying this are complex and not fully understood, but various cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1β (IL-1β), and IL-6, are involved. TNF-α upregulates PU.1, which is a crucial transcription factor in granulocytic differentiation, and downregulates GATA-1, a master transcription factor for erythroid differentiation, in hematopoietic stem cells. TNF-α and IL-1β suppress erythropoietin production in the kidney, whereas IFN-γ downregulates the expression of erythropoietin receptors in erythroid precursor cells. Moreover, IL-6 upregulates the production of hepcidin, the master regulator of systemic iron metabolism, in the liver. Hepcidin reduces the iron available for erythropoiesis by downregulating the rate of iron release from macrophages. Activated macrophages may also contribute to the development of anemia by shortening the erythrocyte lifespan. Proper management of the underlining conditions is necessary in treating anemia associated with inflammation. Erythropoiesis-stimulating agents may be administered to patients with chronic kidney disease, whereas anti-IL-6 agents may be beneficial for anemic patients with rheumatoid arthritis and idiopathic multicentric Castleman disease.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hematinics; Humans; Inflammation; Tumor Necrosis Factor-alpha

Iron stores at birth are essential to meet iron needs during the first 4-6 months of life. The present study aimed to investigate iron stores in normal birth weight, healthy, term neonates. Umbilical cord blood samples were collected from apparently normal singleton vaginal deliveries (n=854). Subjects were screened and excluded if C-reactive protein (CRP) > 5 mg/l or α1-acid glycoprotein (AGP) > 1 g/l, preterm (<37 complete weeks), term < 2500g or term > 4000g. In total, 762 samples were included in the study. Serum ferritin, soluble transferrin receptor (sTfR), hepcidin, and erythropoietin (EPO) were measured in umbilical cord blood samples; total body iron (TBI) (mg/kg) was calculated using sTfR and ferritin concentrations. A total of 19.8% newborns were iron deficient (ferritin 35 μg/l) and an additional 46.6% had insufficient iron stores (ferritin < 76 μg/l). There was a positive association between serum ferritin and sTfR, hepcidin, and EPO. Gestational age was positively associated with ferritin, sTfR, EPO, and hepcidin. In conclusion, we demonstrate a high prevalence of insufficient iron stores in a Chinese birth cohort. The value of cord sTfR and TBI in the assessment of iron status in the newborn is questionable, and reference ranges need to be established.

Topics: Adult; Biomarkers; Birth Weight; C-Reactive Protein; Cordocentesis; Erythropoietin; Female; Ferritins; Fetal Blood; Gestational Age; Hepcidins; Humans; Infant, Newborn; Inflammation; Inflammation Mediators; Iron; Iron Deficiencies; Orosomucoid; Pregnancy; Receptors, Transferrin

Obesity has been linked with altered acute inflammation resolution which contributes to obesity-related clinical complications; however, the mechanisms that contribute to obesity-related unresolved inflammation are not fully known. Here we demonstrated that the deficiency of macrophage erythropoietin (EPO) signaling contributed to delayed acute inflammation resolution in diet-induced obese mice. In zymosan-induced acute peritonitis, in line with the delayed resolution of inflammation, the induction of macrophage EPO signaling was significantly reduced in obese mice relative to normal mice. Exogenous EPO induced macrophage EPO signaling and promoted acute inflammation resolution in obese mice. Efferocytosis of apoptotic cells by macrophages which is central in inflammation resolution was impaired in obese mice and restored by exogenous EPO. Mechanistically, macrophage peroxisome proliferator-activated receptor-γ (PPARγ) was greatly reduced in obese mice and EPO increased macrophage PPARγ to promote efferocytosis in obese mice. Together, our results identify an important mechanism underlying aberrant acute inflammation resolution in obesity, with important implications for regulating unresolved acute inflammation and normalizing macrophage defects in obese and diabetic individuals.

Topics: Acute Disease; Animals; Diet; Erythropoietin; Humans; Inflammation; Macrophages; Mice, Inbred C57BL; Mice, Obese; Phagocytosis; PPAR gamma; Recombinant Proteins; Signal Transduction

Chronic inflammatory diseases are often associated with anemia. In such conditions, anemia is generally treated with erythropoiesis stimulating agents (ESAs) which are associated with potentially hazardous side effects and poor outcomes. Suboptimal erythropoiesis in chronic inflammation is believed to be caused by elevated hepcidin levels, which causes blockade of iron in tissue stores. In the current work using rodent models of inflammation, an orally available small molecule prolyl hydroxylase inhibitor desidustat was assessed as an effective treatment of anemia of inflammation. In BALB/c mice, a single dose treatment of desidustat attenuated the effect of lipopolysaccharide (LPS) - or turpentine oil-induced inflammation and increased serum erythropoietin (EPO), iron, and reticulocyte count, and decreased serum hepcidin levels. In turpentine oil-induced anemia in BALB/c mice, repeated dose desidustat treatment increased hemoglobin, RBC and hematocrit in a dose related manner. In female Lewis rats, treatment with desidustat markedly reduced PGPS-induced anemia and increased hemoglobin, red blood cell (RBC) and white blood cell (WBC) count, hematocrit, serum iron and spleen iron. These effects of desidustat were associated with reduction in hepcidin (HAMP) expression as well as reduction in serum hepcidin, and increased EPO expression in liver and kidneys. Desidustat treatment caused a significant increase in expression of Duodenal cytochrome B (DcytB), ferroportin (FPN1) and divalent metal transporter 1 (DMT1) in duodenum, and FPN1 and monocyte chemoattractant protein-1 (MCP-1) in liver suggesting an overall influence on iron metabolism. Thus, pharmacological inhibition of prolyl hydroxylase enzymes can be useful in treatment of anemia of inflammation.

Topics: Anemia; Animals; Down-Regulation; Erythropoiesis; Erythropoietin; Female; Hepcidins; Inflammation; Iron; Liver; Male; Mice, Inbred BALB C; Prolyl-Hydroxylase Inhibitors; Quinolones; Rats, Inbred Lew; Reticulocyte Count

The bone morphogenetic protein (BMP)-SMAD signaling pathway is a key transcriptional regulator of hepcidin in response to tissue iron stores, serum iron, erythropoietic drive and inflammation to increase the iron supply when needed for erythropoiesis, but to prevent the toxicity of iron excess. Recently, BMP2 was reported to play a non-redundant role in hepcidin regulation in addition to BMP6. Here, we used a newly validated BMP2 ELISA assay and mice with a global or endothelial conditional knockout (CKO) of Bmp2 or Bmp6 to examine how BMP2 is regulated and functionally contributes to hepcidin regulation by its major stimuli. Erythropoietin (EPO) did not influence BMP2 expression in control mice, and still suppressed hepcidin in Bmp2 CKO mice. Lipopolysaccharide (LPS) reduced BMP2 expression in control mice, but still induced hepcidin in Bmp2 CKO mice. Chronic dietary iron loading that increased liver iron induced BMP2 expression, whereas acute oral iron gavage that increased serum iron without influencing liver iron did not impact BMP2. However, hepcidin was still induced by both iron loading methods in Bmp2 CKO mice, although the degree of hepcidin induction was blunted relative to control mice. Conversely, acute oral iron gavage failed to induce hepcidin in Bmp6

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 6; Erythropoietin; Hepcidins; Inflammation; Iron; Lipopolysaccharides; Mice; Mice, Knockout

Associations among inflammatory cytokines, erythropoietin (EPO), and anemia in critically ill septic patients remain unclear. This study tested the hypothesis that elevated inflammatory cytokines and decreased EPO would be associated with iron-restricted anemia while accounting for operative blood loss, phlebotomy blood loss, and red blood cell (RBC) transfusion volume.. Prospective observational cohort study of 42 critically ill septic patients was conducted. Hemoglobin (Hb) at sepsis onset and hospital discharge were used to calculate ΔHb. Operative blood loss, phlebotomy blood loss, and RBC transfusion volume were used to calculate adjusted ΔHb (AdjΔHb) assuming that 300 mL RBC is equal to 1 g/dL Hb. Patients with AdjΔHb of greater than 0 (positive AdjΔHb, n = 18) were compared with patients with AdjΔHb of less than or equal to 0 (negative AdjΔHb, n = 24).. Plasma tumor necrosis factor α, granulocyte colony-stimulating factor, interleukin (IL)-6, IL-8, EPO, erythrocyte mean corpuscular volume, and serum transferrin receptor were measured on days 0, 1, 4, 7, and 14. Patients with negative AdjΔHb had significantly higher day 14 levels of IL-6 (37.4 vs. 15.2 pg/mL, p < 0.05), IL-8 (39.1 vs. 18.2 pg/mL, p = 0.01), and granulocyte colony-stimulating factor (101.3 vs. 60.5 pg/mL, p = 0.01), but not EPO. On linear regression analysis, lower AdjΔHb was associated with higher day 14 levels of IL-6 (r = 0.22, p < 0.01), IL-8 (r = 0.10, p = 0.04), stromal cell-derived factor 1 (r = 0.14, p = 0.02), and tumor necrosis factor α (r = 0.13, p = 0.02), but not EPO. Patients with negative AdjΔHb had significantly lower mean corpuscular volume on days 4 (89.6 vs. 93.2 fL/cell, p = 0.04), 7 (92.3 vs. 94.9 fL/cell, p = 0.04), and 14 (92.1 vs. 96.0 fL/cell, p = 0.03) but similar serum transferrin receptor levels.. Persistent elevation of inflammatory cytokines was associated with iron-restricted anemia among critically ill septic patients, occurring in the absence of systemic iron deficiency, independent of endogenous EPO.. Prognostic study, level II.

Topics: Aged; Anemia; Critical Illness; Cytokines; Erythropoietin; Female; Humans; Inflammation; Male; Middle Aged; Prospective Studies; Sepsis

Anaemia affects quality of life and radiographic outcome in rheumatoid arthritis (RA). In a cross-sectional study with 779 patients, we assessed the prognostic potential of the major haematopoietic regulators, hepcidin and erythropoietin, comparing their serum concentrations with respect to different anaemia types, inflammatory activity, anti-cytokine-specific treatment effects and iron deficiency (ID) indices. The results showed that clinical disease activity was more closely associated with haemoglobin levels than with anti-tumour necrosis factor-alpha or interleukin 6 receptor effects. In ID, hepcidin was suppressed, independently of inflammation. Erythropoietin levels were inappropriately low in relation to the degree of anaemia, but, in contrast to low haemoglobin, not directly associated with joint damage progression. Hepcidin and erythropoietin levels are intimately connected with inflammation and ID. Interventional studies on these important targets are already in progress.

Topics: Adult; Anemia, Iron-Deficiency; Arthritis, Rheumatoid; Cross-Sectional Studies; Disease Progression; Erythropoietin; Female; Hemoglobins; Hepcidins; Humans; Inflammation; Joints; Male; Middle Aged

Stress-induced allostatic load affects a variety of biological processes including synaptic plasticity, angiogenesis, oxidative stress, and inflammation in the brain, especially in the hippocampus. Erythropoietin (EPO) is a pleiotropic cytokine that has shown promising neuroprotective effects. Recombinant human EPO is currently highlighted as a new candidate treatment for cognitive impairment in neuropsychiatric disorders. Because EPO enhances synaptic plasticity, attenuates oxidative stress, and inhibits generation of proinflammatory cytokines, EPO may be able to modulate the effects of stress-induced allostatic load at the molecular level. The aim of this study was therefore to investigate how EPO and repeated restraint stress, separately and combined, influence (i) behavior in the novelty-suppressed feeding test of depression/anxiety-related behavior; (ii) mRNA levels of genes encoding proteins involved in synaptic plasticity, angiogenesis, oxidative stress, and inflammation; and (iii) remodeling of the dendritic structure of the CA3c area of the hippocampus in male rats. As expected, chronic restraint stress lowered the number of CA3c apical dendritic terminals, and EPO treatment reversed this effect. Interestingly, these effects seemed to be mechanistically distinct, as stress and EPO had differential effects on gene expression. While chronic restraint stress lowered the expression of spinophilin, tumor necrosis factor α, and heat shock protein 72, EPO increased expression of hypoxia-inducible factor-2α and lowered the expression of vascular endothelial growth factor in hippocampus. These findings indicate that the effects of treatment with EPO follow different molecular pathways and do not directly counteract the effects of stress in the hippocampus.

Topics: Animals; CA3 Region, Hippocampal; Chronic Disease; Dendrites; Erythropoietin; Gene Expression; Inflammation; Male; Neovascularization, Pathologic; Neuronal Plasticity; Oxidative Stress; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stress, Psychological

Inhibition of microglial over-activation is an important strategy to counter balance neurodegenerative progression. We previously demonstrated that the adenosine monophosphate-activated protein kinase (AMPK) may be a therapeutic target in mediating anti-neuroinflammatory responses in microglia. Brain-derived neurotrophic factor (BDNF) is one of the major neurotrophic factors produced by astrocytes to maintain the development and survival of neurons in the brain, and have recently been shown to modulate homeostasis of neuroinflammation. Therefore, the present study focused on BDNF-mediated neuroinflammatory responses and may provide an endogenous regulation of neuroinflammation. Among the tested neuroinflammation, epigallocatechin gallate (EGCG) and minocycline exerted BDNF upregulation to inhibit COX-2 and proinflammatory mediator expressions. Furthermore, both EGCG and minocycline upregulated BDNF expression in microglia through AMPK signaling. In addition, minocycline and EGCG also increased expressions of erythropoietin (EPO) and sonic hedgehog (Shh). In the endogenous modulation of neuroinflammation, astrocyte-conditioned medium (AgCM) also decreased the expression of COX-2 and upregulated BDNF expression in microglia. The anti-inflammatory effects of BDNF were mediated through EPO/Shh in microglia. Our results indicated that the BDNF-EPO-Shh novel-signaling pathway underlies the regulation of inflammatory responses and may be regarded as a potential therapeutic target in neurodegenerative diseases. This study also reveals a better understanding of an endogenous crosstalk between astrocytes and microglia to regulate anti-inflammatory actions, which could provide a novel strategy for the treatment of neuroinflammation and neurodegenerative diseases.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Brain-Derived Neurotrophic Factor; Catechin; Cell Line; Culture Media, Conditioned; Cyclooxygenase 2; Erythropoietin; Hedgehog Proteins; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharides; Mice; Microglia; Minocycline; Models, Biological; Neuroprotective Agents; Signal Transduction

Because anemia of inflammation is common in ICU patients and hepcidin is the key regulator of iron homeostasis, we examined time-dependent changes in hepcidin, erythropoietin, iron, and inflammatory markers in surgical ICU patients with anemia.. Prospective single-center clinical noninterventional study.. Surgical ICUs; U.S. university hospital.. One hundred surgical adult ICU patients.. Time-dependent changes in serum hepcidin, hematologic, and erythropoietic studies were performed on ICU admission and at serial time-points through day 28, and correlated with hematologic and iron parameters and inflammatory response. Median serum hepcidin levels were significantly increased at ICU admission and decreased over time (144-36 ng/mL; p < 0.0001). Despite increased reticulocyte counts (1.3-2.9%), mean serum erythropoietin levels remained low (29-44 mU/mL) and hemoglobin did not significantly change. Hepcidin was positively correlated with RBC transfusion, C-reactive protein, interleukin-6, ferritin, and negatively correlated with iron, total iron binding capacity, transferrin, and reticulocyte response. Hepcidin did not correlate with tumor necrosis factor-α serum concentrations. Regression analyses confirmed that ferritin, C-reactive protein, and reticulocyte number were predictive of same-day hepcidin; hepcidin and C-reactive protein were predictive of same-day reticulocyte count.. Hepcidin serum concentrations are markedly increased on ICU admission, and decrease significantly over the course of the ICU stay (28 d). Decreased hepcidin concentrations are associated with increased reticulocyte response and decreased inflammatory response reflected by decreased interleukin-6 and C-reactive protein concentrations, but not with anemia resolution.

Topics: Aged; Anemia; Biomarkers; Critical Care; Erythropoietin; Female; Hepcidins; Humans; Inflammation; Iron; Male; Middle Aged; Prospective Studies; Surgical Procedures, Operative

Systemic lupus erythematosus (SLE) is an autoimmune disease, which results in various organ pathologies. However, current treatment towards SLE is suboptimal. Erythropoietin (EPO) has been shown to promote SLE recovery, but clinical application can be limited by its haematopoiesis-stimulating effects. EPO-derived helix-B peptide (ARA290) is non-erythrogenic but has been reported to retain the anti-inflammatory and tissue-protective functions of EPO. Therefore, here we investigated the effects and potential mechanisms of ARA290 on SLE. The administration of ARA290 to pristane-induced SLE and MRL/lpr mice significantly suppressed the level of serum antinuclear autoantibodies (ANAs) and anti-dsDNA autoantibodies, reduced the deposition of IgG and C3, and ameliorated the nephritis symptoms. Moreover, the serum concentrations of inflammatory cytokine IL-6, MCP-1 and TNF-α in SLE mice were reduced by ARA290. Further, ARA290 decreased the number of apoptotic cells in kidney. In vitro experiment revealed that ARA290 inhibited the inflammatory activation of macrophages and promoted the phagocytotic function of macrophages to apoptotic cells. Finally, ARA290 did not induce haematopoiesis during treatment. In conclusion, ARA290 ameliorated SLE, which at least could be partly due to its anti-inflammatory and apoptotic cell clearance promoting effects, without stimulating haematopoiesis, suggesting that ARA290 could be a hopeful candidate for SLE treatment.

Topics: Animals; Cytokines; Disease Models, Animal; Erythropoietin; Female; Hematopoiesis; Inflammation; Kidney; Lupus Erythematosus, Systemic; Macrophage Activation; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Oligopeptides; Phagocytosis; RAW 264.7 Cells; Terpenes

The role of hepcidin in iron homeostasis in preeclamptic pregnant women is unclear. To test the hypothesis that increased serum iron in women diagnosed with preeclampsia results from decreased production of hepcidin, we performed an observational case-control study in which serum hepcidin concentration, dietary iron intake, hematological indices, iron status, liver function, and inflammatory markers in 18 preeclamptic women and 18 healthy normotensive pregnant women of similar age range were evaluated. Iron intake was established via a food frequency questionnaire, whereas hematological indices, iron status, liver function, and inflammatory markers were assessed using standard protocols. Hematocrit was significantly higher (P = .031) in the preeclamptic group compared with the control, whereas erythropoietin level was significantly lower (P = .003). The pronounced inflammatory status of preeclamptic women was confirmed by significantly higher concentrations of interleukin-6 (P = .001), tumor necrosis factor-α (P < .001), and ferritin (P < .001). Nonetheless, the preeclamptic group exhibited significantly higher serum iron (P = .012) and transferrin saturation (P = .006), and these alterations were accompanied by lower hepcidin levels (P = .047). No significant correlations between hepcidin concentration and iron status parameters were observed in either group. However, a positive and significant correlation between hepcidin concentration and C-reactive protein was observed in the preeclamptic group (r = 0.474; P = .047). We conclude that high serum iron in preeclamptic women is likely caused by low production of hepcidin, thus supporting the hypothesis originally stated.

Topics: Adolescent; Adult; C-Reactive Protein; Case-Control Studies; Diet Surveys; Erythropoietin; Female; Ferritins; Hematocrit; Hepcidins; Homeostasis; Humans; Inflammation; Interleukin-6; Iron; Iron Overload; Iron, Dietary; Nutritional Status; Pre-Eclampsia; Pregnancy; Transferrin; Tumor Necrosis Factor-alpha; Young Adult

The mechanism underlying the anti‑inflammatory or antifibrotic activity of erythropoietin (EPO) in myocardial fibrosis (MF) remains elusive. In the current study, abdominal aortic constriction (AAC) was performed on rats and EPO and/or Toll‑like receptor (TLR)4 were overexpressed in rat hearts through intramyocardial administration of lentivirus expressing the EPO and TLR4 genes. Hematoxylin and eosin staining and Masson's trichrome staining were performed on tissue sections from rat hearts for histopathological examination. ELISA was used to determine the levels of inflammatory mediators in serum. Gene expression levels were determined by quantitative polymerase chain reaction analysis and protein expression levels were determined by western blot analysis and immunofluorescence staining. The results indicated that EPO overexpression improved MF in rat hearts, by inhibiting the release of transforming growth factor (TGF)‑β1, tumor necrosis factor (TNF)‑α, interleukin (IL)‑6, IL‑1β, IL‑17A, matrix metalloproteinase (MMP)‑9 and MMP‑2. Moreover, EPO overexpression suppressed the expression of TLR4, while promoting phosphoinositide 3‑kinase (PI3K) and phosphorylated AKT serine/threonine kinase 1 (Akt) expression levels. However, the beneficial effects of EPO were attenuated by overexpression of TLR4. In addition, inhibition of PI3K/Akt signaling activity by treatment with LY294002 markedly reversed the protective effect of EPO on the AAC‑induced MF. Taken together, the present study demonstrated that EPO may have a critical role against MF by activating PI3K/Akt signaling and by downregulating TLR4 expression, thereby inhibiting the release of TGF‑β1, TNF‑α, IL‑6, IL‑1β, IL‑17A, MMP‑9 and MMP‑2. These findings suggest that the PI3K/Akt/TLR4 signaling pathway is associated with the anti‑inflammatory effects of EPO and may play a role in attenuating AAC‑induced MF.

Topics: Animals; Cardiomegaly; Cytokines; Erythropoietin; Fibrosis; Gene Expression Regulation; Inflammation; Inflammation Mediators; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardium; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Toll-Like Receptor 4; Transforming Growth Factor beta1

An increasing body of data has shown that erythropoietin (EPO) plays multiple roles in inflammation control and immunoregulation. However, less attention has been given to its effects on lupus nephritis (LN). In this study, we investigated the therapeutic effects of EPO on LN in MRL/lpr mice, a well-studied animal model for lupus. MRL/lpr mice were randomly divided into an EPO and control group. Mice in the EPO group were treated with EPO; saline was given to the control group. Both groups were treated for 10 weeks. We analyzed the differences of general disease condition, histopathologic changes, Th lymphocytes subsets, and the expression of inflammatory factors of mice between the groups. Compared to the control group, mice in the EPO group showed less spleen hyperplasia, less urinary protein, and lower serum anti-dsDNA antibody; they also had lower renal histopathologic scores and less deposition of IgG/C3 within glomeruli. Moreover, Th1 and Th17 levels were decreased, while Th2 and Treg levels were increased in the spleen, and the expression of inflammatory cytokines decreased in both the spleen and kidneys. EPO increased Th2 and Treg lymphocytes, decreased Th1, Th17 lymphocytes in the spleen, and inhibited the inflammatory reactions in both the spleen and kidneys, thus ameliorating LN of MRL/lpr mice.

Topics: Animals; Cytokines; Erythropoietin; Inflammation; Kidney; Lupus Nephritis; Mice; Mice, Inbred MRL lpr; Proteinuria; Spleen; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

Erythropoietin (EPO), which is clinically used for renal anaemia, reportedly exerts beneficial pleiotropic effects in atherosclerosis. This aim of this study was to investigate the effects of EPO on macrophage inflammation and polarization under hyperglycaemic conditions and to identify the effects of EPO-treated macrophage supernatants (SNs) on endothelial cell (EC) function.. Peritoneal macrophages (pMΦs) were isolated from normal, diabetic or EPO-injected mice. Pro-inflammatory factors were detected by qRT-PCR and ELISA, and macrophage phenotype markers were evaluated by flow cytometry. High glucose culture was used to mimic the hyperglycaemic microenvironment of diabetes mellitus (DM) in vitro. After exposure to various doses of stimuli, macrophage inflammation and phenotype were detected via ELISA, qRT-PCR and flow cytometry. The underlying mechanism was investigated through western blotting. To examine the communication between macrophages and ECs, ECs were cultured with the SN of macrophages treated with different stimuli, and the tube formation ability of ECs was detected using Matrigel. The VEGF, ICAM-1 and VCAM-1 protein expression levels were determined by western blotting, and the nitric oxide (NO) and endothelin-1 (ET-1) expression levels were measured with a nitric oxide indicator and by ELISA, respectively.. EPO treatment increased the M2 macrophage population and decreased the number of M1 macrophages. EPO decreased the secretion of pro-inflammatory factors, including TNF-α, iNOS and IL-6. The JAK2/STAT3 signalling pathway was also identified as being involved in the M1 macrophage transition. The SN of macrophages treated with EPO (SN-EPO) presented increased NO and ET-1 levels and decreased ICAM-1 and VCAM-1 levels. Tube formation assays revealed that the SN-EPO promoted the ability of ECs to form capillary-like structures in vitro. In contrast, AZD1480, a JAK2 inhibitor, abolished this SN-EPO effect.. EPO treatment alleviated the inflammatory reaction in DM mice and inhibited M1 polarization through the JAK2/STAT3 pathway. Moreover, EPO treatment promoted the tube formation ability of ECs in a VEGF-dependent manner and decreased the production of adhesion molecules, a vasodilator and a vasoconstrictor.

Topics: Animals; Cell Polarity; Diabetes Mellitus; Erythropoietin; Humans; Hyperglycemia; Inflammation; Intercellular Adhesion Molecule-1; Janus Kinase 2; Macrophages; Macrophages, Peritoneal; Male; Mice, Inbred C57BL; Neovascularization, Physiologic; Phenotype; Signal Transduction; STAT3 Transcription Factor; Vascular Cell Adhesion Molecule-1

Acute kidney injury (AKI) is a frequent complication of sepsis, with a high mortality. Hallmarks of septic-AKI include inflammation, endothelial injury, and tissue hypoxia. Therefore, it would be of interest to develop therapeutic approaches for improving the microvascular damage in septic-AKI. Erythropoietin (EPO) is a well-known cytoprotective multifunctional hormone. Thus, the aim of this study was to evaluate the protective effects of EPO on microvascular injury in a murine model of endotoxemic AKI. Male Balb/c mice were divided into four groups: control, LPS (8 mg/kg, ip.), EPO (3000 IU / kg, sc.) and LPS + EPO. A time course study (0-48 h) was designed. Experiments include, among others, immunohistochemistry and Western blottings of hypoxia-inducible transcription factor (HIF-1α), erythropoietin receptor (EPO-R), vascular endothelial growth factor system (VEGF/VEGFR-2), platelet and endothelial adhesion molecule-1 (PeCAM-1), inducible nitric oxide synthase (iNOS) and phosphorylated nuclear factor kappa B p65 (NF-κB). Data showed that EPO attenuates renal microvascular damage during septic-AKI progression through a) the decrease of HIF-1 alpha, iNOS, and NF-κB and b) the enhancement of EPO-R, PeCAM-1, VEGF, and VEGFR-2 expression. In summary, EPO renoprotection involves the attenuation of septic-induced renal hypoxia and inflammation as well as ameliorates the endotoxemic microvascular injury.

Topics: Acute Kidney Injury; Animals; Blotting, Western; Disease Models, Animal; Disease Progression; Endotoxemia; Erythropoietin; Immunohistochemistry; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Microvessels; Sepsis; Time Factors

We studied the expression of Hif-1α, Nf-κb, and Vegf genes in the liver and serum levels of HIF-1α, erythropoietin, VEGF, TGF-β, 8-isoprostane, and corticosterone in Wistar rats with different resistance to hypoxia in 5 and 90 min after acute exposure to hypobaric hypoxia. In 5 min after hypoxic exposure, Hif-1α expression in the liver and serum levels of erythropoietin, VEGF, and TGF-β in high-resistant rats were higher than in low-resistant animals. In highresistant rats, the increment in expression of Nf-κb gene responsible for the control over the inflammatory processes was more pronounced than in low-resistant animals. In 90 min after hypoxic exposure, the serum levels of HIF-1α, erythropoietin, VEGF, and TGF-β returned to normal in high-resistant rats, while in low-resistant animals, an increase in 8-isoprostane and TGF-β concentrations was observed. The rats with different resistance to hypoxia were characterized by different changes in biomolecular parameters determining predilection to inflammatory diseases.

Topics: Animals; Corticosterone; Dinoprost; Erythropoietin; Gene Expression Profiling; Gene Expression Regulation; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Liver; Male; NF-kappa B; Rats; Rats, Wistar; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Anemia is a common feature in critically ill patients. Serum soluble-Fas (sFas) levels are associated with anemia in chronic kidney disease. It is possible that sFas levels are also associated with anemia in acute kidney injury (AKI) patients. The study aims to investigate the relationship between serum levels of sFas, erythropoietin (Epo), inflammatory cytokines, and hemoglobin (Hb) concentration in critically ill patients with AKI. We studied 72 critically ill patients with AKI (AKI group; n = 53) or without AKI (non-AKI group; n = 19), and 18 healthy volunteers. Serum sFas, Epo, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-10, iron status, and Hb concentration were analyzed in all groups. We also investigated the correlation between these variables in the AKI group. Critically ill patients (AKI and non-AKI groups) had higher serum levels of Epo than healthy volunteers. Hb concentration was lower in the AKI group than in the other groups. Serum sFas, IL-6, TNF-α, and ferritin levels were higher in the AKI group. Hb concentration correlated negatively with serum IL-6 (r = -0.37, P = 0.008), sFas (r = -0.35, P = 0.01), and Epo (r = -0.27, P = 0.04), while serum sFas correlated positively with iron levels (r = 0.36, P = 0.008) and IL-6 (r = 0.28, P = 0.04) in the AKI group. In multivariate analysis, after adjusting for markers of inflammation and iron stores, only serum sFas levels (P = 0.03) correlated negatively with Hb concentration in the AKI group. Serum Epo and inflammatory cytokine levels are elevated in critically ill patients with or without AKI. Serum levels of sFas are elevated and independently associated with anemia in critically ill patients with AKI.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Cytokines; Erythropoietin; fas Receptor; Female; Humans; Inflammation; Inflammation Mediators; Male; Middle Aged

Salidroside is being investigated for its therapeutic potential in stroke because it is neuroprotective over an extended therapeutic window of time. In the present study, we investigated the mechanisms underlying the anti-inflammatory effects of salidroside (50 mg/kg intraperitoneally) in rats, given 1 h after reperfusion of a middle cerebral artery that had been occluded for 2 h. After 24 h, we found that salidroside increased the neuronal nuclear protein NeuN and reduced the marker of microglia and macrophages CD11b in the peri-infarct area of the brain. Salidroside also decreased IL-6, IL-1β, TNF-α, CD14, CD44, and iNOs mRNAs. At the same time, salidroside increased the ratio of phosphorylated protein kinase B (p-Akt) to total Akt. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 prevented this increase in p-Akt and reversed the inhibitory effects of salidroside on CD11b and inflammatory mediators. Salidroside also elevated the protein levels of hypoxia-inducible factor (HIF) subunits HIF1α, HIF2α, HIF3α, and of erythropoietin (EPO). The stimulatory effects of salidroside on HIFα subunits were blocked by LY294002. Moreover, YC-1, a HIF inhibitor, abolished salidroside-mediated increase of HIF1α and prevented the inhibitory effects of salidroside on CD11b and inflammatory mediators. Taken together, our results provide evidence for the first time that all three HIFα subunits and EPO can be regulated by PI3K/Akt in cerebral tissue, and that salidroside entrains this signaling pathway to induce production of HIFα subunits and EPO, one or more of which mediate the anti-inflammatory effects of salidroside after cerebral IRI.

Topics: Animals; Anti-Inflammatory Agents; Brain Ischemia; Erythropoietin; Glucosides; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Phenols; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Reperfusion Injury; Signal Transduction

Anemia and low-grade inflammation are reported to be associated with impaired long-term graft outcome in renal transplant (RTx) recipients. In this study, hemoglobin (Hb) and inflammation marker levels were correlated with measured glomerular filtration rate (GFR) in 128 pediatric RTx recipients over a median follow-up period of 10 years.. Serum levels of erythropoietin (EPO), hepcidin-25, high-sensitivity C-reactive protein (CRP) (hsCRP) and interleukin-6 (IL-6) were analyzed by enzyme-linked immunosorbent assays, and GFR was analyzed by. The median levels of Hb (115 g/L), hsCRP (0.4 mg/L) and IL-6 (1.4 pg/mL) and the median erythrocyte sedimentation rate (ESR; 19 mm/h) remained stable after the first post-operative year. However, approximately half of the patients had a normocytic, normochromic anemia, and one-third had elevated levels of hsCRP (>1 mg/L) and ESR (>25 mm/h), indicating continuous low-grade inflammation. Low Hb levels preceded increased fibrosis in protocol biopsies taken at 1.5 and 3 years after transplantation and preceded decreased GFR by several years. Hb levels showed an inverse correlation with EPO levels (r = -0.206, p = 0.038) and ESR (r = -0.369, p < 0.001), but not with hepcidin-25, hsCRP or IL-6 levels. The levels of the major inflammatory markers IL-6 and hsCRP did not show a significant correlation with GFR at either the early maintenance phase or later. In the multivariable analysis, low Hb levels performed better than any other marker with respect to predicting concomitant and subsequent GFR.. Anemia, but not elevated inflammatory indices, was associated with poor concomitant and subsequent graft function during a 10-year follow-up in pediatric RTx patients.

Topics: Anemia; Biomarkers; C-Reactive Protein; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Glomerular Filtration Rate; Hepcidins; Humans; Infant; Inflammation; Interleukin-6; Kidney Transplantation; Longitudinal Studies; Male

The erythropoiesis in hepatitis C virus infection is unclear. We aimed to evaluate the erythropoietic components in chronic hepatitis C (CHC) patients.. The red blood cell (RBC) components, serum erythropoietin (EPO) levels, and their relationship to clinical characteristics were evaluated between 124 age-matched and sex-matched healthy controls and 248 histology-proven CHC patients.. Chronic hepatitis C patients had significantly higher serum levels of EPO (1.44 ± 0.36 log mIU/mL versus 1.03 ± 0.31 log mIU/mL, P < 0.0001) and lower hemoglobin (Hb) concentrations (14.6 ± 1.4 g/dL versus 15.3 ± 1.2 g/dL, P < 0.001) as compared with healthy controls. Among the CHC patients, the serum EPO level was negatively associated with the Hb concentration (β = -0.227; 95% confidence intervals [CI]: -0.09-0.027; P < 0.001) and RBC counts (β = -0.204; 95% CI: -0.245-0.061; P = 0.001) and was positively correlated with necroinflammatory activity (β = 0.201; 95% CI: 0.009-0.046; P = 0.003) and fibrosis (β = 0.143; 95% CI: 0.003-0.076; P = 0.04) of liver histopathology. For non-cirrhotic CHC patients, the severity of liver necroinflammatory activity was positively correlated with the reticulocyte and serum EPO levels (P = 0.001 and 0.008, respectively), and negatively related to the RBC counts (P = 0.03). Using stepwise multivariate linear regression analysis, the grade of necroinflammatory activity was positive (β = 0.214; 95% CI: 0.046-0.209, P = 0.002), whereas the Hb concentration was inversely (β = -0.205; 95% CI: -0.09-0.018, P = 0.004) associated with the serum EPO levels in CHC patients.. The disease activity in CHC patients had a negative impact on erythropoiesis with compensatory higher but blunted EPO responses.

Topics: Adult; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Fibrosis; Hemoglobins; Hepatitis C, Chronic; Humans; Inflammation; Liver; Male; Middle Aged; Severity of Illness Index

To evaluate whether in children born extremely preterm, indicators of sustained systemic inflammation in the first month of life are associated with cognitive impairment at school age.. A total of 873 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborn Study from 2002 to 2004 were evaluated at age 10 years. We analyzed the relationship between elevated blood concentrations of inflammation-associated proteins in the first 2 weeks ("early elevations"; n = 812) and the third and fourth week ("late elevations"; n = 532) of life with neurocognition.. Early elevations of C-reactive protein, tumor necrosis factor-α, interleukin (IL)-8, intercellular adhesion molecule (ICAM)-1, and erythropoietin were associated with IQ values >2 SD below the expected mean (ORs: 2.0-2.3) and with moderate to severe cognitive impairment on a composite measure of IQ and executive function (ORs: 2.1-3.6). Additionally, severe cognitive impairment was associated with late protein elevations of C-reactive protein (OR: 4.0; 95% CI 1.5, 10), IL-8 (OR: 5.0; 1.9, 13), ICAM-1 (OR: 6.5; 2.6, 16), vascular endothelial growth factor-receptor 2 (OR: 3.2; 1.2, 8.3), and thyroid-stimulating hormone (OR: 3.1; 1.3, 7.3). Moderate cognitive impairment was most strongly associated with elevations of IL-8, ICAM-1, and vascular endothelial growth factor-receptor 2. When 4 or more inflammatory proteins were elevated early, the risk of having an IQ <70 and having overall impaired cognitive ability was more than doubled (ORs: 2.1-2.4); the presence of 4 or more inflammatory protein elevated late was strongly linked to adverse cognitive outcomes (ORs: 2.9-4.8).. Extremely preterm children who had sustained elevations of inflammation-related proteins in the first postnatal month are more likely than extremely preterm peers without such elevations to have cognitive impairment at 10 years.

Topics: C-Reactive Protein; Child; Cognitive Dysfunction; Erythropoietin; Female; Humans; Infant, Extremely Premature; Infant, Newborn; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Male; Prospective Studies; Vascular Endothelial Growth Factor A

The rise in serum ferritin levels among US maintenance hemodialysis patients has been attributed to higher intravenous iron administration and other changes in practice. We examined ferritin trends over time in hemodialysis patients and whether iron utilization patterns and other factors [erythropoietin-stimulating agent (ESA) prescribing patterns, inflammatory markers] were associated with ferritin trajectory.. In a 5-year (January 2007–December 2011) cohort of 81 864 incident US hemodialysis patients, we examined changes in ferritin averaged over 3-month intervals using linear mixed effects models adjusted for intravenous iron dose, malnutrition and inflammatory markers. We then examined ferritin trends across strata of baseline ferritin level, dialysis initiation year, cumulative iron and ESA use in the first dialysis year and baseline hemoglobin level.. In models adjusted for iron dose, malnutrition and inflammation, mean ferritin levels increased over time in the overall cohort and across the three lower baseline ferritin strata. Among patients initiating dialysis in 2007, mean ferritin levels increased sharply in the first versus second year of dialysis and again abruptly increased in the fifth year independent of iron dose, malnutrition and inflammatory markers; similar trends were observed among patients who initiated dialysis in 2008 and 2009. In analyses stratified by cumulative iron use, mean ferritin increased among groups receiving iron, but decreased in the no iron group. In analyses stratified by cumulative ESA dose and baseline hemoglobin, mean ferritin increased over time.. While ferritin trends correlated with patterns of iron use, increases in ferritin over time persisted independent of intravenous iron and ESA exposure, malnutrition and inflammation.

Topics: Administration, Intravenous; Aged; Biomarkers; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Longitudinal Studies; Male; Malnutrition; Middle Aged; Renal Dialysis

Erythropoietin (EPO), a hematopoietic hormonal cytokine induced in response to hypoxia, has neuroprotective effects. EPO receptor (EPOR) is expressed in microglia, resident immune cells in the brain. However, the effect of EPO on microglial activation is not clear. In the present study, we demonstrated that the EPOR is highly expressed in microglia, rather than in neurons or astrocytes, in in vitro experiments. Therefore, we investigated whether EPO could attenuate lipopolysaccharide (LPS)-mediated activation of microglia in vitro. The BV-2 microglial cell line was treated with LPS in the absence or presence of EPO. In the presence of EPO, microglial expression of LPS-induced inflammatory cytokine genes was significantly decreased. In addition, EPO suppressed the LPS-induced phagocytic activity of BV-2 cells towards fluorescent beads, as well as induction of inducible nitric oxide synthase. In in vivo experiments, EPO significantly decreased the LPS-induced expression of inflammatory cytokine genes in mouse brains. Furthermore, morphological analysis of cortical microglia in the brains of mice stimulated with LPS revealed that combined treatment with EPO alleviated LPS-induced morphological changes in the microglia. These data indicate that EPO attenuates microglial activation, including morphological changes in vivo, phagocytosis in vitro, and the production of inflammatory cytokines in vivo and in vitro. Further investigation of EPO modulation of LPS-induced microglial activation may contribute to the development of novel neuroprotective therapies.

Topics: Animals; Astrocytes; Brain; Cell Culture Techniques; Cytokines; Erythropoietin; Inflammation; Lipopolysaccharides; Macrophage Activation; Mice; Microglia; Neurons; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase Type II; Phagocytosis; Rats; Receptors, Erythropoietin

A common complication in patients undergoing peritoneal dialysis (PD) is a chronic inflammatory state and anemia that can be treating by recombinant human erythropoietin (rHuEPO). Higher required dose of rHuEPO could be expected in patients with higher cytokine levels. Additionally, it is known that peritoneal inflammation can be correlated with systemic inflammation and this could contribute to the compromised rHuEPO required dose in anemic patients with end stage renal disease (ESRD). Thus, the current study aimed to evaluate the association between levels of systemic and local interferon (IFN)-γ, interleukin (IL)-17 and other cytokines and the dose of rHuEPO used by patients undergoing PD for the correction of anemia.. Thirty-one patients under PD using rHuEPO were evaluated in this cross-sectional study. Plasma and dialysate levels of IL-2, IL-4, IL-6, IL-10, IL-17, tumour necrosis factor (TNF)-α and IFN-γ were determined using the Cytometric Bead Array TM kit (CBA; BD Bioscences, San Jose, CA). The relation between the levels of each cytokine levels and the tertiles of rHuEPO were plotted on box-plot graphics and then the medians of interleukins levels were compared by median comparison test. The significance level adopted was 5% and the analysis was performed by the softwares STATA (version 12.0) and GraphPad Prism 3.0.. The median of IL-17 and IFN-γ plasma levels were significant higher in the group with higher rHuEPO dosage. However, this association was not observed in the dialysate levels, as well as was not observed a relationship between the other plasma and dialysate cytokines evaluated in this study and the dose of rHuEPO.. Our study found increased IL-17 and IFN-γ plasma, but no dialysate levels, in patients receiving higher doses of rHuEPO, suggesting may exist a relationship between systemic inflammation of ESRD, and the necessary levels of rHuEPO for the correction of anemia in these patients.

Topics: Aged; Anemia; Cross-Sectional Studies; Cytokines; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Inflammation; Interferon-gamma; Interleukin-17; Male; Middle Aged; Peritoneal Dialysis; Renal Insufficiency, Chronic

It is known that inadequate erythropoietin (EPO) production contributes to the pathogenesis of anemia of inflammation, although the exact molecular mechanism is unknown. Aryl hydrocarbon receptor (AhR) may compete with hypoxia-inducible factor 2α (HIF-2α), the master regulator of EPO production, for binding with HIF-1β. The effect of kynurenine, an endogenous AhR activator that increases in inflammation, on EPO and hepcidin production was evaluated. HepG2 cells were treated with the hypoxia mimetic CoCl2, kynurenine, the AhR inhibitor CH223191, and combinations of these. EPO and hepcidin production was measured with enzyme-linked immunosorbent assay. HIF-2α and CYP1A1 levels, a transcriptional target of AhR, were assessed by Western blotting. CoCl2 increased EPO production and decreased hepcidin and CYP1A1. Kynurenine exerted the opposite effects. Wherever CH223191 was added, the inhibitor overcorrected kynurenine-induced alterations in both the presence and the absence of CoCl2. Also, treatment with CH223191 alone increased EPO and decreased hepcidin, indicating that there is a degree of constitutive AhR activation, possibly by other endogenous AhR activators. In conclusion, kynurenine, by competing with HIF-2α, may contribute to anemia of inflammation by decreasing EPO and increasing hepcidin production. The fact that inactivation of AhR alone induces EPO makes this transcription factor a potential therapeutic target in situations that require increased EPO.

Topics: Anemia; Erythropoietin; Hep G2 Cells; Hepcidins; Humans; Inflammation; Kynurenine; Receptors, Aryl Hydrocarbon

Aging is a natural process accompanied with many disorders, including the memory decline. The underlying mechanisms for the age-related memory decline are complicated. Previous work suggested that oxidative stress, inflammatory disturbance, and the neurotropic absence play important roles in the age-related disorders. Thus, to seek a drug to target those abnormalities might be a possible protective approach for aging. Here, we reported that supplements with exogenous erythropoietin (EPO) for 4 weeks could partially rescue the spatial and fear memory impairments in aged rats. The EPO treatment also suppresses the oxidative stress and inflammatory response. Most importantly, EPO supplement restores the mRNA and protein levels of brain-derived neurotrophic factor (BDNF), the critical neurotropic factor for synaptic plasticity and memory. Our study strongly suggests the potential usage of EPO in an anti-aging agent clinically.

Topics: Aging; Animals; Brain; Brain-Derived Neurotrophic Factor; Erythropoietin; Fear; Inflammation; Male; Memory; Memory Disorders; Oxidative Stress; Rats, Wistar

Inflammatory responses play critical roles in carbon monoxide (CO) poisoning-induced cerebral injury. The present study investigated whether erythropoietin (EPO) modulates the toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) inflammatory signaling pathways in brain injury after acute CO poisoning. EPO (2500 and 5000 U/kg) was injected subcutaneously twice a day after acute CO poisoning for 2 days. At 48 h after treatment, the expression levels of TLR4 and NF-κB as well as the levels of inflammatory cytokines in the hippocampal tissues were measured. Our results showed that CO poisoning induced a significant upregulation of TLR4, NF-κB, and inflammatory cytokines in the injured rat hippocampal tissues. Treatment with EPO remarkably suppressed the gene and protein expression levels of TLR4 and NF-κB, as well as the concentrations of TNF-α, IL-1β, and IL-6 in the hippocampal tissues. EPO treatment ameliorated CO poisoning-induced histological edema and neuronal necrosis. These results suggested that EPO protected against CO poisoning-induced brain damage by inhibiting the TLR4-NF-κB inflammatory signaling pathway.

Topics: Animals; Brain Injuries; Carbon Monoxide; Carbon Monoxide Poisoning; Edema; Erythropoietin; Hippocampus; Inflammation; Interleukin-1beta; Interleukin-6; Male; Maze Learning; Necrosis; NF-kappa B; Rats; Rats, Sprague-Dawley; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Acute and severe anemia of inflammation (AI) is a common complication of various clinical syndromes, including fulminant infections, critical illness with multiorgan failure, and exacerbations of autoimmune diseases. Building on recent data showing beneficial results with isocitrate treatment for chronic low-grade AI in a rat model, we used a mouse model of acute and severe AI induced by intraperitoneal heat-killed Brucella abortus to determine if isocitrate would be effective in this more stringent application. Inflamed mice treated with isocitrate developed an early but transient improvement in hemoglobin compared to solvent-treated controls, with a robust improvement on day 7, and only a trend towards improvement by day 14. Reticulocyte counts were increased in treated mice transiently, with no significant difference by day 21. Serum erythropoietin (EPO) levels were similar in treated versus control mice, indicating that isocitrate increased sensitivity to EPO. Serum and tissue iron levels showed no significant differences between the treated and control mice, ruling out improved iron availability as the cause of the increased response to endogenous EPO. Compared to the milder rat model, much higher doses of isocitrate were required for a relatively modest benefit.

Topics: Acute Disease; Anemia; Animals; Brucella abortus; Brucellosis; Disease Models, Animal; Erythropoiesis; Erythropoietin; Hepcidins; Inflammation; Iron; Isocitrates; Male; Mice

Clinical studies showed that high doses of recombinant human erythropoietin (rHuEPO) used to correct anaemia in chronic kidney disease (CKD) hyporesponsive patients may lead to deleterious effects. The aim of this study was to analyze the effects of rHuEPO in doses usually used to correct CKD-anaemia (100, 200 IU/kg body weight (BW) per week) and in higher doses used in the treatment of hyporesponsive patients (400, 600 IU/kg BW per week), focusing on renal damage, hypoxia, inflammation and fibrosis. Male Wistar rats with chronic renal failure (CRF) induced by 5/6 nephrectomy were treated with rHuEPO or with vehicle, over a 3-week period. Haematological, biochemical and renal function analyses were performed. Kidney and liver mRNA levels were evaluated by quantitative real-time polymerase chain reaction (qPCR) and protein expression by Western blot and immunohistochemistry. Kidney histopathological evaluations were also performed. The CRF group developed anaemia, hypertension and a high score of renal histopathologic lesions. Correction of anaemia was achieved with all rHuEPO doses, with improvement in hypertension, renal function and renal lesions. In addition, the higher rHuEPO doses also improved inflammation. Blood pressure was reduced in all rHuEPO-treated groups, compared to the CRF group, but increased in a dose-dependent manner. The current study showed that rHuEPO treatment corrected anaemia and improved urinary albumin excretion, particularly at lower doses. In addition, it is suggested that a short-term treatment with high doses, used to overcome an episode of hyporesponsiveness to rHuEPO therapy, can present benefits by reducing inflammation, without worsening of renal lesions; however, the pro-hypertensive effect should be considered, and carefully managed to avoid a negative cardiorenal impact.

Topics: Anemia; Animals; Blood Pressure; Body Weight; Cell Hypoxia; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Fibrosis; Gene Expression Regulation; Humans; Hypertension; Inflammation; Kidney; Kidney Failure, Chronic; Male; Organ Size; Rats; Recombinant Proteins; Risk; Risk Assessment

AMP activated protein kinase (AMPK) is a pivotal metabolic regulatory enzyme and novel target of controlling inflammation. Our previous studies had demonstrated that 5-amino-4-imidazolecarboxamide riboside (AICAR), an AMPK activator, attenuated lipopolysaccharide (LPS)/D-galactosamine (D-gal)-induced fulminant hepatitis via suppressing inflammatory response. Since inflammation usually activates the coagulation response and aggravates inflammation-induced tissue injury, the present study was to explore the effects of AICAR on inflammation-induced activation of coagulation. Male BALB/c mice received LPS/D-gal intraperitoneal injection were used as fulminant hepatitis model. Western blot was used to detect tissue factor (TF) and hypoxia-inducible factor 1α (HIF-1α) protein expressions in hepatic tissue, as well as nuclear factor kappa B (NF-κB) p65 translocation into the nucleus. Real-time quantitative PCR was used to analyze erythropoietin (EPO) mRNA expression level. Lactic acid (LA) level in hepatic tissue was detected by kit. The results showed that LPS/D-gal induced the enhanced expression of TF, elevation of NF-κB p65 nuclear translocation, up-regulation of HIF-1α and EPO expressions, and increased LA level. These above alterations could be suppressed by AICAR. These results suggest that AICAR may down-regulate LPS/D-gal-induced TF expression (coagulation activity), and relieve hepatic hypoxia and metabolic disorder via suppressing the activity of NF-κB, which may be a novel mechanism of the beneficial effect of AICAR on LPS/D-gal-induced fulminant hepatitis.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Down-Regulation; Erythropoietin; Hepatitis; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Lipopolysaccharides; Male; Mice; NF-kappa B; Thromboplastin; Up-Regulation

The most important cause of anemia in CKD is relative deficiency of erythropoietin (EPO) secretion from the diseased kidney and EPO therapy has become the standard treatment for anemia of CKD. However, some patients do not respond well to erythropoiesis stimulating agent (ESA), so-called ESA resistance. One of the most important causes of ESA resistance is chronic inflammation in hemodialysis (HD) patients. ESA hyporesponsiveness index (EHRI), calculated as the weekly dose of EPO divided by kilograms of body weight divided by the hemoglobin level, and has been considered useful to assess the EPO resistance. Neutrophil/lymphocyte (NLR) ratio and platelet/lymphocyte ratio (PLR) were also found to be associated with inflammation in HD patients. However, the relationship between NLR, PLR and EHRI has not been investigated before. HD patients underwent medical history taking, physical examination, calculation of dialysis adequacy and biochemical analysis and calculation of EHRI. Logarithmically converted EHRI (logEHRI) was correlated only with hemoglobin (r -0.381, P < 0.0001) and PLR (r = 0.227, P = 0.021) but not with NLR. Comparison of PLR among 25th, 50th and 75th percentile of EHRI showed that PLR levels increased going from the 25th to 75(th) percentile (P = 0.032). Posthoc analysis revealed that 25-75th percentile (P = 0.014) and 50-75th percentile (P = 0.033) were different with respect to PLR. In linear regression analysis, PLR (standardized β = 0.296, confidence interval: 0.000-0.001, P = 0.003) was independently associated with logEHRI. We found that PLR was independently associated with EHRI in HD patients. PLR, which is quite a simple and cheap method, may guide clinicians for detecting EPO resistance.

Topics: Aged; Anemia; Blood Platelets; Cross-Sectional Studies; Darbepoetin alfa; Drug Resistance; Erythropoietin; Female; Hematinics; Humans; Inflammation; Linear Models; Lymphocytes; Male; Middle Aged; Neutrophils; Predictive Value of Tests; Renal Dialysis; Renal Insufficiency, Chronic

The anemia of inflammation is a common problem in inflammatory and autoimmune diseases. We characterized a mouse model of anemia of chronic inflammation induced by repeated injections of low doses of heat-killed Brucella abortus (HKBA), and determined the effects of T administration on erythropoiesis in this model. Female C57BL/6NCrl mice were injected weekly with HKBA for 10 wk. Weekly injections of T or vehicle oil were started 4 wk later. Control mice were injected with saline and vehicle oil in parallel. HKBA-injected mice had significantly lower hemoglobin, hematocrit, mean corpuscular volume, reticulocyte hemoglobin, transferrin saturation (TSAT), and tissue nonheme iron in liver and spleen, enlarged spleen, and up-regulated hepatic expression of inflammatory markers, serum amyloid A1, and TNFα, but down-regulated IL-6, bone morphogenic protein 6, and hepcidin compared with saline controls. HKBA also reduced serum hepcidin and increased serum erythropoietin. Bone marrow erythroid precursors were substantially reduced in HKBA-injected mice. Cotreatment with T increased the percentage of late-stage erythroid precursors in the bone marrow relative to HKBA-injected and saline controls and reversed HKBA-induced suppression of hemoglobin and hematocrit. T also normalized serum erythropoietin, TSAT, and reticulocyte hemoglobin without correcting the expression of the hepatic inflammation markers. Conclusions are that low-dose HKBA induces moderate anemia characterized by chronic inflammation, decreased iron stores, and suppression of erythroid precursors in the bone marrow. T administration reverses HKBA-induced anemia by stimulating erythropoiesis, which is associated with a shift toward accelerated maturation of erythroid precursors in the bone marrow.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Estradiol; Female; Hemoglobins; Inflammation; Mice; Mice, Inbred C57BL; Testosterone

Stroke is associated with neuroinflammation, neuronal loss and blood-brain barrier (BBB) breakdown. Thus far, recombinant tissue-type plasminogen activator (rtPA), the only approved treatment for acute ischemic stroke, increases the risk of intracerebral hemorrhage and is poorly efficient in disaggregating platelet-rich thrombi. Therefore, the development of safer and more efficient therapies is highly awaited. Encouraging neuroprotective effects were reported in mouse models of ischemic stroke following administration of erythropoietin (EPO). However, previous preclinical studies did not investigate the effects of EPO in focal ischemic stroke induced by a platelet-rich thrombus and did not consider the implication of age. Here, we performed middle cerebral artery occlusion by inducing platelet-rich thrombus formation in chimeric 5- (i.e. young) and 20- (i.e. aged) months old C57BL/6 mice, in which hematopoietic stem cells carried the green fluorescent protein (GFP)-tag. Recombinant human EPO (rhEPO) was administered 24 hours post-occlusion and blood-circulating monocyte populations were studied by flow cytometry 3 hours post-rhEPO administration. Twenty-four hours following rhEPO treatment, neuronal loss and BBB integrity were assessed by quantification of Fluoro-Jade B (FJB)-positive cells and extravasated serum immunoglobulins G (IgG), respectively. Neuroinflammation was determined by quantifying infiltration of GFP-positive bone marrow-derived cells (BMDC) and recruitment of microglial cells into brain parenchyma, along with monocyte chemotactic protein-1 (MCP-1) brain protein levels. Here, rhEPO anti-inflammatory properties rescued ischemic injury by reducing neuronal loss and BBB breakdown in young animals, but not in aged littermates. Such age-dependent effects of rhEPO must therefore be taken into consideration in future studies aiming to develop new therapies for ischemic stroke.

Topics: Age Factors; Animals; Blood-Brain Barrier; Brain; Brain Ischemia; Chemokine CCL2; Disease Models, Animal; Erythropoietin; Flow Cytometry; Green Fluorescent Proteins; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Cerebral Artery; Neuroprotective Agents; Recombinant Proteins; Stroke; Thrombosis

Inflammation resolution is an active process, the failure of which causes uncontrolled inflammation which underlies many chronic diseases. Therefore, endogenous pathways that regulate inflammation resolution are fundamental and of wide interest. Here, we demonstrate that phagocyte respiratory burst-induced hypoxia activates macrophage erythropoietin signalling to promote acute inflammation resolution. This signalling is activated following acute but not chronic inflammation. Pharmacological or genetical inhibition of the respiratory burst suppresses hypoxia and macrophage erythropoietin signalling. Macrophage-specific erythropoietin receptor-deficient mice and chronic granulomatous disease (CGD) mice, which lack the capacity for respiratory burst, display impaired inflammation resolution, and exogenous erythropoietin enhances this resolution in WT and CGD mice. Mechanistically, erythropoietin increases macrophage engulfment of apoptotic neutrophils via PPARγ, promotes macrophage removal of debris and enhances macrophage migration to draining lymph nodes. Together, our results provide evidences of an endogenous pathway that regulates inflammation resolution, with important implications for treating inflammatory conditions.

Topics: Animals; Cell Movement; Erythropoietin; Hypoxia; Inflammation; Lymph Nodes; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout; Phagocytosis; PPAR gamma; Receptors, Erythropoietin; Respiratory Burst; Signal Transduction

Anemia is associated commonly with acute and chronic inflammation, but the mechanisms of their interaction are not clear. We investigated whether microRNA 122 (MIR122), which is generated in the liver and is secreted into the blood, is involved in the development of anemia associated with inflammation.. We characterized the primary transcript of the human liver-specific MIR122 using Northern blot, quantitative real-time polymerase chain reaction, and 3' and 5' rapid amplification of cDNA ends analyses. We studied regulation of MIR122 in human hepatocellular carcinoma cell lines (Huh7 and HepG2) as well as in C57BL/6 and mice with disruption of the tumor necrosis factor (Tnf) gene. Liver tissues were collected and analyzed by bioluminescence imaging or immunofluorescence. Inflammation in mice was induced by lipopolysaccharide (LPS) or by cerulein injections. Mice were given 4 successive injections of LPS, leading to inflammation-induced anemia. Steatohepatitis was induced with a choline-deficient, high-fat diet. Hemolytic anemia was stimulated by phenylhydrazine injection. MIR122 was inhibited in mice by tail-vein injection of an oligonucleotide antagonist of MIR122. MicroRNA and messenger RNA levels were determined by quantitative real-time polymerase chain reaction.. The primary transcript of MIR122 spanned 5 kb, comprising 3 exons; the third encodes MIR122. Within the MIR122 promoter region we identified a nuclear factor-κB binding site and showed that RELA (NF-κB p65 subunit), as well as activators of NF-κB (TNF and LPS), increased promoter activity of MIR122. Administration of LPS to mice induced secretion of MIR122 into blood, which required TNF. Secreted MIR122 reached the kidney and reduced expression of erythropoietin (Epo), which we identified as a MIR122 target gene. Injection of mice with an oligonucleotide antagonist of MIR122 increased blood levels of EPO, reticulocytes, and hemoglobin. We found an inverse relationship between blood levels of MIR122 and EPO in mice with acute pancreatitis or steatohepatitis, and also in patients with acute inflammation.. In mice, we found that LPS-induced inflammation increases blood levels of MIR122, which reduces expression of Epo in the kidney; this is a mechanism of inflammation-induced anemia. Strategies to block MIR122 in patients with inflammation could reduce the development or progression of anemia.

Topics: Anemia; Animals; Biomarkers; Blotting, Northern; Erythropoietin; Female; Hep G2 Cells; Humans; Inflammation; Kidney; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Real-Time Polymerase Chain Reaction

Little attention has been placed on the unique iron demands that may exist in women with multiple gestations. This merits attention because iron deficiency (ID) during pregnancy is associated with adverse pregnancy outcomes that are known to be more prevalent in multiple births.. We characterized longitudinal changes in iron status across pregnancy in a cohort of healthy women with multiple gestations and identified determinants of maternal ID and anemia.. A group of 83 women carrying twins, triplets, or quadruplets (aged 20-46 y) was recruited from 2011 to 2014. Blood samples obtained during pregnancy (∼24 wk; n = 73) and at delivery (∼35 wk; n = 61) were used to assess hemoglobin, serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, serum iron, erythropoietin, serum folate, vitamin B-12, C-reactive protein, and interleukin-6.. The prevalence of tissue ID (sTfR >8.5 mg/L) increased significantly from pregnancy to delivery (9.6% compared with 23%, P = 0.03). Women with depleted iron stores (SF <12 μg/L, n = 20) during pregnancy had a 2-fold greater risk of anemia at delivery, and 25% (n = 5) developed iron deficiency anemia (IDA). Overall, 44.6% of women studied (n = 37/83) were anemic at delivery, and 18% of women (n = 11/61) had IDA. Erythropoietin during pregnancy was significantly negatively associated with hemoglobin at delivery. Women with erythropoietin >75th percentile during pregnancy exhibited a 3-fold greater risk of anemia, suggesting that erythropoietin is a sensitive predictor of anemia at delivery. Inflammation was present at delivery, which limited the utility of ferritin or hepcidin as iron-status indicators at delivery.. ID and anemia are highly prevalent in women with multiple gestations. Additional screening and iron supplementation may be warranted in this high-risk population given the known associations between ID anemia and adverse maternal and neonatal outcomes. This trial was registered at clinicaltrials.gov as NCT01582802.

Topics: Adult; Anemia, Iron-Deficiency; C-Reactive Protein; Erythropoietin; Female; Ferritins; Hemoglobins; Hepcidins; Humans; Inflammation; Interleukin-6; Iron; Iron Deficiencies; Longitudinal Studies; Nutritional Requirements; Nutritional Status; Pregnancy; Pregnancy Complications; Pregnancy, Multiple; Prevalence; Quadruplets; Triplets; Twins

Periodontal disease (PDD) was associated with inflammation, malnutrition, and higher mortality in hemodialysis (HD) patients.. Cross-sectional observational study, aiming to assess the prevalence of PDD and the possible relationship among PDD, inflammation, and malnutrition in HD patients.. Single HD center, 263 patients (age: 57.4 ± 12.3 years; 60% males; HD vintage 6.6 ± 4.9 years; the primary renal diseases were mainly primary glomerular nephropathies in 34% cases, with 11% diabetic nephropathy).. Oral health status was assessed by the Silness and Loe plaque index, loss of clinical attachment level, periodontal pocket depth according to World Health Organization recommendations, by a single examiner. Patients were stratified by periodontal pocket depth (PPD): normal oral status/mild PDD (PPD < 4 mm), moderate PDD (PPD 4-5 mm), and severe PDD (PPD ≥ 6 mm). Demographic, smoking status, hematologic, dialysis-related data and parameters of the nutritional (Subjective Global Assessment score, anthropemetrical, and biochemical) and inflammatory status were collected.. Poor periodontal status was shown by 75% of patients, 23% of them with severe PDD. Patients with PDD were older; higher percentages of them were smokers, diabetics, had malnutrition, and inflammation. Subjects with severe PDD had higher HD vintage, lower hemoglobin, and required higher darbepoetin doses than those with healthy periodontium. Darbepoetin resistance index was higher in patients with severe PDD than in those with normal periodontium. Models of multivariable linear logistic regression for the potential promoters and for the consequences of PDD revealed smoking and HD duration as significant contributors; increased C-reactive protein was associated with severe PDD.. Cross-sectional observational design.. Impaired periodontal health is highly prevalent in HD patients. PDD is more frequent in elderly diabetic smokers and in those with longer HD vintage; smoking and HD duration seems to be the most important determinants. The prevalence is higher in malnourished and in inflamed patients; inflammation seems to accompany PDD and to influence anemia response to treatment.

Topics: Aged; C-Reactive Protein; Cross-Sectional Studies; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Kidney Diseases; Linear Models; Logistic Models; Male; Malnutrition; Middle Aged; Multivariate Analysis; Nutritional Status; Periodontal Diseases; Prevalence; Renal Dialysis

Patients on hemodialysis (HD) are usually anemic because of defective erythropoeisis. Hepcidin is a polypeptide that regulates iron homeostasis and could serve as an indicator of functional iron deficiency in patients with end-stage renal disease (ESRD); this may also aid in the assessment of patient's response to erythropoietin (EPO). The present study was directed to investigate serum levels of hepcidin, iron status and inflammation markers such as C-reactive protein (CRP) in patients with ESRD on maintenance HD and to observe the correlation of serum hepcidin with conventional iron and inflammatory markers. A total of 42 patients of both sexes on maintenance HD and EPO therapy were enrolled; 42 ageand sex-matched healthy subjects were included as controls. Laboratory tests including complete blood count, serum hepcidin, total iron binding capacity (TIBC), serum ferritin, serum iron and CRP were performed. Serum hepcidin levels were significantly higher in patients with ESRD than in the control group (18.2 ± 2.8 ng/mL and 8.5 ± 2.3 ng/mL, respectively P = 0.000). The hemoglobin, hematocrit, serum iron, TIBC and transferrin saturation levels in the patient group were significantly lower than in the control group. Higher hepcidin levels were found in EPO non-responders (19.6 ± 2.4 ng/mL) while lower levels (16.9 ± 2.5 ng/mL) were seen in responders (P = 0.001). A positive and significant correlation was observed between the values of serum hepcidin and CRP. Our study indicates that higher hepcidin levels are found in ESRD patients on HD and in those not responding to EPO. Our findings suggest that hepcidin might play a role in the pathophysiology of anemia associated with chronic diseases as well as EPO resistance.

Topics: Adolescent; Adult; Anemia, Iron-Deficiency; Biomarkers; C-Reactive Protein; Case-Control Studies; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Hepcidins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Transferrin; Young Adult

Recently it was found that the erythropoietin receptor (EpoR) is expressed on innate immune cells, such as dendritic cells and macrophages. We found that murine bone marrow-derived mast cells express the EpoR and that its expression is increased under hypoxic conditions. Interestingly, Epo stimulation of the cells did not activate signal transducer and activator of transcription molecules, nor did we find differences in the expression of typical STAT-dependent genes, the proliferation rate, and the ability to differentiate or to protect the cells from apoptosis. Instead, we demonstrate that stimulation of mast cells with Epo leads to phosphorylation of the receptor tyrosine kinase c-kit. We hypothesize that this is due to the formation of a receptor complex between the EpoR and c-kit. The common beta chain of the IL-3 receptor family, which was described as part of the tissue protective receptor (TPR) on other non-erythroid cells, however is not activated. To investigate whether the EpoR/c-kit complex has tissue protective properties, cells were treated with the Toll-like receptor ligand LPS. Combined Epo and LPS treatment downregulated the inflammatory response of the cells as detected by a decrease in IL-6 and TNF-α secretion.

Topics: Animals; Antibiotics, Antineoplastic; Cell Hypoxia; Cells, Cultured; Doxorubicin; Erythropoietin; Female; Inflammation; Inflammation Mediators; Interleukin-6; Lipopolysaccharides; Mast Cells; Mice; Mice, Inbred C57BL; Multiprotein Complexes; Phosphorylation; Proto-Oncogene Proteins c-kit; Receptors, Erythropoietin; Signal Transduction; STAT3 Transcription Factor; STAT5 Transcription Factor; Tumor Necrosis Factor-alpha

Microglial activation has been widely demonstrated to mediate inflammatory processes that are crucial in several neurodegenerative disorders. Pharmaceuticals that can deliver direct inhibitory effects on microglia are therefore considered as a potential strategy to counter balance neurodegenerative progression. Caffeic acid phenethyl ester (CAPE), a natural phenol in honeybee propolis, is known to possess antioxidant, anti-inflammatory and anti-microbial properties. Accordingly, the current study intended to probe the effects of CAPE on microglia activation by using in vitro and in vivo models. Western blot and Griess reaction assay revealed CAPE significantly inhibited the expressions of inducible nitric oxide synthase (NOS), cyclooxygenase (COX)-2 and the production of nitric oxide (NO). Administration of CAPE resulted in increased expressions of hemeoxygenase (HO)-1and erythropoietin (EPO) in microglia. The phosphorylated adenosine monophosphate-activated protein kinase (AMPK)-α was further found to regulate the anti-inflammatory effects of caffeic acid. In vivo results from immunohistochemistry along with rotarod test also revealed the anti-neuroinflammatory effects of CAPE in microglia activation. The current study has evidenced several possible molecular determinants, AMPKα, EPO, and HO-1, in mediating anti-neuroinflammatory responses in microglial cells.

Topics: AMP-Activated Protein Kinases; Animals; Caffeic Acids; Cell Line; Cyclooxygenase 2; Erythropoietin; Heme Oxygenase-1; Inflammation; Male; Mice; Mice, Inbred ICR; Microglia; Nitric Oxide Synthase Type II; Phenylethyl Alcohol

The inflammatory response plays an important role in liver dysfunction after hepatic ischemia/reperfusion (I/R), which is tightly regulated by the Toll-like receptor 2 (TLR2)/nuclear factor (NF)-κB pathway; suppression of TLR2/NF-κB signaling has therefore become a promising target for anti-inflammatory treatment in hepatic I/R injury. Erythropoietin (EPO) is a glycoprotein cytokine produced primarily by the kidney that has anti-inflammatory activities. The purpose of the present study was to investigate the effect of EPO preconditioning, if any, against hepatic I/R injury in rats and its underlying mechanisms.. Male Sprague-Dawley rats were subjected to partial (70%) hepatic ischemia for 45 minutes after pretreatment with either saline or EPO followed by 24-hour reperfusion. Hepatic injury was evaluated according to biochemical and histopathologic examinations. The expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were measured by using enzyme-linked immunosorbent assay and real-time polymerase chain reaction. The expression of nuclear translocation and phosphorylation of NF-κB p65, EPOR receptor (EPOR), p-EPOR, p-IκB-α, IκB-α, and TLR2 were determined by using Western blot analysis.. EPO treatment significantly improved hepatic function and histology, as indicated by reduced transaminase levels and pathologic changes. The expression of TNF-α, IL-1β, IL-6, p-IκB-α, and TLR2 was significantly decreased with up-regulation of p-EPOR by EPO. Moreover, EPO pretreatment also reduced I/R-induced the phosphorylation and nuclear translocation of NF-κB p65 subunits in liver tissue, but EPO had no influence on the expression of p65 and IκB-α.. These results suggest that EPO pretreatment ameliorates hepatic I/R injury, which is involved in suppressing TLR2/NF-κB-mediated inflammation.

Topics: Animals; Enzyme-Linked Immunosorbent Assay; Erythropoietin; I-kappa B Proteins; Inflammation; Interleukin-1beta; Interleukin-6; Ischemic Preconditioning; Liver; Male; NF-KappaB Inhibitor alpha; Peptide Fragments; Phosphorylation; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Erythropoietin; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 2; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Up-Regulation

We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI).. Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age.. Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI.. hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.

Topics: Brain Injuries; Cerebral Palsy; Confidence Intervals; Erythropoietin; Gestational Age; Humans; Infant, Extremely Premature; Infant, Newborn; Inflammation; Logistic Models; Microcephaly; Odds Ratio; Psychomotor Performance; Risk Factors

Anemia is a common complication of chronic kidney disease (CKD) that develops early and its severity increases as renal function declines. It is mainly due to a reduced production of erythropoietin (EPO) by the kidneys; however, there are evidences that iron metabolism disturbances increase as CKD progresses. Our aim was to study the mechanisms underlying the development of anemia of CKD, as well as renal damage, in the remnant kidney rat model of CKD induced by 5/6 nephrectomy. This model of CKD presented a sustained degree of renal dysfunction, with mild and advanced glomerular and tubulointerstitial lesions. Anemia developed 3 weeks after nephrectomy and persisted throughout the protocol. The remnant kidney was still able to produce EPO and the liver showed an increased EPO gene expression. In spite of the increased EPO blood levels, anemia persisted and was linked to low serum iron and transferrin levels, while serum interleukin (IL)-6 and high sensitivity C-reactive protein (hs-CRP) levels showed the absence of systemic inflammation. The increased expression of duodenal ferroportin favours iron absorption; however, serum iron is reduced which might be due to iron leakage through advanced kidney lesions, as showed by tubular iron accumulation. Our data suggest that the persistence of anemia may result from disturbances in iron metabolism and by an altered activity/function of EPO as a result of kidney cell damage and a local inflammatory milieu, as showed by the increased gene expression of different inflammatory proteins in the remnant kidney. In addition, this anemia and the associated kidney hypoxia favour the development of fibrosis, angiogenesis and inflammation that may underlie a resistance to EPO stimuli and reduced iron availability. These findings might contribute to open new windows to identify putative therapeutic targets for this condition, as well as for recombinant human EPO (rHuEPO) resistance, which occurs in a considerable percentage of CKD patients.

Topics: Anemia; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Erythropoietin; Fibrosis; Hepcidins; Inflammation; Iron; Kidney; Liver; Male; Organ Size; Rats; Rats, Wistar; Receptors, Erythropoietin; RNA, Messenger

Small-molecule inhibitors of prolyl hydroxylase (PHD) enzymes are a novel target for the treatment of anaemia and functional iron deficiency (FID). Other than being orally bioavailable, the differentiation of PHD inhibitors from recombinant human erythropoietin (rhEPO) has not been demonstrated.. JNJ-42905343 was identified and characterized as a novel inhibitor of PHD and its action was compared with rhEPO in healthy rats and in a rat model of inflammation-induced anaemia and FID [peptidoglycan-polysaccharide (PGPS) model].. Oral administration of JNJ-42905343 to healthy rats increased the gene expression of cytochrome b (DcytB) and divalent metal-ion transporter 1 (DMT1) in the duodenum, and increased plasma EPO. Repeated administration of JNJ-42905343 for 28 days increased blood haemoglobin, mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV). The serum iron concentration was increased with low doses (0.3 mg·kg(-1) ) but reduced at high doses (6 mg·kg(-1) ). In PGPS-treated rats, administration of JNJ-42905343 for 28 days corrected FID and anaemia, as reflected by increased blood haemoglobin, MCH and MCV. Increased expression of DcytB and DMT1 genes in the duodenum resulting in increased iron availability was defined as the mechanism for these effects. rhEPO did not affect DcytB and DMT1 and was not effective in PGPS-treated rats.. PHD inhibition has a beneficial effect on iron metabolism in addition to stimulating the release of EPO. Small-molecule inhibitors of PHD such as JNJ-42905343 represent a mechanism distinct from rhEPO to treat anaemia and FID.

Topics: Anemia; Animals; Cation Transport Proteins; Cytochromes b; Duodenum; Erythrocyte Indices; Erythropoietin; Female; Gene Expression; Hemoglobins; Inflammation; Iron; Kidney; Liver; Peptidoglycan; Prolyl-Hydroxylase Inhibitors; Pyrazoles; Quinazolinones; Rats, Inbred Lew

In contrast to considerable data demonstrating a decrease in cytochrome P450 (CYP) activity in inflammation and infection, clinically, traumatic brain injury (TBI) results in an increase in CYP and UDP glucuronosyltransferase (UGT) activity. The objective of this study was to determine the effects of TBI alone and with treatment with erythropoietin (EPO) or anakinra on the gene expression of hepatic inflammatory proteins, drug-metabolizing enzymes, and transporters in a cortical contusion impact (CCI) injury model. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Plasma cytokine and liver protein concentrations of CYP2D4, CYP3A1, EPHX1, and UGT2B7 were determined. There was no effect of TBI, TBI + EPO, or TBI + anakinra on gene expression of the inflammatory factors shown to be associated with decreased expression of hepatic metabolic enzymes in models of infection and inflammation. IL-6 plasma concentrations were increased in TBI animals and decreased with EPO and anakinra treatment. There was no significant effect of TBI and/or anakinra on gene expression of enzymes or transporters known to be involved in drug disposition. TBI + EPO treatment decreased the gene expression of Cyp2d4 at 72 h with a corresponding decrease in CYP2D4 protein at 72 h and 7 days. CYP3A1 protein was decreased at 24 h. In conclusion, EPO treatment may result in a significant decrease in the metabolism of Cyp-metabolized drugs. In contrast to clinical TBI, there was not a significant effect of experimental TBI on CYP or UGT metabolic enzymes.

Topics: Animals; Brain Injuries; Cytochrome P-450 Enzyme System; Cytokines; Disease Models, Animal; Erythropoietin; Gene Expression Regulation; Glucuronosyltransferase; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Liver; Male; Membrane Transport Proteins; Rats; Rats, Sprague-Dawley; Time Factors

Erythropoietin (EPO), the key factor for erythropoiesis, also protects macrophage foam cells from lipid accumulation, yet the definitive mechanisms are not fully understood. β common receptor (βCR) plays a crucial role in the nonhematopoietic effects of EPO. In the current study, we investigated the role of βCR in EPO-mediated protection in macrophages against oxidized low-density lipoprotein- (oxLDL-) induced deregulation of lipid metabolism and inflammation. Here, we show that βCR expression was mainly in foamy macrophages of atherosclerotic aortas from apolipoprotein E-deficient mice. Results of confocal microscopy and immunoprecipitation analyses revealed that βCR was colocalized and interacted with EPO receptor (EPOR) in macrophages. Inhibition of βCR activation by neutralizing antibody or small interfering RNA (siRNA) abolished the EPO-conferred protection in oxLDL-induced lipid accumulation. Furthermore, EPO-promoted cholesterol efflux and upregulation of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 were prevented by pretreatment with βCR neutralizing antibody or βCR siRNA. Additionally, blockage of βCR abrogated the EPO-conferred anti-inflammatory action on oxLDL-induced production of macrophage inflammatory protein-2. Collectively, our findings suggest that βCR may play an important role in the beneficial effects of EPO against oxLDL-elicited dysfunction of macrophage foam cells.

Topics: Animals; Cells, Cultured; Cholesterol; Cytokine Receptor Common beta Subunit; Erythropoietin; Inflammation; Lipid Metabolism; Lipoproteins, LDL; Macrophages; Mice; Protein Multimerization

Hepcidin is the main regulator of systemic iron homeostasis and its expression is modulated by iron status, hypoxia, erythroid factors and inflammation. The aim of our study was to examine a relationship between level of hepcidin and iron status, erythropoietic activity, hypoxia and inflammation in exacerbations and stable COPD patients. We hypothesized that hepcidin concentration is changed in COPD patients and is substantially influenced by inflammation and/or hypoxia.. The study included 40 COPD patients and 30 healthy subjects. We measured haemoglobin, serum level of hepcidin and parameters indicative for inflammation: interleukin-6 (IL-6) and C reactive protein (CRP); hypoxia: partial oxygen pressure and haemoglobin oxygen saturation; iron status: iron, total iron binding capacity (TIBC), transferring saturation and ferritin; and erythropoietic activity: soluble transferrin receptors, reticulocytes, and erythropoietin.. Hepcidin was elevated in exacerbations and in a stable phase compared to the control group and we found positive correlations of hepcidin with inflammatory markers IL-6 and CRP. Hepcidin also correlated positively with ferritin and inversely with TIBC. However, in COPD patients reticulocyte count was significantly reduced and negative correlation with hepcidin was established in exacerbation. No correlations were observed with iron, or indices of hypoxia. In the control group, positive associations were observed only with indices of iron status, positive with ferritin and negative one with TIBC.. Systemic inflammation and elevated values of IL-6 present in exacerbations and stabile COPD might be responsible for the observed increased hepcidin level.

Topics: Aged; Aged, 80 and over; C-Reactive Protein; Case-Control Studies; Disease Progression; Erythropoietin; Female; Gene Expression; Hemoglobins; Hepcidins; Humans; Hypoxia; Inflammation; Interleukin-6; Iron; Male; Middle Aged; Oxygen; Pulmonary Disease, Chronic Obstructive; Receptors, Transferrin; Reticulocytes; Transferrin

Metformin is a widely‑used antidiabetic drug with hypoglycemic activity and previously described anti‑inflammatory properties. Previous studies have demonstrated that metformin attenuates endotoxic hepatitis, however the mechanisms remain unclear. Inflammation and coagulation are closely associated pathological processes, therefore the potential effects of metformin on key steps in activation of the coagulation system were further investigated in endotoxic hepatitis induced by lipopolysaccharide/D‑galactosamine (LPS/D‑Gal). The current study demonstrated that treatment with metformin significantly suppressed the upregulation of tissue factor and plasminogen activator inhibitor‑1 in LPS/D‑Gal‑exposed mice. In addition, a reduction in the expression of interleukin 6 and inhibition of nuclear translocation of nuclear factor‑κB were observed. These data indicate that the LPS/D‑Gal‑induced elevation of the stable protein level of hypoxia inducible factor 1α, the mRNA level of erythropoietin, vascular endothelial growth factor and matrix metalloproteinase‑3, and the hepatic level of lactic acid were also suppressed by metformin. The current study indicates that the suppressive effects of metformin on inflammation‑induced coagulation may be an additional mechanism underlying the hepatoprotective effects of metformin in mice with LPS/D‑Gal‑induced fulminant hepatitis.

Topics: Animals; Anti-Inflammatory Agents; Blood Coagulation; Disease Models, Animal; Erythropoietin; Galactosamine; Hepatitis; Hypoglycemic Agents; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-6; Lactic Acid; Lipopolysaccharides; Liver; Matrix Metalloproteinase 3; Metformin; Mice; NF-kappa B; Plasminogen Activator Inhibitor 1; RNA, Messenger; Thromboplastin; Up-Regulation; Vascular Endothelial Growth Factor A

Exposure to high-dose radiation results in detrimental effects on survival. The effects of combined trauma, such as radiation in combination with hemorrhage, the typical injury of victims exposed to a radiation blast, on survival and hematopoietic effects have yet to be understood. The purpose of this study was to evaluate the effects of radiation injury (RI) combined with hemorrhage (i.e., combined injury, CI) on survival and hematopoietic effects, and to investigate whether hemorrhage (Hemo) enhanced RI-induced mortality and hematopoietic syndrome. Male CD2F1 mice (10 weeks old) were given one single exposure of γ- radiation (60Co) at various doses (0.6 Gy/min). Within 2 hr after RI, animals under anesthesia were bled 0% (Sham) or 20% (Hemo) of total blood volume via the submandibular vein. In these mice, Hemo reduced the LD50/30 for 30-day survival from 9.1 Gy (RI) to 8.75 Gy (CI) with a DMF of 1.046. RI resulted in leukocytopenia, thrombopenia, erythropenia, and bone marrow cell depletion, but decreased the caspase-3 activation response. RI increased IL-1β, IL-6, IL-17A, and TNF-α concentrations in serum, bone marrow, ileum, spleen, and kidney. Some of these adverse alterations were magnified by CI. Erythropoietin production was increased in kidney and blood more after CI than RI. Furthermore, CI altered the global miRNAs expression in kidney and the ingenuity pathway analysis showed that miRNAs viz., let-7e, miR-30e and miR-29b that were associated with hematopoiesis and inflammation. This study provides preliminary evidence that non-lethal Hemo exacerbates RI-induced mortality and cell losses associated with high-dose γ-radiation. We identified some of the initial changes occurring due to CI which may have facilitated in worsening the injury and hampering the recovery of animals ultimately resulting in higher mortality.

Topics: Anemia; Animals; Body Weight; Bone Marrow Cells; Caspase 3; Cytokines; Disease-Free Survival; Erythropoietin; Hematopoiesis; Hemorrhage; Inflammation; Kidney; Lethal Dose 50; Leukopenia; Male; Mice; MicroRNAs; NF-kappa B; Radiation Injuries; Thrombocytopenia; Water

A previous study showed that a 1-h delay in treatment of thoracic spinal cord injury (SCI) with recombinant human erythropoietin (rhEPO) lacked neuroprotective efficacy. The aim of the present study was to reassess delayed administration of different doses of rhEPO on acute spinal cord compressive injury in rats.. The experiment was divided into first and second stages, which SCI rats were observed for 4 and 28 days, respectively. All rats were randomly divided into four groups at both stages: control group, and rhEPO-3,000U (Unit), rhEPO-4,000U and rhEPO-5,000U groups. SCI rats received rhEPO treatment at different time points. The primary indicators were locomotor recovery, histopathology, apoptotic index, inflammatory index, ultrastructural scoring system and volume of areas of demyelination.. The most significant locomotor functional and histopathological improvements and the best myelin protection were observed after administration of 5,000 U/kg rhEPO. rhEPO at 3,000, 4,000 and 5,000 U/kg showed similar ultrastructural neuroprotection, as well as similar inhibition of apoptosis and regulation of inflammation.. Delayed administration of rhEPO can reduce apoptosis and inflammation, and promote myelin repair and functional recovery following spinal cord compressive injury in rats.

Topics: Animals; Apoptosis; Behavior, Animal; Disease Models, Animal; Erythropoietin; Humans; Inflammation; Male; Motor Activity; Myelin Sheath; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Recovery of Function; Spinal Cord Compression; Spinal Cord Injuries; Time Factors

Erythropoietin (EPO) has been identified as being crucial for obesity modulation; however, its erythropoietic activity may limit its clinical application. EPO-derived Helix B-surface peptide (pHBSP) is nonerythrogenic but has been reported to retain other functions of EPO. The current study aimed to evaluate the effects and potential mechanisms of pHBSP in obesity modulation. We found that pHBSP suppressed adipogenesis, adipokine expression and peroxisome proliferator-activated receptor γ (PPARγ) levels during 3T3-L1 preadipocyte maturation through the EPO receptor (EPOR). In addition, also through EPOR, pHBSP attenuated macrophage inflammatory activation and promoted PPARγ expression. Furthermore, PPARγ deficiency partly ablated the anti-inflammatory activity of pHBSP in macrophages. Correspondingly, pHBSP administration to high-fat diet (HFD)-fed mice significantly improved obesity, insulin resistance (IR) and adipose tissue inflammation without stimulating hematopoiesis. Therefore, pHBSP can significantly protect against obesity and IR partly by inhibiting adipogenesis and inflammation. These findings have therapeutic implications for metabolic disorders, such as obesity and diabetes.

Topics: 3T3-L1 Cells; Adipogenesis; Adipokines; Animals; Biomarkers; Cytokines; Diet, High-Fat; Erythropoietin; Gene Expression Regulation; Hematopoiesis; Inflammation; Inflammation Mediators; Insulin Resistance; Macrophages; Mice; Obesity; Peptides; PPAR gamma

Erythropoietin (EPO) is a key hormone involved in red blood cell formation, but its effects on nonerythroid cells, such as macrophages, have not been described. Macrophages are key cells in controlling histoplasmosis, a fungal infection caused by Histoplasma capsulatum (Hc). Considering that little is known about EPO's role during fungal infections and its capacity to activate macrophages, in this study we investigated the impact of EPO pretreatment on the alveolar immune response during Hc infection. The consequence of EPO pretreatment on fungal infection was determined by evaluating animal survival, fungal burden, activation of bronchoalveolar macrophages, inflammatory mediator release, and lung inflammation. Pretreatment with EPO diminished mononuclear cell numbers, increased the recruitment of F4/80(+)/CD80(+) and F4/80(+)/CD86(+) cells to the bronchoalveolar space, induced higher production of IFN-γ, IL-6, MIP-1α, MCP-1, and LTB4, reduced PGE2 concentration, and did not affect fungal burden. As a consequence, we observed an increase in lung inflammation with extensive tissue damage that might account for augmented mouse mortality after infection. Our results demonstrate for the first time that EPO treatment has a deleterious impact on lung immune responses during fungal infection.

Topics: Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Chemokine CCL3; Chemokines; Erythropoietin; Gene Expression Regulation; Histoplasma; Histoplasmosis; Inflammation; Interferon-gamma; Interleukin-6; Lung; Macrophages; Male; Mice; Mice, Inbred C57BL; Receptors, Leukotriene B4; Recombinant Proteins; Spleen

Disturbed iron homeostasis contributes to resistance to recombinant human erythropoietin (rHuEpo) in hemodialysis (HD) patients. Increased hepcidin, which downregulates the iron exporter ferroportin, has been incriminated. However, other factors also control ferroportin expression in mononuclear phagocyte system. Ferroportin in monocytes, as well as serum hepcidin, interleukin-6 (IL-6) and common markers of iron status were measured and correlations with rHuEpo resistance index (ERI) were evaluated.. After a 4-week washout period from iron treatment, 34 HD patients and 20 healthy volunteers enrolled in the study. Ferroportin was assessed by means of western blotting, whereas hepcidin and IL-6 with enzyme-linked immunosorbent assay. Hemoglobin, serum iron, ferritin and transferrin saturation (TSAT) were also measured.. Ferroportin in monocytes of HD patients was decreased. Serum hepcidin and IL-6 were increased, whereas serum iron and TSAT were decreased. ERI was negatively correlated with ferroportin and all the markers of iron adequacy, but not with hepcidin.. Decreased ferroportin in monocytes of HD patients accompanies increased hepcidin, inflammation, decreased iron availability and is correlated with resistance to rHuEpo treatment.

Topics: Aged; Anemia; Case-Control Studies; Cation Transport Proteins; Darbepoetin alfa; Drug Resistance; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Hepcidins; Humans; Inflammation; Interleukin-6; Iron; Male; Middle Aged; Monocytes; Polyethylene Glycols; Renal Dialysis

Managing critical limb ischemia (CLI) is challenging. Furthermore, ischemic myopathy prevents good functional outcome after revascularization. Hence, we have focused on limiting the tissue damage rather than angiogenesis, which has traditionally been the motivation to develop nonsurgical treatments for CLI. Erythropoietin (EPO) protects ischemic tissue, and this property may also benefit CLI. The objective of this study was to examine the expression of the tissue-protective EPO receptor complex (EPOR-CD131 [β-chain of interleukin (IL)-3/IL-5/granulocyte macrophage colony-stimulating factor receptor]) in skeletal muscle obtained from humans with CLI. Because native EPO is thrombogenic, the antiapoptotic and anti-inflammatory effects of a nonhematopoietic helix-B peptide of EPO (ARA 290) were investigated on ischemic myotubes in vitro.. Tissue was obtained from gastrocnemius muscle of 12 patients undergoing amputation for CLI and from 12 patients without limb ischemia. The expression of EPOR and CD131 was demonstrated by immunohistochemistry and Western blot. A validated in vitro model of myotube ischemia was used in which mature C2C12 myotubes were cultured 6 to 12 hours in a depleted media and gas mixture (20% CO2 and 80% N2). The myotubes were pretreated with EPO or ARA 290 before exposure to simulated ischemia. Apoptosis and cell death were determined by cleaved caspase-3 assay and lactate dehydrogenase release assay. Enzyme-linked immunosorbent assay measured the inflammatory cytokines.. EPOR and CD131 were expressed and significantly upregulated in CLI (average optical density [OD] in Western blot [control vs CLI] EPOR, 0.05 U vs 0.1 U; CD131, 0.10 U vs 0.22 U; P < .01). There was colocalization of EPOR and CD131 in the sarcolemma (cell membrane) of the skeletal myofiber. There was no difference in the distribution of colocalization between the CLI and the normal muscle. The ischemic myotubes treated by ARA 290 in vitro had a significantly decreased number of apoptotic cells (ischemia vs ischemia plus ARA 290: 71.1% vs 55.1%; P < .01), cleaved caspase-3 (OD of ischemia vs ischemia plus ARA 290: 0.15 U vs 0.02 U; P < .01), lactate dehydrogenase release (ischemia vs ischemia plus ARA 290: 32.5 U/L vs 21.3 U/L; P < .01), and IL-6 release (OD at 450 nm, ischemia vs ischemia plus ARA 290: 0.18 vs 0.13; P < .01).. This study demonstrates the expression and the upregulation of EPOR and CD131 in CLI and also shows that EPOR and CDI are colocalized in the cell membrane of both ischemic and control muscle fiber. The in vitro experiments demonstrate that ARA 290 decreases inflammation and apoptosis of ischemic myotubes. ARA 290 may potentially be used as adjunctive treatment for CLI.

Topics: Aged; Apoptosis; Case-Control Studies; Caspase 3; Cell Membrane; Cytokine Receptor Common beta Subunit; Erythropoietin; Extremities; Female; Humans; Inflammation; Interleukin-6; Ischemia; L-Lactate Dehydrogenase; Male; Middle Aged; Muscle Fibers, Skeletal; Oligopeptides; Receptors, Erythropoietin; Up-Regulation

Chronic systemic inflammation, a non traditional risk factor of cardiovascular diseases, is associated with increasing mortality in chronic kidney disease, especially peritoneal dialysis patients. Periodontitis is a potential treatable source of systemic inflammation in peritoneal dialysis patients. Clinical periodontal status was evaluated in 32 stable chronic peritoneal dialysis patients by plaque index and periodontal disease index. Hematologic, blood chemical, nutritional, and dialysis-related data as well as highly sensitive C-reactive protein were analyzed before and after periodontal treatment. At baseline, high sensitive C-reactive protein positively correlated with the clinical periodontal status (plaque index; r = 0.57, P < 0.01, periodontal disease index; r = 0.56, P < 0.01). After completion of periodontal therapy, clinical periodontal indexes were significantly lower and high sensitivity C-reactive protein significantly decreased from 2.93 to 2.21 mg/L. Moreover, blood urea nitrogen increased from 47.33 to 51.8 mg/dL, reflecting nutritional status improvement. Erythropoietin dosage requirement decreased from 8000 to 6000 units/week while hemoglobin level was stable. Periodontitis is an important source of chronic systemic inflammation in peritoneal dialysis patients. Treatment of periodontal diseases can improve systemic inflammation, nutritional status and erythropoietin responsiveness in peritoneal dialysis patients.

Topics: Adult; Aged; Blood Urea Nitrogen; C-Reactive Protein; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Status; Periodontal Index; Periodontitis; Peritoneal Dialysis

Erythropoietin used to correct anaemia in chronic kidney disease (CKD) has been shown to increase blood pressure (BP) in CKD patients and experimental animals. Endothelin (ET)-1 expression is increased in CKD animals and patients, and enhanced by erythropoietin. Erythropoietin-induced BP rise was blunted by ETA receptor blockers. This study was designed to determine whether preexisting endothelin (ET)-1 overexpression is required for erythropoietin to cause adverse vascular effects and whether this could be prevented by exercise training.. Eight to 10-week old male wild-type mice and mice with endothelial-specific ET-1 overexpression (eET-1) were treated or not with EPO (100  IU/kg, SC, 3  times/week). eET-1 was subjected or not to swimming exercise training (1  h/day, 6 days/week) for 8 weeks. SBP, mesenteric artery endothelial function and remodelling, NADPH oxidase activity, reactive oxygen species (ROS) generation, vascular cell adhesion protein (VCAM)-1, monocyte/macrophage infiltration, T regulatory cells (Tregs) and tissue ET-1 and plasma endothelin were determined.. Erythropoietin increased SBP by 24  mmHg (P < 0.05) and decreased by 25% vasodilatory responses to acetylcholine (P < 0.01) in eET-1 mice. Erythropoietin enhanced ET-1 induced increase in resistance artery media/lumen ratio (31%, P < 0.05), aortic NADPH oxidase activity (50%, P < 0.05), ROS generation (93%, P < 0.001), VCAM-1 (80%, P < 0.01) and monocyte/macrophage infiltration (159%, P < 0.001), and raised plasma and aortic ET-1 levels (≥130%, P < 0.05). EPO had no effect in wild-type mice. Exercise training prevented all of the above (P < 0.05).. Erythropoietin-induced adverse vascular effects are dependent on preexisting elevated ET-1 expression. Exercise training prevented erythropoietin-induced adverse vascular effects in part by inhibiting ET-1 overexpression-induced oxidative stress, inflammation and immune activation.

Topics: Animals; Blood Pressure; Endothelin-1; Erythropoietin; Hematocrit; Humans; Hypertension; Immune System; Inflammation; Male; Mice; Mice, Transgenic; NADPH Oxidases; Oxidative Stress; Physical Conditioning, Animal; Reactive Oxygen Species; Swimming; Systole

Cardiovascular morbidity and mortality is very important in patients with chronic renal failure. This occurs even in mild impairment of renal function and may be related to oxidative stress and chronic inflammation. The nephrectomized apo E knockout mouse is an accepted model for evaluating atherosclerosis in renal dysfunction. Erythropoietin derivates showed anti-oxidative and anti-inflammatory effects. Therefore, this study evaluates the effects of Darbepoetin on markers of oxidative stress and chronic inflammation in atherosclerotic lesions in apo E knockout mice with renal dysfunction.. Apo E knockout mice underwent unilateral (Unx, n = 20) or subtotal (Snx, n = 26) nephrectomy or sham operation (Sham, n = 16). Mice of each group were either treated with Darbepoetin or saline solution, a part of Snx mice received a tenfold higher dose of Darbepoetin. The aortic plaques were measured and morphologically characterized. Additional immunhistochemical analyses were performed on tissue samples taken from the heart and the aorta.. Both Unx and Snx mice showed increased expression of markers of oxidative stress and chronic inflammation. While aortic plaque size was not different, Snx mice showed advanced plaque stages when compared to Unx mice. Darbepoetin treatment elevated hematocrit and lowered Nitrotyrosin as one marker of oxidative stress, inflammation in heart and aorta, plaque stage and in the high dose even plaque cholesterol content. In contrast, there was no influence of Darbepoetin on aortic plaque size; high dose Darbepoetin treatment resulted in elevated renal serum parameters.. Darbepoetin showed some protective cardiovascular effects irrespective of renal function, i.e. it improved plaque structure and reduced some signs of oxidative stress and chronic inflammation without affecting plaque size. Nevertheless, the dose dependent adverse effects must be considered as high Darbepoetin treatment elevated serum urea. Elevation of hematocrit might be a favorable effect in anemic Snx animals but a thrombogenic risk in Sham animals.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Darbepoetin alfa; Erythropoietin; Inflammation; Mice; Mice, Knockout; Oxidative Stress; Renal Insufficiency

Experimental autoimmune neuritis (EAN) is an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system. Erythropoietin (EPO) has been known to promote EAN recovery but its haematopoiesis stimulating effects may limit its clinic application. Here we investigated the effects and potential mechanisms of an EPO-derived nonerythropoietic peptide, ARA 290, in EAN. Exogenous ARA 290 intervention greatly improved EAN recovery, improved nerve regeneration and remyelination, and suppressed nerve inflammation. Furthermore, haematopoiesis was not induced by ARA 290 during EAN treatment. ARA 290 intervention suppressed lymphocyte proliferation and altered helper T cell differentiation by inducing increase of Foxp3+/CD4+ regulatory T cells and IL-4+/CD4+ Th2 cells and decrease of IFN-γ+/CD4+ Th1 cells in EAN. In addition, ARA 290 inhibited inflammatory macrophage activation and promoted its phagocytic activity. In vitro, ARA 290 was shown to promote Schwann cell proliferation and inhibit its inflammatory activation. In summary, our data demonstrated that ARA 290 could effectively suppress EAN by attenuating inflammation and exerting direct cell protection, indicating that ARA 290 could be a potent candidate for treatment of autoimmune neuropathies.

Topics: Animals; Cell Differentiation; Cell Proliferation; Erythropoietin; Inflammation; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Nerve Regeneration; Neuritis, Autoimmune, Experimental; Neuropeptides; Neuroprotective Agents; Oligopeptides; Rats; Rats, Inbred Lew; Sciatic Nerve; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Th1-Th2 Balance

Obesity-induced white adipose tissue (WAT) inflammation and insulin resistance are associated with macrophage (Mф) infiltration and phenotypic shift from "anti-inflammatory" M2-like to predominantly "proinflammatory" M1-like cells. Erythropoietin (EPO), a glycoprotein hormone indispensable for erythropoiesis, has biological activities that extend to nonerythroid tissues, including antiapoptotic and anti-inflammatory effects. Using comprehensive in vivo and in vitro analyses in mice, EPO treatment inhibited WAT inflammation, normalized insulin sensitivity, and reduced glucose intolerance. We investigated EPO receptor (EPO-R) expression in WAT and characterized the role of its signaling during obesity-induced inflammation. Remarkably, and prior to any detectable changes in body weight or composition, EPO treatment reduced M1-like Mф and increased M2-like Mф in WAT, while decreasing inflammatory monocytes. These anti-inflammatory effects were found to be driven, at least in part, by direct EPO-R response in Mф via Stat3 activation, where EPO effects on M2 but not M1 Mф required interleukin-4 receptor/Stat6. Using obese ∆EpoR mice with EPO-R restricted to erythroid cells, we demonstrated an anti-inflammatory role for endogenous EPO. Collectively, our findings identify EPO-R signaling as a novel regulator of WAT inflammation, extending its nonerythroid activity to encompass effects on both Mф infiltration and subset composition in WAT.

Topics: Adipose Tissue, White; Animals; Cells, Cultured; Diet, High-Fat; Erythropoietin; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Panniculitis; Receptors, Erythropoietin; Signal Transduction

Use of erythropoiesis-stimulating agents (ESAs) has improved the management of anemia in patients on maintenance hemodialysis (MHD). Iron deficiency and inflammation cause ESAs resistance and are both common among indigenous people of Northern Australia. As part of quality assurance in our Renal Anaemia Management program, we observed that there was use of higher doses of ESAs and adjuvant iron therapy in our MHD patients. This study aimed to explore the relationship among iron studies, inflammation, ESA responsiveness, and ESAs and iron requirements in indigenous patients on MHD from the Top End of Northern Australia. We performed a retrospective cohort analysis of anemia management in a cohort of our patients on MHD. We extracted data for 178 indigenous and 19 non-indigenous patients from 1 March 2009 to 28 February 2010 from the Renal Anaemia Management database, which collects data prospectively in MHD patients. Ninety-nine percent of the whole sample had a ferritin level above the international guidelines threshold of >500 µg/L. Indigenous patients had higher ferritin (1534 ± 245.5 µg/L vs. 1013 ± 323.3 µg/L, P = 0.002). C-reactive protein (CRP) was high in 56.9% of the total cohort. One hundred percent of those with normal CRP had high ferritin (>500 µg/L). C-reactive protein was higher in indigenous than in non-indigenous patients. Erythropoiesis-stimulating agents hyporesponsiveness was higher in indigenous patients (P < 0.0001). There was no significant difference in ESAs hyporesponsiveness among different levels of CRP (P = 0.116), ferritin (P = 0.408), and transferrin saturation (P = 0.503). Indigenous patients required higher total iron dose (2820.30 [2000-4350] vs. 2336.12 [1912-2900], P = 0.02). There was no significant relationship between the high ferritin and CRP. In indigenous dialysis patients, iron therapy and ESAs use are higher. The high iron use is due to a lack of published evidence to guide the administration of iron in patients with high ferritin. The high ferritin and ESAs resistance could not be fully explained by inflammation and need further evaluation. Further studies are required to determine the safe use of iron and management of ESAs resistance in our hemodialysis population.

Topics: Anemia; Australia; C-Reactive Protein; Cohort Studies; Drug Resistance; Erythropoietin; Female; Ferritins; Hematinics; Humans; Inflammation; Iron; Kidney Failure, Chronic; Male; Middle Aged; Native Hawaiian or Other Pacific Islander; Renal Dialysis; Retrospective Studies

Topics: Adipose Tissue, White; Animals; Erythropoietin; Inflammation; Male; Obesity; Panniculitis

Erythropoietin, a pluripotent glycoprotein essential for erythropoiesis, fetal growth, and development, has recently been implicated in innate immune regulation. Data from the ELGAN Study allowed us to evaluate relationships between endogenous erythropoietin and 25 inflammation-related proteins in extremely premature newborns.. We measured the concentrations of 25 inflammation-related proteins and of erythropoietin in blood spots collected on postnatal days 1, 7, and 14 from 936 infants born before 28 weeks gestation. We calculated the odds that infants with an inflammation-related protein in the highest quartile for gestational age and collection day had an erythropoietin concentration in the highest or lowest quartile.. The proportion of children with inflammation-associated protein concentrations in the top quartile tended to increase monotonically with increasing quartile of EPO concentrations on 2 of the 3 days assessed. To a large extent, on each of the 3 days assessed, the odds ratios for an erythropoietin concentration in the top quartile were significantly elevated among those with an inflammation-related protein concentration in the top quartile.. Our findings suggest that in very preterm newborns, circulating levels of endogenous erythropoietin vary significantly with circulating levels of inflammation-related proteins. Elevation of endogenous erythropoietin might not be an epiphenomenon, but instead might contribute to subsequent events, by either promoting or reducing inflammation, or by promoting an anti-injury or repair capability.

Topics: Cell Adhesion Molecules; Cytokines; Dried Blood Spot Testing; Erythropoietin; Gestational Age; Humans; Infant, Extremely Premature; Infant, Newborn; Inflammation; Matrix Metalloproteinases

Inflammation contributes to hemopoiesis by lowering responses to epoetin (EPO) and to an increase in the mortality of patients on hemodialysis. However, nutritional status might alter associations among inflammation, EPO responsiveness, and the risk of mortality. We assessed the effect of inflammation on mortality according to nutritional status among EPO responses in a cohort of prevalent hemodialysis patients.. The observational cohort study analyzed data from the Japanese Dialysis Registry (2005-2006; n = 36,956; mean follow-up 11.5 months). Patients were categorized into tertiles of the EPO responsiveness index (ERI; the weekly weight-adjusted EPO dose [IU/kg/week] divided by hemoglobin [g/dL]) and an EPO-free group. Body mass index (BMI) and C-reactive protein (CRP) levels were measured.. Bimodal peaks indicated associations between CRP and BMI in each group. Hazard ratio (HR) curves of CRP for mortality according to BMI in the upper ERI tertile, particularly among those with diabetes mellitus (DM), were reverse J-shaped. However, HR curves in the other groups were increased below a threshold BMI of 21 kg/m(2). These associations were confirmed in propensity score-matched populations.. Risk of CRP for death is apparently changed by BMI in hemodialysis patients with a lower EPO response, especially in those with DM.

Topics: Aged; Body Mass Index; C-Reactive Protein; Cohort Studies; Diabetes Mellitus; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Inflammation; Male; Middle Aged; Nutritional Status; Renal Dialysis; Renal Insufficiency

Pregnant adolescents (aged ≤ 18 y, n = 253) were followed from ≥ 12 wk of gestation to delivery to assess longitudinal changes in anemia and iron status and to explore associations between iron status indicators, hepcidin, and inflammatory markers. Hemoglobin, soluble transferrin receptor (sTfR), ferritin, serum iron, erythropoietin (EPO), hepcidin, C-reactive protein, interleukin-6 (IL-6), folate, and vitamin B-12 were measured, and total body iron (TBI) (milligrams per kilogram) was calculated using sTfR and ferritin values. Anemia prevalence increased from trimesters 1 and 2 (3-5%, <28 wk) to trimester 3 (25%, 33.2 ± 3.7 wk, P < 0.0001). The prevalence of iron deficiency (sTfR > 8.5 mg/L) doubled from pregnancy to delivery (7% to 14%, P = 0.04). Ferritin and hepcidin concentrations at delivery may have been elevated as a consequence of inflammation because IL-6 concentrations at delivery were 1.6-fold higher than those obtained at 26.1 ± 3.3 wk of gestation (P < 0.0001), and a positive association was found between IL-6 and both hepcidin and ferritin at delivery (P < 0.01). EPO was consistently correlated with hemoglobin (r = -0.36 and -0.43, P < 0.001), ferritin (r = -0.37 and -0.32, P < 0.0001), sTfR (r = 0.35 and 0.25, P < 0.001), TBI (r = -0.44 and -0.37, P < 0.0001), and serum iron (r = -0.22 and -0.16, P < 0.05) at mid-gestation and at delivery, respectively. EPO alone explained the largest proportion of variance in hemoglobin at 26.0 ± 3.3 wk of gestation (R(2) = 0.13, P = 0.0001, n = 113) and at delivery (R(2) = 0.19, P < 0.0001, n = 192). Pregnant adolescents are at high risk of anemia. EPO is a sensitive indicator of iron status across gestation, is not affected by systemic inflammation, and may better predict risk of anemia at term. The trial was registered at clinicaltrials.gov as NCT01019902.

Topics: Adolescent; Anemia, Iron-Deficiency; C-Reactive Protein; Cross-Sectional Studies; Delivery, Obstetric; Dietary Supplements; Erythropoietin; Female; Ferritins; Folic Acid; Hemoglobins; Hepcidins; Humans; Inflammation; Interleukin-6; Iron, Dietary; Longitudinal Studies; Multivariate Analysis; Nutrition Assessment; Nutritional Status; Pregnancy; Prevalence; Receptors, Transferrin; Regression Analysis; Surveys and Questionnaires; Vitamin B 12

Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month.. Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction.. Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001).. Prenatal TSHI and TSHI + LPS lead to different patterns of injury with respect to myelination, axon integrity and gait deficits. Dual injury leads to acute alterations in glial response and cellular inflammation, while TSHI alone causes more prominent chronic white matter and axonal injury. Both injuries cause significant gait deficits. Further study will contribute to stratification of injury mechanisms in preterm infants, and guide the use of promising therapeutic interventions.

Topics: Animals; Animals, Newborn; Axons; Brain; Calcium-Binding Proteins; Disease Models, Animal; Embryo, Mammalian; Erythropoietin; Female; Gene Expression Regulation, Developmental; Glial Fibrillary Acidic Protein; Hypoxia-Ischemia, Brain; Inflammation; Leukoencephalopathies; Lipopolysaccharides; Microfilament Proteins; Myelin Basic Protein; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin

Anemia is a major consequence of chronic kidney disease (CKD) that develops early in the course of illness and affects most patients who exhibit some degree of reduced renal function. Erythropoietin (EPO) deficiency is considered the most important cause of anemia in CKD. Renal anemia has serious clinical consequence. In addition to reducing patient physical capacity and quality of life, anemia induces adaptive cardiovascular mechanisms that increase the risk of cardiovascular disease and death. Thus, treatment of anemia in CKD is very important. While EPO is effective in correcting anemia in most cases, up to 10% of patients however, have an inadequate response to therapy. The two most common and important reasons why patients become relatively unresponsive to EPO therapy are the development of true iron deficiency and the onset of an inflammatory state that impairs the response to EPO. Indeed, the role of inflammation and pro-inflammatory cytokines in resistance to EPO therapy is gaining increasing recognition. On the other hand, the main organ for C-reactive protein (CRP) synthesis is the liver and it is well known that the synthesis of an acute-phase proteins by the liver is up regulated by inflammation. The main consequence of nonalcoholic fatty liver disease (NAFLD) is sub-chronic liver inflammation that leads and contributes to dyslipidemia, inflammation, enhanced oxidative stress and endothelial dysfunction. Considering the recent data about high prevalence of NAFLD in CKD patients, probably due to shared metabolic risk factors, we hypothesized that end-stage renal disease (ESRD) patients with NAFLD will need a much higher dose of EPO to achieve the target hemoglobin levels in comparison with ESRD patients without NAFLD. The possible underlying mechanism is sub-chronic liver inflammation in NAFLD patients that leads and contributes to poor response to EPO. Therefore, we believe that NAFLD could be a new clinical marker of poor response to EPO therapy in ESRD patients. Optimizing response to EPO therapy is important for both patient outcomes and the cost of treatment, and require consideration of a growing number of factors. Detection of NAFLD by some of non-invasive methods in ESRD patients could identify responsiveness and resistance to EPO therapy. Furthermore, we propose that all the patients who undergo dialysis treatment should be screened for NAFLD in order to identify the patients that will have a poor response to EPO therapy. The work coul

Topics: Anemia; C-Reactive Protein; Cardiovascular Diseases; Dyslipidemias; Erythropoietin; Humans; Inflammation; Kidney Failure, Chronic; Liver; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Prevalence; Quality of Life; Recombinant Proteins; Renal Dialysis; Risk Factors

Experimental autoimmune neuritis (EAN), an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system, is characterized by self-limitation. Here we investigated the regulation and contribution of erythropoietin (EPO) in EAN self-limitation. In EAN sciatic nerves, hypoxia, and protein and mRNA levels of hypoxia-inducible factor 1α (HIF-1α), HIF-2α, EPO and EPO receptor (EPOR) were induced in parallel at disease peak phase but reduced at recovery periods. Further, the deactivation of HIF reduced EAN-induced EPO/EPOR upregulation in EAN, suggesting the central contribution of HIF to EPO/EPOR induction. The deactivation of EPOR signalling exacerbated EAN progression, implying that endogenous EPO contributed to EAN recovery. Exogenous EPO treatment greatly improved EAN recovery. In addition, EPO was shown to promote Schwann cell survival and myelin production. In EAN, EPO treatment inhibited lymphocyte proliferation and altered helper T cell differentiation by inducing increase of Foxp3(+)/CD4(+) regulatory T cells and decrease of IFN-γ(+)/CD4(+) Th1 cells. Furthermore, EPO inhibited inflammatory macrophage activation and promoted its phagocytic activity. In summary, our data demonstrated that EPO was induced in EAN by HIF and contributed to EAN recovery, and endogenous and exogenous EPO could effectively suppress EAN by attenuating inflammation and exerting direct cell protection, indicating that EPO contributes to the self-recovery of EAN and could be a potent candidate for treatment of autoimmune neuropathies.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Proliferation; Cells, Cultured; Erythropoietin; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Jurkat Cells; Lymphocyte Activation; Lymphocytes; Macrophages; Male; Mice; Neuritis, Autoimmune, Experimental; Phagocytosis; Rats; Rats, Inbred Lew; Receptors, Erythropoietin; Schwann Cells; Sciatic Nerve; T-Lymphocytes, Regulatory; Th1 Cells

Experimental data confirmed that erythropoietin (EPO) administration alters the course of various pathological situations such as heart failure and tumor growth by inducing vascular endothelial growth factor-A (VEGF-A) expression. The effect of EPO dose on plasma VEGF-A level in hemodialysis (HD) patients was evaluated. The effect of EPO dose on plasma angiogenin level in HD patients was also evaluated, since angiogenin is necessary for angiogenesis induced by VEGF-A.. Thirty two HD patients (10 diabetics) enrolled into the study. Patients were iron replete and did not suffer from infections, autoimmune diseases or malignancies. Plasma VEGF-A and angiogenin, as well as serum interleukin-6 and tumor necrosis factor-α were measured by means of ELISA.. Weekly EPO dose per kg of dry body weight was positively related to both VEGF-A and angiogenin, whereas no relation was detected among VEGF-A or angiogenin and hemoglobin, inflammation or presence of diabetes mellitus. These relations among EPO dose and VEGF-A or angiogenin remained after adjustment for hemoglobin concentration or inflammation or presence of diabetes mellitus.. EPO dose may affect plasma VEGF-A and angiogenin concentrations in HD patients.

Topics: Aged; Diabetes Complications; Dose-Response Relationship, Drug; Erythropoietin; Female; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Ribonuclease, Pancreatic; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Topics: Aged; DNA; Erythropoietin; Female; Humans; Inflammation; Iron; Male; Middle Aged; Renal Dialysis

Ischemia reperfusion (IR) and cyclosporine A (CsA) injuries are unavoidable in kidney transplantation and are associated with allograft dysfunction. Herein, the effect and mechanism of a novel tissue protective peptide, helix B surface peptide (HBSP) derived from erythropoietin, were investigated in a rat model. The right kidney was subjected to 45 min ischemia, followed by left nephrectomy and 2-week reperfusion, with or without daily treatment of CsA 25 mg/kg and/or HBSP 8 nmol/kg. Blood urea nitrogen was increased by CsA but decreased by HBSP at 1 week and 2 weeks, while the same changes were revealed in urinary protein/creatinine only at 2 weeks. HBSP also significantly ameliorated tubulointerstitial damage and interstitial fibrosis, which were gradually increased by IR and CsA. In addition, apoptotic cells, infiltrated inflammatory cells, and active caspase-3+ cells were greatly reduced by HBSP in the both IR and IR + CsA groups. The 17 kD active caspase-3 protein was decreased by HBSP in the IR and IR + CsA kidneys, with decreased mRNA only in the IR + CsA kidneys. Taken together, it has been demonstrated, for the first time, that HBSP effectively improved renal function and tissue damage caused by IR and/or CsA, which might be through reducing caspase-3 activation and synthesis, apoptosis, and inflammation.

Topics: Acute Kidney Injury; Animals; Apoptosis; Caspase 3; Cyclosporine; Enzyme Activation; Erythropoietin; Fibrosis; Gene Expression; Inflammation; Kidney; Kidney Function Tests; Male; Peptide Fragments; Protective Agents; Rats; Reperfusion Injury; RNA, Messenger

Diffuse axonal injury is a common consequence of traumatic brain injury (TBI) and often co-occurs with hypoxia, resulting in poor neurological outcome for which there is no current therapy. Here, we investigate the ability of the multifunctional compound erythropoietin (EPO) to provide neuroprotection when administered to rats after diffuse TBI alone or with post-traumatic hypoxia.. Sprague-Dawley rats were subjected to diffuse traumatic axonal injury (TAI) followed by 30 minutes of hypoxic (Hx, 12% O2) or normoxic ventilation, and were administered recombinant human EPO-α (5000 IU/kg) or saline at 1 and 24 hours post-injury. The parameters examined included: 1) behavioural and cognitive deficit using the Rotarod, open field and novel object recognition tests; 2) axonal pathology (NF-200); 3) callosal degradation (hematoxylin and eosin stain); 3) dendritic loss (MAP2); 4) expression and localisation of the EPO receptor (EpoR); 5) activation/infiltration of microglia/macrophages (CD68) and production of IL-1β.. EPO significantly improved sensorimotor and cognitive recovery when administered to TAI rats with hypoxia (TAI + Hx). A single dose of EPO at 1 hour reduced axonal damage in the white matter of TAI + Hx rats at 1 day by 60% compared to vehicle. MAP2 was decreased in the lateral septal nucleus of TAI + Hx rats; however, EPO prevented this loss, and maintained MAP2 density over time. EPO administration elicited an early enhanced expression of EpoR 1 day after TAI + Hx compared with a 7-day peak in vehicle controls. Furthermore, EPO reduced IL-1β to sham levels 2 hours after TAI + Hx, concomitant to a decrease in CD68 positive cells at 7 and 14 days.. When administered EPO, TAI + Hx rats had improved behavioural and cognitive performance, attenuated white matter damage, resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammation, alongside enhanced expression of EpoR. These data provide compelling evidence of EPO's neuroprotective capability. Few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPO's neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic.

Topics: Animals; Axons; Behavior, Animal; Brain Injuries; Erythropoietin; Hypoxia, Brain; Immunohistochemistry; Inflammation; Male; Motor Activity; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recovery of Function; Up-Regulation

The aim of this study was to determine the influence of inflammatory markers, predictive values of CRP and target hemoglobin (Hb) in patients on chronic hemodialysis.. Made is a cross-sectional study of inflammatory agents serum levels-CRP, fibrinogen and ferritin before hemodialysis in 114 patients divided into two groups according to the achieved or unachieved target hemoglobin level in the Cantonal Hospital in Zenica.. The 57 patients (test group) did not reached the target hemoglobin in the range from 10-12 g/dl and CRP values were significantly higher compared to the control group (57 patients) who had reached targeted hemoglobin values. Levels of fibrinogen and ferritin were not significantly different between the control and the test group. CRP values are in negative correlation with the Hb concentration, while fibrinogen and ferritin values had a positive correlation. Significant negative correlation was only found in case of CRP, respectively, higher CRP was at lower levels of blood Hb. It was found that the predictive value of CRP is 6.5 mg/L to achieve target Hb level. If the CRP increases by 1 mg/L, possibilities to achieve the target Hb level in dialysis patients is reduced by 7.5%, with a sensitivity of 51% and specificity of 77%. Ferritin was elevated due to iatrogenic iron saturation, because all patients received intravenous iron and was treated with erythropoietin. By identification and analysis of inflammatory agents and duration ofhemodialysis, are explored the primary influence on hematopoiesis, of course, with the primary application of erythropoietin and adjuvant agents. It has been shown that CRP alone has an impact on the target Hb level, depending on the hemodialysis duration.. The research results show how what looks as routine findings may be helpful in the timely detection of threatening complications and their treatment, and provide extended and improved quality of life for patients on hemodialysis.

Topics: Aged; Anemia; Biomarkers; C-Reactive Protein; Case-Control Studies; Cross-Sectional Studies; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Fibrinogen; Glucaric Acid; Hemoglobins; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Predictive Value of Tests; Renal Dialysis; ROC Curve; Sucrose

Cell encapsulation technology holds promise for the sustained and controlled delivery of different therapeutic proteins. Alginate-poly-L-lysine-alginate (APA) microcapsules represent one of the most widely studied alginate-polycation microcapsules. On the basis of this technology, two types of hydrogel-based scaffolds have been developed and analyzed with the aim of improving the retention and the retrieval of erythropoietin (Epo) secreting cell-loaded microcapsules in the tissue where they are implanted. Furthermore, these hydrogels may help to reduce the post-transplant inflammation and pericapsular fibrotic overgrowth typically observed around capsules. The hydrogel-based scaffolds could be administered as implantable forms (preformed scaffolds) or injectable forms (in situ formed scaffolds). The in vitro studies confirmed the correct adaptation of the enclosed cells to the scaffolds in terms of viability and protein expression. The posterior implantation of the cell-loaded capsules containing hydrogel-based scaffolds in mice revealed that the hematocrit levels were maintained up to 80% for at least 2 months. The histological analysis of the explanted microcapsules performed at that point showed that pericapsular overgrowth was reduced when cell-loaded microcapsules were enclosed in the hydrogels scaffolds. Incorporating microencapsulated cells within hydrogel-based scaffolds may help to improve their administration protocol and retention while reducing post-transplantation inflammation.

Topics: Alginates; Animals; Biocompatible Materials; Capsules; Drug Compounding; Drug Delivery Systems; Erythropoietin; Female; Hydrogels; Inflammation; Mice; Mice, Inbred BALB C; Myoblasts; Polylysine

Erythropoietin (EPO) has multiple biological functions, including the modulation of glucose metabolism. However, the mechanisms underlying the action of EPO are still obscure. This study is aimed at investigating the potential mechanisms by which EPO improves glucose tolerance in an animal model of type 2 diabetes. Male C57BL/6 mice were fed with high-fat diet (HFD) for 12 weeks and then treated with EPO (HFD-EPO) or vehicle saline (HFD-Con) for two week. The levels of fasting blood glucose, serum insulin and glucose tolerance were measured and the relative levels of insulin-related phosphatidylinositol 3-kinase (PI3K)/Akt, insulin receptor (IR) and IR substrate 1 (IRS1) phosphorylation were determined. The levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6- phosphatase (G6Pase), toll like receptor 4 (TLR4), tumor necrosis factor (TNF)-α and IL-6 expression and nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK) and p38 MAPK activation in the liver were examined. EPO treatment significantly reduced the body weights and the levels of fasting blood glucose and serum insulin and improved the HFD-induced glucose intolerance in mice. EPO treatment significantly enhanced the levels of Akt, but not IR and IRS1, phosphorylation, accompanied by inhibiting the PEPCK and G6Pase expression in the liver. Furthermore, EPO treatment mitigated the HFD-induced inflammatory TNF-α and IL-6 production, TLR4 expression, NF-κB and JNK, but not ERK and p38 MAPK, phosphorylation in the liver. Therefore, our data indicated that EPO treatment improved glucose intolerance by inhibiting gluconeogenesis and inflammation in the livers of HFD-fed mice.

Topics: Animals; Blood Glucose; Body Weight; Diet, High-Fat; Erythropoietin; Fasting; Feeding Behavior; Gene Expression Regulation; Gluconeogenesis; Glucose Intolerance; Glucose Tolerance Test; Glucose-6-Phosphatase; Humans; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Liver; Mice; Mice, Inbred C57BL; Obesity; Phosphoenolpyruvate Carboxykinase (ATP); Proto-Oncogene Proteins c-akt; Receptor, Insulin; Receptors, Erythropoietin; RNA, Messenger; Signal Transduction

Inflammation is a physiological defense response, but may also represent a potential pathological process in neurological diseases. In this regard, microglia have a crucial role in either progression or amelioration of degenerative neuronal damage. Because of the role of hypoxia in pro-inflammatory mechanisms in the nervous system, and the potential anti-inflammatory protective effect of erythropoietin (Epo), we focused our investigation on the role of this factor on activation of microglia and neuroprotection. Activation of microglial cells (EOC-2) was achieved by chemical hypoxia induced by cobalt chloride (CoCl2 ) and characterized by increased levels of nitrite, tumor necrosis factor-α and reactive oxygen species production, as well as up-regulation of inducible nitric oxide synthase expression. Under these conditions, cell proliferation data and proliferating cell nuclear antigen (PCNA) staining demonstrated a mitogenic effect of chemical hypoxia. Even though pre-treatment with Epo did not prevent nitrite production, inducible nitric oxide synthase protein expression or tumor necrosis factor-α secretion, it prevented the oxidative stress induced by CoCl2 as well as cell proliferation. Neuronal cells (SH-SY5Y) cultured in the presence of conditioned medium from activated EOC-2 cells or macrophages (RAW 264.7) developed significant apoptosis, an effect that was abolished by Epo via Epo/Epo receptor activation. The results show that even though Epo did not exert a direct anti-inflammatory effect on microglia activation, it did increase the resistance of neurons to subsequent damage from pro-inflammatory agents. In addition to its anti-apoptotic ability, the Epo antioxidant effect may have an indirect influence on neuronal survival by modulation of the pro-inflammatory environment.

Topics: Animals; Cell Hypoxia; Cell Proliferation; Cells, Cultured; Cobalt; Culture Media, Conditioned; Erythropoietin; Humans; Inflammation; Mice; Microglia; Neurons; Neuroprotective Agents; Neurotoxicity Syndromes; Nitric Oxide Synthase Type II; Nitrites; Proliferating Cell Nuclear Antigen; Reactive Oxygen Species; Receptors, Erythropoietin; Tumor Necrosis Factor-alpha

Alternate erythropoietin (EPO)-mediated signaling via the heteromeric receptor composed of the EPO receptor and the β-common receptor (CD131) exerts the tissue-protective actions of EPO in various types of injuries. Herein we investigated the effects of the EPO derivative helix beta surface peptide (synonym: ARA290), which specifically triggers alternate EPO-mediated signaling, but does not bind the erythropoietic EPO receptor homodimer, on the progression of secondary tissue damage following cutaneous burns. For this purpose, a deep partial thickness cutaneous burn injury was applied on the back of mice, followed by systemic administration of vehicle or ARA290 at 1, 12, and 24 h postburn. With vehicle-only treatment, wounds exhibited secondary microvascular thrombosis within 24 h postburn, and subsequent necrosis of the surrounding tissue, thus converting to a full-thickness injury within 48 h. On the other hand, when ARA290 was systemically administered, patency of the microvasculature was maintained. Furthermore, ARA290 mitigated the innate inflammatory response, most notably tumor necrosis factor-alpha-mediated signaling. These findings correlated with long-term recovery of initially injured yet viable tissue components. In conclusion, ARA290 may be a promising therapeutic approach to prevent the conversion of partial- to full-thickness burn injuries. In a clinical setting, the decrease in burn depth and area would likely reduce the necessity for extensive surgical debridement as well as secondary wound closure by means of skin grafting. This use of ARA290 is consistent with its tissue-protective properties previously reported in other models of injury, such as myocardial infarction and hemorrhagic shock.

Topics: Animals; Burns; Cell Line; Erythropoietin; Inflammation; Male; Mice; Mice, Inbred C57BL; Microvessels; Signal Transduction; Skin; Thrombosis; Tumor Necrosis Factor-alpha; Wound Healing

Topics: Erythropoietin; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Kidney Failure, Chronic; Male; Renal Dialysis

Drug delivery to the brain is challenging because systemic delivery requires high doses to achieve diffusion across the blood-brain barrier and often results in systemic toxicity. Intracerebroventricular implantation of a minipump/catheter system provides local delivery, yet results in brain tissue damage and can be prone to infection. An alternate local delivery strategy, epi-cortical delivery, releases the biomolecule directly to the brain while causing minimal tissue disruption. We pursued this strategy with a hyaluronan/methyl cellulose (HAMC) hydrogel for the local release of erythropoietin to induce endogenous neural stem and progenitor cells of the subventricular zone to promote repair after stroke injury in the mouse brain. Erythropoeitin promotes neurogenesis when delivered intraventricularly, thereby making it an ideal biomolecule with which to test this new epi-cortical delivery strategy. We investigated HAMC in terms of the host tissue response and the diffusion of erythropoeitin therefrom in the stroke-injured brain for neural repair. Erythropoietin delivered from HAMC at 4 and 11 days post-stroke resulted in attenuated inflammatory response, reduced stroke cavity size, increased number of both neurons in the peri-infarct region and migratory neuroblasts in the subventricular zone, and decreased apoptosis in both the subventricular zone and the injured cortex. We demonstrate that HAMC-mediated epi-cortical administration is promising for minimally invasive delivery of erythropoeitin to the brain.

Topics: Animals; Apoptosis; Brain; Cell Count; Cerebral Cortex; DNA-Binding Proteins; Doublecortin Domain Proteins; Drug Administration Routes; Drug Delivery Systems; Erythropoietin; Humans; Hyaluronic Acid; Hydrogel, Polyethylene Glycol Dimethacrylate; In Situ Nick-End Labeling; Inflammation; Ki-67 Antigen; Methylcellulose; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Nerve Tissue Proteins; Neuropeptides; Nuclear Proteins; Receptors, Erythropoietin; Stem Cells; Stroke

The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-κB activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLP+EPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-l-arginine methyl ester (l-NAME) simultaneously with EPO administration (CLP+EPO+l-NAME). A fifth group (CLP+EPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLP+EPO rats presented significantly higher inulin clearance than did CLP and CLP+EPO+l-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLP+EPO rats; and inulin clearance was significantly higher in CLP+EPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLP+EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-α activation, NF-κB activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-κB downregulation.

Topics: Acute Kidney Injury; Animals; Creatinine; Cytokines; Down-Regulation; Drug Therapy, Combination; Enzyme Inhibitors; Erythropoietin; I-kappa B Kinase; Inflammation; Inulin; Male; NF-kappa B; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Receptors, Erythropoietin; Sepsis; Up-Regulation

Erythropoietin (EPO) reduces symptoms of experimental autoimmune encephalomyelitis in rodents and shows neuroregenerative effects in chronic progressive multiple sclerosis. The mechanisms of action of EPO in these conditions with shared immunological etiology are still unclear. Therefore, we used a model of toxic demyelination allowing exclusion of T cell-mediated inflammation. In a double-blind (for food/injections), placebo-controlled, longitudinal four-arm design, 8-wk-old C57BL/6 mice (n = 26/group) were assigned to cuprizone-containing (0.2%) or regular food (ground chow) for 6 wks. After 3 wks, mice were injected every other day with placebo or EPO (5,000 IU/kg intraperitoneally) until the end of cuprizone feeding. Half of the mice were exposed to behavioral testing, magnetic resonance imaging (MRI) and histology immediately after treatment cessation, whereas the other half were allowed a 3-wk treatment-free recovery. Immediately after termination of cuprizone feeding, all toxin-exposed mice were compromised regarding vestibulomotor function/coordination, with EPO-treated animals performing better than placebo. Likewise, ventricular enlargement after cuprizone, as documented by MRI, was less pronounced upon EPO. After a 3-wk recovery, remarkable spontaneous improvement was observed in all mice with no measurable further benefit in the EPO group ("ceiling effect"). Histological analysis of the corpus callosum revealed attenuation by EPO of the cuprizone-induced increase in microglial numbers and amyloid precursor protein accumulations as a readout of inflammation and axonal degeneration. To conclude, EPO ameliorates neurological symptoms in the cuprizone model of demyelination, possibly by reduction of inflammation-associated axonal degeneration in white matter tracts. These findings underscore the value of future therapeutic strategies for multiple sclerosis based on EPO or EPO variants.

Topics: Amyloid beta-Protein Precursor; Animals; Axons; Cerebral Ventricles; Corpus Callosum; Cuprizone; Demyelinating Diseases; Erythropoietin; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Postural Balance; Psychomotor Performance

Chronic inflammation is increasingly recognized as a major contributor of human colorectal cancer (CRC). While gut microbiota can trigger inflammation in the intestinal tract, the precise signaling pathways through which host cells respond to inflammatory bacterial stimulation are unclear. Here, we show that gut microbiota enhances intestinal tumor load in the APC(Min/+) mouse model of CRC. Furthermore, systemic anemia occurs coincident with rapid tumor growth, suggesting a role for intestinal barrier damage and erythropoiesis-stimulating mitogens. Short-term stimulation assays of murine colonic tumor cells reveal that lipopolysaccharide, a microbial cell wall component, can accelerate cell growth via a c-Jun/JNK activation pathway. Colonic tumors are also infiltrated by CD11b+ myeloid cells expressing high levels of phospho-STAT3 (p-Tyr705). Our results implicate the role of gut microbiota, through triggering the c-Jun/JNK and STAT3 signaling pathways in combination with anemia, in the acceleration of tumor growth in APC(Min/+) mice.

Topics: Anemia; Animals; CD11b Antigen; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Erythropoietin; Genes, APC; Inflammation; Intestinal Mucosa; Intestines; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Macrophages; Metagenome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Tumor Burden

Anemia linked to a relative deficiency of renal erythropoietin production is a significant cause of morbidity and medical expenditures in the developed world. Recombinant erythropoietin is expensive and has been linked to excess cardiovascular events. Moreover, some patients become refractory to erythropoietin because of increased production of factors such as hepcidin. During fetal life, the liver, rather than the kidney, is the major source of erythropoietin. In the present study, we show that it is feasible to reactivate hepatic erythropoietin production and suppress hepcidin levels using systemically delivered siRNAs targeting the EglN prolyl hydroxylases specifically in the liver, leading to improved RBC production in models of anemia caused by either renal insufficiency or chronic inflammation with enhanced hepcidin production.

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; Base Sequence; Cells, Cultured; Erythropoiesis; Erythropoietin; Feasibility Studies; Female; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Procollagen-Proline Dioxygenase; Renal Insufficiency; RNA Interference; RNA, Small Interfering

Anaemia in heart failure (HF) is associated with a poor prognosis. Although inflammation is assumed to be an important cause of anaemia, the association between anaemia and inflammatory markers in patients with HF has not been well established.. Data from a multicentre randomised clinical trial, in which patients were eligible if they were >18 years of age and admitted for HF (New York Heart Association II-IV), were used. In a subset of 326 patients, haemoglobin (Hb), haematocrit, high sensitivity C-reactive protein (hsCRP), interleukin-(IL) 6, soluble tumour necrosis factor receptor (sTNFR)-1 and erythropoietin (Epo) were measured at discharge and the primary endpoint was all-cause mortality. Follow-up was 18 months.. Anaemia (Hb <13 g/dl (men) and <12 g/dl (women)) was present in 40% (130/326) of the study population. Median levels of IL-6, hsCRP and sTNFR-1 were significantly higher in anaemic patients than in non-anaemic patients. Logistic regression demonstrated that each increase in hsCRP values (OR 1.58 per SD log hsCRP; 95% CI 1.09 to 2.29; p=0.016) and each increase in sTNFR-1 values (OR 1.62 per SD log sTNFR-1; 95% CI 1.24 to 2.11; p<0.001) were independently associated with anaemia. Epo (HR 1.31 per log Epo; 95% CI 1.01 to 1.69; p=0.041) and sTNFR-1 (HR 1.47 per log sTNFR-1; 95% CI 1.16 to 1.86; p=0.001) levels were independently associated with outcome.. Anaemia is present in 40% of patients hospitalised for HF and is independently associated with inflammation.

Topics: Aged; Aged, 80 and over; Anemia; Biomarkers; C-Reactive Protein; Chi-Square Distribution; Erythropoietin; Female; Heart Failure; Hematocrit; Hemoglobins; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Logistic Models; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; Netherlands; Odds Ratio; Prognosis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Receptors, Tumor Necrosis Factor, Type I; Retrospective Studies; Risk Assessment; Risk Factors; Survival Analysis; Time Factors

Erythropoietin (EPO), used clinically for renal anemia, reportedly exerts beneficial pleiotropic effects in various tissues. Recent studies suggest that nitric oxide (NO) plays an important role in EPO-induced tissue protection. The present study investigated whether recombinant human EPO (rHuEPO) exhibits vasoprotective effects even in the NO synthase-inhibited state. Rats that received a NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), in drinking water (0.7 mg/ml) were treated with rHuEPO (75 U/kg, s.c.) three times a week for 2 weeks. The administration of rHuEPO to L-NAME-treated rats had no effect on hematocrit values or increased blood pressure. Vasodilation in response to acetylcholine in the aortic ring was impaired in the L-NAME-treated rats, and improved by rHuEPO. Immunohistochemical staining revealed that infiltration by macrophages and expression of osteopontin were enhanced in the L-NAME-treated rat aorta, and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Activation of Akt signaling was evident in rHuEPO-treated rats as the increased expression of phosphorylated Akt. rHuEPO enhanced the expression of antioxidant enzymes such as Cu/Zn-superoxide dismutase and heme oxygenase-1 in the aorta. In addition, rHuEPO reduced NADPH oxidase-dependent superoxide production and enhanced the expression of suppressor of cytokine signaling-1(SOCS-1) in the L-NAME-treated rat aorta. These results suggest that a low dose of rHuEPO results in the normalization of endothelial function and vascular inflammation beyond hematopoiesis even in a pharmacologically NO synthase-inhibited state. These effects might be due to the antioxidant properties of rHuEPO. SOCS-1 overexpression would play an important role in suppressing NADPH oxidase activation.

Topics: Acetylcholine; Adventitia; Animals; Aorta; Blood Pressure; Body Weight; Erythropoietin; Gene Expression Regulation; Hematocrit; Heme Oxygenase-1; Humans; Hypertension; Inflammation; Macrophages; Male; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Osteopontin; Phosphoproteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Superoxide Dismutase; Superoxides; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins

Cardiovascular diseases are the major cause of morbidity and mortality in hemodialysis (HD) patients. These patients present reduced paraoxonase 1 (PON1) activity that depends on genetic and non-genetic factors; however, how these factors influence PON1 activity in HD patients is poorly clarified. Our aim was to evaluate the influence of two polymorphisms and non-genetic factors on PON1 activity in HD patients.. We evaluated 183 HD patients under recombinant human erythropoietin (rhEPO) treatment and 22 healthy individuals. The lipid profile [total cholesterol, triglycerides, HDL-c, LDL-c, apolipoprotein (Apo) A-I, Apo B, lipoprotein(a) and oxidized low-density lipoprotein (Ox-LDL)], inflammatory markers [adiponectin, interleukin-6 (IL-6) and C-reactive protein (CRP)], PON1 activity and PON1 gene polymorphisms (L55M and Q192R) were evaluated.. HD patients presented higher levels of IL-6, CRP and Ox-LDL/LDL-c, and lower PON1 activity, total cholesterol, HDL-c, LDL-c, Apo A and Apo B; the most frequent genotype was heterozygosity for L55M polymorphism and homozygosity for the Q allele, the more frequent genotype of Q192R polymorphism. Multiple regression analysis identified heterozygosity and homozygosity for L55M and Q192R polymorphisms, very low-density lipoproteins, LDL-c, Apo A and CRP levels, time on dialysis and rhEPO dose, as the independent variables significantly associated with PON1 activity. The associations with CRP, rhEPO and time on dialysis were negative.. Our results show that the reduced PON1 activity in HD patients who are not under statin therapy is strongly associated with inflammation, longer time on dialysis and high rhEPO doses, suggesting that the reduction in PON1 activity may worsen the prognosis of these patients.

Topics: Adiponectin; Aged; Aged, 80 and over; Anemia; Aryldialkylphosphatase; Biomarkers; C-Reactive Protein; Enzyme Activation; Erythropoietin; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interleukin-6; Kidney Failure, Chronic; Lipids; Male; Middle Aged; Polymorphism, Genetic; Prognosis; Renal Dialysis; Risk Factors

New therapeutic strategies for chronic kidney disease (CKD) are necessary to offset the rising incidence of CKD and donor shortage. Erythropoietin (EPO), a cytokine produced by fibroblast-like cells in the kidney, has recently emerged as a renoprotective factor with anti-inflammatory, antioxidant properties. This study (a) determined whether human renal cultures (human primary kidney cells [hPKC]) can be enriched in EPO-positive cells (hPKC(F+)) by using magnetic-bead sorting; (b) characterized hPKC(F+) following cell separation; and (c) established that intrarenal delivery of enriched hPKC(F+) cells would be more beneficial in treatment of renal injury, inflammation, and oxidative stress than unsorted hPKC cultures in a chronic kidney injury model. Fluorescence-activated cell sorting analysis revealed higher expression of EPO (36%) and CD73 (27%) in hPKC(F+) as compared with hPKC. After induction of renal injury, intrarenal delivery of hPKC(F+) or hPKC significantly reduced serum creatinine, interstitial fibrosis in the medulla, and abundance of CD68-positive cells in the cortex and medulla (p < .05). However, only hPKC(F+) attenuated interstitial fibrosis in the renal cortex and decreased urinary albumin (3.5-fold) and urinary tubular injury marker kidney injury molecule 1 (16-fold). hPKC(F+) also significantly reduced levels of renal cortical monocyte chemotactic protein 1 (1.8-fold) and oxidative DNA marker 8-hydroxy-deoxyguanosine (8-OHdG) (2.4-fold). After 12 weeks, we detected few injected cells, which were localized mostly to the cortical interstitium. Although cell therapy with either hPKC(F+) or hPKC improved renal function, the hPKC(F+) subpopulation provides greater renoprotection, perhaps through attenuation of inflammation and oxidative stress. We conclude that hPKC(F+) may be used as components of cell-based therapies for degenerative kidney diseases.

Topics: Animals; Blotting, Western; Cell Proliferation; Cell Separation; Cell- and Tissue-Based Therapy; Erythropoietin; Female; Humans; Inflammation; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Rats; Rats, Nude; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Anemia is common in patients with chronic kidney disease (CKD). Recently, the erythropoiesis-stimulating agent/hemoglobin level (ESA/Hb) index emerged as a new factor associated with increased morbidity and mortality in this population. In this study, we evaluated the factors that influence the ESA/Hb index in a pre-dialysis CKD population.. Ninety-five patients were evaluated for clinical and laboratory parameters, nutritional status and ESA/Hb index. For comparison, we divided our population into 3 groups: G I--no ESA treatment, G II--patients with ESA/index below 50th percentile and G III--patients with ESA/Hb index above 50th percentile. We performed single and multiple regression models and logistic regression analysis.. In a multiple regression model, age (t = -3.456, P = 0.001), SGA (t = 2.059, P = 0.047), ferritin (t = 2.386, P = 0.027), Ca × P (t = 2.066, P = 0.043), TNF-α (t = 2.673, P = 0.009) and IL-6 (t = 2.939, P = 0.004) independently influenced the ESA/Hb index. At logistic regression analysis, gender, cardiovascular disease and TNF-α were independently associated with ESA/Hb higher than 50th percentile compared to the other patients (R(2) = 0.457).. In a pre-dialysis population, female gender, cardiovascular disease, malnutrition and inflammation are associated with a higher ESA/Hb index.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Anemia; Cardiovascular Diseases; Chi-Square Distribution; Darbepoetin alfa; Drug Resistance; Erythropoietin; Female; Ferritins; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Inflammation; Interleukin-6; Kidney Failure, Chronic; Logistic Models; Male; Malnutrition; Middle Aged; Risk Factors; Sex Factors; Tumor Necrosis Factor-alpha

The hurtful feelings associated with failing can be devastating especially if the failure occurs after the investment of a considerable effort. The reflection of a lifetime of work in translational medicine has revealed that the study of failures can give birth to new insights that can be explored with important consequences. This article discusses the analysis of two failures that have led to remarkable discoveries. The first led to the discovery of TNF as an important mediator of inflammation that can, if unchecked, cause severe damage in mammals. The second is the identification of erythropoietin as the natural inhibitor of the production and biological activity of TNF. I hope that this paper will help give students the courage to persist in looking for the insights that are the by-products of failure, and to understand the long time lines in the path of discoveries.

Topics: Animals; Disease Models, Animal; Erythropoietin; History, 20th Century; Humans; Incidental Findings; Inflammation; Tumor Necrosis Factor-alpha

Systemic inflammation may represent a possible cause of anemia. Previous data support that anemic patients with COPD present high erythropoietin (EPO) levels, suggestive of EPO resistance, possibly mediated through inflammatory mechanisms.. We aimed to determine whether systemic inflammation, which is usually up-regulated during exacerbations of COPD (ECOPD) is associated with low hemoglobin levels expressing erythropoietin resistance.. Hemoglobin (Hb), EPO and serum biomarkers of systemic inflammation [CRP, TNF-α, fibrinogen and IL-6] were assessed at three time points (admission, resolution and stable phases) in a selected cohort of 93 COPD patients.. Hemoglobin levels were significantly lower on admission compared to resolution and stable phases (median 12.1 g/dl [interquartile ranges 11.2-12.7], vs 13.5 [12.4-14.3] vs 13.4 [12.7-14.08], respectively p=0.002), whereas EPO was significantly higher on admission compared to resolution and stable phases. A negative association between Hb and IL-6 and a positive association between EPO and IL-6 were observed only during the acute phase of exacerbation. EPO and Hb were negatively associated during the acute phase, whereas they were positively associated during discharge and stable phase.. In this observational study we have shown that during admission for ECOPD Hb levels are decreased and EPO levels are increased. We have also identified a negative association between Hb and EPO. The above association is mainly related to increased IL-6 levels, indicating a possible EPO resistance through the mechanism of increased systemic inflammatory process.

Topics: Aged; Biomarkers; Cohort Studies; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Recurrence; Risk Assessment; Risk Factors; Tumor Necrosis Factor-alpha

This study aimed to explore the relationship between recombinant human erythropoietin (EPO) responsiveness, insulin resistance, and malnutrition-inflammation-atherosclerosis (MIA) syndrome in hemodialysis patients.. This was an observational cohort study in hemodialysis patients. Adipokines, inflammatory cytokines, and required EPO dosage were measured in diabetes (DM; n=58) and non-diabetes (non-DM; n=58) groups over 48 weeks. Furthermore, the EPO responsiveness index (required EPO dosage divided by hemoglobin) was evaluated with or without MIA syndrome in both groups.. The DM group had significantly higher plasma leptin, interleukin-6 (IL-6), and high sensitivity C-reactive protein (hs-CRP) levels but lower plasma high molecular weight (HMW) adiponectin levels compared to the non-DM group. Although hemoglobin levels were not significantly different, required EPO dosage was significantly higher in the DM group than in the non-DM group, particularly in the presence of MIA syndrome. The DM group with MIA syndrome had significantly higher plasma leptin, IL-6, and hs-CRP levels but lower plasma HMW adiponectin levels compared to the non-DM group with MIA syndrome. There was also a significant association between EPO dosage and homeostasis model assessment for insulin resistance (HOMA-IR), hs-CRP, IL-6, tumor necrosis factor a, leptin, and HMW adiponectin levels in DM patients with MIA syndrome.. Diabetic hemodialysis patients with MIA syndrome have a lower response to EPO and a higher resistance to insulin. This fact may explain the poor outcome of these patients and demonstrate the importance of diagnosis and therapeutic management.

Topics: Aged; Analysis of Variance; Anemia; Atherosclerosis; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glycated Hemoglobin; Hematinics; Humans; Inflammation; Inflammation Mediators; Insulin Resistance; Japan; Kidney Failure, Chronic; Lipids; Male; Malnutrition; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Syndrome; Time Factors; Treatment Outcome

Erythropoietin (EPO) is a multifunctional cytokine with anti-apoptotic, anti-inflammatory, and organ protective effects. EPO protects against ischemia-reperfusion injuries, and recent reports suggest that EPO also prevents organ dysfunction in experimental sepsis. The aims of this study were to determine whether EPO prevents endotoxemia-induced organ dysfunction in a porcine model and to characterize the immunomodulatory and anti-apoptotic effects of EPO.. Twenty-eight pigs were randomly assigned to three groups: (1) endotoxemia treated with EPO 5000 IU/kg, (2) endotoxemia treated with placebo, and (3) a sham group anesthetized and submitted to sham operation without treatment. A laparotomy was performed, and a flow probe was placed around the left renal artery, which allowed renal blood flow (RBF) measurements. Endotoxemia was induced by an infusion of lipopolysaccharide. After 2 h, the infusion was reduced to a maintenance dose and the animals were fluid resuscitated. The glomerular filtration rate (GFR), RBF, renal oxygen consumption, and plasma cytokines [interleukin (IL)-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha] were analyzed. Renal biopsies were analyzed for cytokine content and apoptosis.. Endotoxemia elicited impaired renal function, estimated as GFR, and increased the levels of renal apoptotic cells, with no modifying effect of EPO. Furthermore, EPO had no effect on RBF, renal oxygen consumption, or the systemic hemodynamic response to endotoxemia. EPO did not modify the inflammatory response, measured as changes in cytokine levels in plasma and organs.. EPO did not confer renal protection in this fluid-resuscitated porcine model of endotoxemia, and EPO did not modify the inflammatory response.

Topics: Animals; Apoptosis; Caspase 3; Cytokines; Endotoxemia; Erythropoietin; Female; Glomerular Filtration Rate; Hemodynamics; Immunohistochemistry; Inflammation; Kidney; Kidney Diseases; Kidney Function Tests; Lipopolysaccharides; Oxygen Consumption; Recombinant Proteins; Renal Circulation; Resuscitation; Swine; Tumor Necrosis Factor-alpha

Ischemia reperfusion injury associated with apoptosis and inflammation plays crucial roles in renal transplantation. Erythropoietin provides renoprotection, but its effects and mechanisms on kidney preservation are not fully defined. Porcine kidneys, subjected to 10 min warm ischemia, underwent 16 h cold storage followed by 2 h normothermic hemoperfusion with or without 5000 units/L erythropoietin. Apoptotic cells were increased in tubular lumens and interstitial areas by normothermic perfusion alone, but decreased in tubular areas by additional erythropoietin. Myeloperoxidase+ cells, free cells and cell debris in tubular lumens were gradually increased by cold storage, normothermic perfusion and erythropoietin in normothermic perfusion. Accordingly, caspase-3 activity as well as its active proteins was increased by normothermic perfusion and furthered by erythropoietin. In contrast, macrophage L1 protein positive cells in tubulointerstitial areas, cytokine interleukin (IL)-1β activation, tubular dilation and vacuolation were raised by normothermic perfusion, but all alleviated by erythropoietin, with higher urine output. The migration of myeloperoxidase+ cells with apoptotic features and apoptotic cells with polymorphous nuclei from tubulointerstitial areas into tubular lumens was widely displayed in the kidneys, especially those preserved by erythropoietin in normothermic perfusion. HSP70 protein was enhanced by normothermic perfusion regardless of erythropoietin. In addition, erythropoietin induced a dose-dependent increase in caspase-3 precursor in porcine proximal tubular cells (LLC-PK1) and also stimulated caspase-3 cleavage in cisplatin-treated cells. In conclusion, erythropoietin promotes inflammatory cell apoptosis, drives inflammatory and apoptotic cells into tubular lumens, eventually leads to inflammation clearance, renoprotection and tissue remodelling through caspase-3 and IL-1β in isolated haemoperfused kidneys.

Topics: Animals; Apoptosis; Caspase 3; Cell Line; Cold Temperature; Erythropoietin; Hemoperfusion; HSP70 Heat-Shock Proteins; In Vitro Techniques; Inflammation; Interleukin-1beta; Ischemic Preconditioning; Kidney; Kidney Tubules; Molecular Weight; Swine

Patients with end-stage renal disease are prone to inflammation and inflammation is related to erythropoietin-stimulating agent hyporesponsiveness and mortality in this population. Statins have been demonstrated to reduce cardiovascular mortality in selected populations of end-stage renal disease patients. These drugs have pleiotrophic effects such as anti-inflammation. In this retrospective analysis, we determined whether the use of statins improves inflammation and inflammation-related anemia in a cohort of hemodialysis patients. Data were analyzed from Fresenius Medical Care Dialysis Clinics in Turkey between 2005 and 2007. Seventy prevalent hemodialysis patients who were on statins at the start of the study and have been on statins during follow-up (statin users) and 1293 patients who were not on statin at the start of the study and had never been prescribed any lipid-modifying drugs during follow-up (statin nonusers) were included in the study. High-sensitive C-reactive protein levels were significantly decreased in statin users (1.50±1.49 vs. 1.33±1.11 mg/L, P=0.05) compared with nonusers (1.93±3.22 vs. 2.05±2.77 mg/L). Hemoglobin levels and the rate of erythropoietin-stimulating agent users were similar. However, the prescribed erythropoietin-stimulating agent dose (31.6±27.5 vs. 47.3±45.2 U/kg/week, P<0.05) and the erythropoietin response index (2.90±2.73 vs. 4.51±4.48 U/kg/week/Hb, P=0.001) were lower in statin users compared with statin nonusers. On stepwise multiple regression analysis, gender, high-sensitive C-reactive protein, duration of hemodialysis, serum ferritin, and statin use were independent determinants of the erythropoietin responsiveness index. Our results suggest that statin treatment leads to lower inflammation and improves hematopoiesis in hemodialysis patients.

Topics: Adult; Aged; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Retrospective Studies

Periventricular leukomalacia (PVL) is the predominant pathology in premature infants, characterized by prominent cerebral white matter injury, and commonly caused by hypoxia-ischemia and inflammation. Activated microglia trigger white matter damage and play a major role in the development of PVL. Erythropoietin (EPO) and its derivative carbamylated erythropoietin (CEPO) have been shown to be neuroprotective in several brain disease models. Here we investigated whether EPO and CEPO could provide protection in mouse models of PVL induced by hypoxia-ischemia or hypoxia-ischemia-inflammation. We administered EPO or CEPO to mice with PVL, and found that both EPO and CEPO treatments decreased microglia activation, oligodendrocyte damage and myelin depletion. We also noted improved performance in neurological function assays. Inhibited disease progression in PVL mice by EPO or CEPO treatment was associated with decreased poly-(ADP-ribose) polymerase-1 (PARP-1) activity. PARP-1 activity was increased dramatically in activated microglia in untreated mice with PVL. Furthermore, we demonstrated that the neuroprotective properties of EPO and CEPO were diminished after PARP-1 gene depletion. The therapeutic doses of EPO and CEPO used in this study did not interfere with normal oligodendrocyte maturation and myelination. Together, our data demonstrate that EPO and CEPO are neuroprotective in cerebral white matter injury via a novel microglial PARP-1 dependent mechanism, and hold promise as a future treatment for PVL and other hypoxic-ischemic/inflammatory white matter diseases.

Topics: Animals; Brain; Brain Ischemia; Disease Models, Animal; Erythropoietin; Humans; Hypoxia; Infant, Newborn; Inflammation; Leukomalacia, Periventricular; Mice; Microglia; Myelin Sheath; Neurons; Neuroprotective Agents; Oligodendroglia

To accurately determine the causes of anemia and proportion of unexplained anemia in a racially diverse cohort of older adults after a comprehensive and standardized evaluation.. We evaluated results from a single-institutional university anemia clinic. Patients with anemia, defined as a hemoglobin less than 13.0 g/dL for men and less than 12.0 g/dL for women, underwent a prospective standardized history, physical examination, and laboratory measures, with additional studies including bone marrow examination as indicated. Empiric treatment trials were given for identified deficiencies.. One hundred and seventy-four primarily community-dwelling adults aged 65 years and older were evaluable. African Americans accounted for 69% of patients and whites were 27%. Anemia etiologies included iron deficiency anemia at 25.3%, anemia of chronic inflammation at 9.8%, and hematologic malignancy in 7.5%. Unexplained anemia in the elderly accounted for 43.7% and predominated in both African Americans and whites. The prevalence of iron deficiency anemia and hematologic malignancies did not differ by race. Unexplained anemia in the elderly showed a consistent phenotype composed of a hypoproliferative mild-to-moderate anemia with suppressed serum erythropoietin. Specifically, erythropoietin levels showed no correlation with hemoglobin concentration in unexplained anemia in the elderly (r = -.15, p = .19) as opposed to iron deficiency anemia (r = -.63, p < .0001).. In summary, an intensive hematologic evaluation reveals a wide number of anemia etiologies among older adults, including 7.5% with hematologic malignancies; nevertheless, unexplained anemia in the elderly prevails as the most common category in whites and African Americans.

Topics: Aged; Aging; Anemia; Anemia, Iron-Deficiency; Black or African American; Chronic Disease; Cohort Studies; Erythropoietin; Female; Hematologic Neoplasms; Hemoglobins; Humans; Inflammation; Male; Outpatient Clinics, Hospital; Prevalence; Prospective Studies; Referral and Consultation; White People

Stroke affects infants at a rate of 26/100,000 live births each year. Of these strokes, approximately 6.7 are hemorrhagic strokes. Erythropoietin (EPO) is an anti-apoptotic and neuroprotective hormone. In adult rodents, EPO attenuates inflammatory factor expression and blood-brain barrier damage after intracerebral hemorrhage (ICH). However, the effect of EPO in neonatal ICH stroke remains unexplored. This investigation aimed to elucidate the underpinnings of inflammation after ICH in postnatal day 7 (P7) rats and the effect of human recombinant EPO (hrEPO) treatment on ICH-induced inflammation. The P7 rat pups were pretreated with hrEPO (5,000 U/kg i.p.) or saline vehicle 4 h prior to the induction of ICH by blood injection into the right cerebral cortex and basal ganglia. Supplemental half doses of hrEPO treatment or saline injections were subsequently given 16 h after ICH induction. Real-time PCR done 24 h after ICH showed reductions in interleukin1-β (IL1-β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) mRNA expression in the basal ganglia of the hrEPO-treated rats compared to saline-treated rats. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining indicated fewer dying cells in the hrEPO-treated brain. Our data suggest that hrEPO has an anti-inflammatory action in neonates after ICH. The suppression of inflammatory cascades likely contributes to hrEPO's neuroprotective effect, which may be explored as a therapeutic treatment for ICH.

Topics: Analysis of Variance; Animals; Animals, Newborn; Cell Death; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Erythropoietin; Gene Expression Regulation; In Situ Nick-End Labeling; Inflammation; Rats; Rats, Wistar; RNA, Messenger

Anemia and inflammation are prevalent in diabetic patients with chronic kidney disease (CKD). The role of endogenous erythropoietin (EPO) in the pathophysiology of anemia in chronic diseases and its relationship to clinical outcomes remain uncertain. In this cohort study, we aimed to identify factors associated with endogenous EPO levels and investigate their relation to all-cause mortality.. Between 2004 and 2005, 215 patients with type 2 diabetes were enrolled. Exclusion criteria included stage renal disease ESRD and any form of anemia therapy. The association of EPO levels with clinical and laboratory variables was investigated by linear regression modeling. Predictors of all-cause mortality were evaluated by Cox proportional hazards analyses.. Patients (median age, 67 years; 52% men; median duration of diabetes, 10 years; median estimated GFR, 49 ml/min per 1.73 m²) were followed for up to 7.0 years. Forty-one patients died. Elevated EPO levels were independently associated with elevated C-reactive protein, low ferritin, and hypertension, in a multivariate model that also included age, cardiovascular disease, kidney function, albumin, cholesterol, and hemoglobin. Higher EPO levels were independently predictive for mortality, as were age, low levels of albumin, and cardiovascular disease.. In diabetic patients with CKD, elevated endogenous EPO levels were predictive for mortality and were related mainly to markers of inflammation, independent of kidney function, and despite low hemoglobin levels. Understanding the phenomenon of EPO resistance and iron dysregulation caused by inflammation is crucial for effective and safe treatment of anemia in patients with CKD.

Topics: Aged; Analysis of Variance; Anemia; Biomarkers; C-Reactive Protein; Chronic Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Germany; Humans; Inflammation; Inflammation Mediators; Kaplan-Meier Estimate; Linear Models; Longitudinal Studies; Male; Prognosis; Proportional Hazards Models; Risk Assessment; Risk Factors; Time Factors; Up-Regulation

Painful stimuli during neonatal stage may affect brain development and contribute to abnormal behaviors in adulthood. Very few specific therapies are available for this developmental disorder. A better understanding of the mechanisms and consequences of painful stimuli during the neonatal period is essential for the development of effective therapies. In this study, we examined brain reactions in a neonatal rat model of peripheral inflammatory pain. We focused on the inflammatory insult-induced brain responses and delayed changes in behavior and pain sensation. Postnatal day 3 pups received formalin injections into the paws once a day for 3 days. The insult induced dysregulation of several inflammatory factors in the brain and caused selective neuronal cell death in the cortex, hippocampus and hypothalamus. On postnatal day 21, rats that received the inflammatory nociceptive insult exhibited increased local cerebral blood flow in the somatosensory cortex, hyperalgesia, and decreased exploratory behaviors. Based on these observations, we tested recombinant human erythropoietin (rhEPO) as a potential treatment to prevent the inflammatory pain-induced changes. rhEPO treatment (5,000 U/kg/day, i.p.), coupled to formalin injections, ameliorated neuronal cell death and normalized the inflammatory response. Rats that received formalin plus rhEPO exhibited normal levels of cerebral blood flow, pain sensitivity and exploratory behavior. Treatment with rhEPO also restored normal brain and body weights that were reduced in the formalin group. These data suggest that severe inflammatory pain has adverse effects on brain development and rhEPO may be a possible therapy for the prevention and treatment of this developmental disorder.

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Brain; Cell Death; Cerebrovascular Circulation; Cytokines; Disease Models, Animal; Erythropoietin; Exploratory Behavior; Formaldehyde; Humans; Hyperalgesia; Inflammation; Inflammation Mediators; Neurons; Neuroprotective Agents; Organ Size; Pain; Rats

It is not clear why cardiac or renal cachexia in chronic diseases is associated with poor cardiovascular outcomes. Platelet reactivity predisposes to thromboembolic events in the setting of atherosclerotic cardiovascular disease, which is often present in patients with end-stage renal disease (ESRD).. We hypothesized that ESRD patients with relative thrombocytosis (platelet count >300 × 10(3)/μL) have a higher mortality rate and that this association may be related to malnutrition-inflammation cachexia syndrome (MICS).. We examined the associations of 3-mo-averaged platelet counts with markers of MICS and 6-y all-cause and cardiovascular mortality (2001-2007) in a cohort of 40,797 patients who were receiving maintenance hemodialysis.. The patients comprised 46% women and 34% African Americans, and 46% of the patients had diabetes. The 3-mo-averaged platelet count was 229 ± 78 × 10(3)/μL. In unadjusted and case-mix adjusted models, lower values of albumin, creatinine, protein intake, hemoglobin, and dialysis dose and a higher erythropoietin dose were associated with a higher platelet count. Compared with patients with a platelet count of between 150 and 200 × 10(3)/μL (reference), the all-cause (and cardiovascular) mortality rate with platelet counts between 300 and <350, between 350 and <400, and ≥400 ×10(3)/μL were 6% (and 7%), 17% (and 15%), and 24% (and 25%) higher (P < 0.05), respectively. The associations persisted after control for case-mix adjustment, but adjustment for MICS abolished them.. Relative thrombocytosis is associated with a worse MICS profile, a lower dialysis dose, and higher all-cause and cardiovascular disease death risk in hemodialysis patients; and its all-cause and cardiovascular mortality predictability is accounted for by MICS. The role of platelet activation in cachexia-associated mortality warrants additional studies.

Topics: Adult; Aged; Albumins; Atherosclerosis; Black or African American; Cachexia; Cause of Death; Cohort Studies; Creatinine; Diabetes Mellitus; Dialysis; Dietary Proteins; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Kidney Failure, Chronic; Male; Malnutrition; Middle Aged; Platelet Count; Prevalence; Thrombocytosis

This study tested the superiority of combined cyclosporine A (CsA)-erythropoietin (EPO) therapy compared with either one in limiting brain infarction area (BIA) and preserving neurological function in rat after ischemic stroke (IS).. Fifty adult-male SD rats were equally divided into sham control (group 1), IS plus intra-peritoneal physiological saline (at 0.5/24/48 h after IS) (group 2), IS plus CsA (20.0 mg/kg at 0.5/24h, intra-peritoneal) (group 3), IS plus EPO (5,000IU/kg at 0.5/24/48h, subcutaneous) (group 4), combined CsA and EPO (same route and dosage as groups 3 and 4) treatment (group 5) after occlusion of distal left internal carotid artery.. BIA on day 21 after acute IS was higher in group 2 than in other groups and lowest in group 5 (all p < 0.01). The sensorimotor functional test showed higher frequency of left turning in group 2 than in other groups and lowest in group 5 (all p < 0.05). mRNA and protein expressions of apoptotic markers and number of apoptotic nuclei on TUNEL were higher in group 2 than in other groups and lowest in group 1 and 5, whereas the anti-apoptotic markers exhibited an opposite trend (all p < 0.05). The expressions of inflammatory and oxidized protein were higher in group 2 than in other groups and lowest in group 1 and 5, whereas anti-inflammatory markers showed reversed changes in group 1 and other groups (all p < 0.05). The number of aquaporin-4+ and glial fibrillary acid protein+ stained cells were higher in group 2 as compared to other groups and lowest in groups 1 and 5 (all p < 0.01).. combined treatment with CsA and EPO was superior to either one alone in protecting rat brain from ischemic damage after IS.

Topics: Animals; Apoptosis; Aquaporin 4; Brain Infarction; Cell Nucleus; Cyclosporine; Cytochromes c; Drug Therapy, Combination; Erythropoietin; Gene Expression Regulation; Glial Fibrillary Acidic Protein; In Situ Nick-End Labeling; Inflammation; Male; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Sprague-Dawley; Recovery of Function; RNA-Binding Proteins; RNA, Messenger; Stroke; Transcription Factors

Erythropoietin (EPO) is a pleiotropic cytokine originally identified for its role in erythropoiesis. In addition, in various preclinical models EPO exhibited protective activity against tissue injury. There is an urgent need for potent treatments of autoimmune driven disorders of the peripheral nervous system (PNS), such as the Guillain-Barré syndrome (GBS), a disabling autoimmune disease associated with relevant morbidity and mortality. To test the therapeutic potential of EPO in experimental autoimmune neuritis (EAN) - an animal model of human GBS--immunological and clinical effects were investigated in a preventive and a therapeutic paradigm. Treatment with EPO reduced clinical disease severity and if given therapeutically also shortened the recovery phase of EAN. Clinical findings were mirrored by decreased inflammation within the peripheral nerve, and myelin was well maintained in treated animals. In contrast, EPO increased the number of macrophages especially in later stages of the experimental disease phase. Furthermore, the anti-inflammatory cytokine transforming growth factor (TGF)-beta was upregulated in the treated cohorts. In vitro experiments revealed less proliferation of T cells in the presence of EPO and TGF-beta was moderately induced, while the secretion of other cytokines was almost not altered by EPO. Our data suggest that EPO revealed its beneficial properties by the induction of beneficial macrophages and the modulation of the immune system towards anti-inflammatory responses in the PNS. Further studies are warranted to elaborate the clinical usefulness of EPO for treating immune-mediated neuropathies in affected patients.

Topics: Animals; Cytokines; Erythropoietin; Inflammation; Macrophages; Neuritis, Autoimmune, Experimental; Rats; Transcriptional Activation; Transforming Growth Factor beta; Treatment Outcome

Cancer is known to be an important cause of anaemia due to several factors including iron deficiency and inflammation. Hepcidin, a key regulator of iron metabolism, is up-regulated by iron and inflammatory stimuli such as interleukin 6, and decreased by iron deficiency, enhanced erythropoiesis and hypoxia. It is supposed to play a crucial role in changes of iron metabolism in anaemia of chronic disease, which is characterized by sequestering iron in macrophages and decreasing its availability for red blood cell production. To study the effect of tumour growth on hepcidin expression, we implanted human melanoma cells into mice and studied the changes of the amount of liver hepcidin mRNA by real-time PCR. We observed development of anaemia, which correlated with the size of the tumour. Hepcidin expression significantly decreased with the anaemia development, but in late stages we observed an increase of its expression together with an increase of mRNA for interleukin 6. However, the increase of hepcidin expression could be inhibited by exogenous erythropoietin administration. In our model of tumour growth, hepcidin expression reflected anaemia development and iron deficiency, erythropoietin administration and inflammation, and we suppose that it could therefore serve as a useful marker of these clinical situations common in cancer patients and play a role in the pathogenesis of cancer-associated anaemia.

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; Cell Proliferation; Erythropoietin; Gene Expression Regulation, Neoplastic; Hepcidins; Humans; Inflammation; Injections, Subcutaneous; Interleukin-6; Iron Deficiencies; Liver; Male; Melanoma; Mice; Mice, Inbred C57BL; Neoplasm Proteins; RNA, Messenger; Xenograft Model Antitumor Assays

This protocol describes microsphere-based protease assays for use in flow cytometry and high-throughput screening. This platform measures a loss of fluorescence from the surface of a microsphere due to the cleavage of an attached fluorescent protease substrate by a suitable protease enzyme. The assay format can be adapted to any site or protein-specific protease of interest and results can be measured in both real time and as endpoint fluorescence assays on a flow cytometer. Endpoint assays are easily adapted to microplate format for flow cytometry high-throughput analysis and inhibitor screening.

Topics: Animals; Biotinylation; Flow Cytometry; Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins; High-Throughput Screening Assays; Humans; Inflammation; Kinetics; Microspheres; Peptide Hydrolases; Peptides; Reproducibility of Results; Temperature

It is known that pro-inflammatory cytokines suppress in vitro the gene expression and protein production of erythropoietin (Epo). We hypothesized that systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) may influence Epo production, particularly during episodes of exacerbation of the disease (ECOPD) where an inflammatory burst is known to occur.. We compared the plasma levels of Epo and high-sensitivity (hs) C-reactive protein (hsC-RP) in patients hospitalized because of ECOPD (n = 26; FEV(1): 48 +/- 15% predicted), patients with clinically stable COPD (n = 31; FEV(1): 49 +/- 17% predicted), smokers with normal lung function (n = 9), and healthy never smokers (n = 9).. Venous blood samples were taken between 9 and 10 a.m. after an overnight fast into tubes with EDTA (10 ml) or without EDTA (10 ml). Plasma levels of Epo (R&D Systems Inc., Minneapolis, Minn., USA) and hsC-RP (BioSource, Belgium) were determined by ELISA.. Log-Epo plasma levels were significantly lower (0.46 +/- 0.32 mU/ml) in ECOPD than in stable COPD (1.05 +/- 0.23 mU/ml), smokers (0.95 +/- 0.11 mU/ml) and never smokers with normal lung function (0.92 +/- 0.19 mU/ml) (p < 0.01, each). In a subset of 8 COPD patients who could be studied both during ECOPD and clinical stability, log-Epo increased from 0.49 +/- 0.42 mU/ml during ECOPD to 0.97 +/- 0.19 mU/ml during stability (p < 0.01). In patients with COPD log-Epo was significantly related to hsC-RP (r = -0.55, p < 0.0001) and circulating neutrophils (r = -0.48, p < 0.0001).. These results show that the plasma levels of Epo are reduced during ECOPD likely in relation to a burst of systemic inflammation.

Topics: Aged; C-Reactive Protein; Erythropoietin; Humans; Inflammation; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Smoking

Exercise in humans augments the mobilization of circulating hematopoietic progenitor cells (CD34(+)) from the bone marrow. We investigated the effect of inflammation on erythroid marrow activity by mobilization of erythroid progenitor cells (EPs) along with soluble markers of erythropoiesis.. Ten healthy athletes who participated in an ultradistance foot race participated in the study. Peripheral blood mononuclear cells were isolated, before (phase I), at the end (phase II), and at 48 h post-race (phase III). EPs were detected as burst colony forming units (BFU-e) and colonies were scored at day 14. Markers of inflammation (C-reactive protein, serum amyloid-A, interleukin-6, ferritin and S100B) and bone marrow activity (erythropoietin, soluble transferrin receptor and lipocalin-2) were assessed.. An approximately three-fold decrease in BFU-e number was observed at phase II. sTfR concentrations were also decreased at phase II and remained decreased at phase III. However, EPO and lipocalin-2 concentrations reached a maximum value at phase II, with a tendency to decrease at phase III.. These findings indicate that exercise-induced inflammation modulates bone marrow homeostasis leading to an increase in leukocyte turnover and a decrease in erythroid compartment. It appears that lipocalin-2 is the main factor that regulates the production and mobilization of EPs.

Topics: Acute-Phase Proteins; Athletes; Biomarkers; Bone Marrow; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Ferritins; Humans; Inflammation; Lipocalin-2; Lipocalins; Physical Exertion; Proto-Oncogene Proteins; Receptors, Transferrin; Running; Time Factors

Soluble Fas levels (sFas) are increased in the serum of uremic patients and are associated with the presence of anemia and recombinant human EPO (rHuEPO) dosage in dialysis patients. It is possible that sFas levels are associated with an increased need for serum erythropoietin levels (Epo) in chronic kidney disease and dialysis patients in order to maintain hematocrit (Hct) levels.. To investigate the relationship between serum sFas levels, serum Epo levels and the ratio between Epo levels and Hct in uremic patients.. We studied 52 predialysis chronic kidney disease patients (CKD; 33 M, 57 +/- 12 years, hematocrit (Hct) = 37 +/- 7%), 29 peritoneal dialysis patients (PD; 12 M, 54 +/- 14 years, Hct = 36 +/- 7%), 29 hemodialysis patients (HD; 19 M, 47 +/- 14 years, Hct = 33 +/- 5%) and 29 healthy volunteers (control group 17 M, 50 +/- 16 years, Hct = 43 +/- 3%). We examined the relationship between Hct and serum levels of Epo, sFas, C-reactive protein, IL-6 and iron status. The ratio of serum Epo divided by Hct (Epo/Hct) was used as an indicator of Epo responsiveness.. Compared to normal subjects, the CKD, PD and HD groups presented lower Hct levels and higher serum levels of sFas, Epo, Epo/Hct and IL-6. Serum levels of sFas correlated negatively with albumin (r = -0.24, p = 0.02), IL-6 (r = -0.18, p = 0.04) and Epo/Hct (r = -0.37, p < 0.001). In multivariate analysis, after adjusting for markers of iron store and inflammation, only sFas correlated with Epo/Hct. In the CKD group, there were negative correlations between serum levels of sFas and glomerular filtration rate (GFR) (r = -0.45, p < 0.001) and between Epo/Hct and GFR (r = -0.32; p = 0.02). There was a positive correlation between Epo/Hct and serum levels of sFas in the CKD group (r = 0.31, p = 0.03) and in the HD groups (r = 0.58, p = 0.001).. Our findings show that serum sFas is associated with higher Epo/Hct ratio, suggesting that sFas may be a marker of Epo hyporesponsiveness in uremia. Further studies are needed to determine whether sFas is just a marker of Epo hyporesponsiveness or is also involved in its pathophysiology.

Topics: Adult; Aged; Analysis of Variance; Anemia, Iron-Deficiency; C-Reactive Protein; Chi-Square Distribution; Erythropoietin; Fas Ligand Protein; Female; Humans; Inflammation; Interleukin-6; Iron; Kidney Failure, Chronic; Male; Middle Aged; Patient Selection; Regression Analysis; Renal Dialysis

Intrauterine infection and inflammation have been causally linked to preterm birth and fetal brain injury. Using an ovine model of endotoxin-induced brain injury we have recently shown that recombinant human erythropoietin (rhEPO) reduces brain injury and protects against damage to myelination in major myelinated axon tracts. Our present objective was to determine whether rhEPO is also protective of the placenta and the fetal liver, organs which could influence fetal well-being. At 107 +/- 1 days of gestational age (DGA) chronically catheterized fetal sheep were randomly assigned to receive, on 3 consecutive days, either: 1) an i.v. bolus dose of lipopolysaccharide (LPS; approximately 0.9 microg/kg; n = 8); 2) i.v. bolus dose of LPS, followed at 1 h by 5000 IU/kg of rhEPO (LPS + rhEPO, n = 8); 3) rhEPO (n = 3). Seven untreated fetuses served as controls (n = 7). The placenta and fetal liver were examined histologically at 116 +/- 1 DGA; a placental injury index was formulated comprising measures of placental area, apoptosis, tissue injury and the size of the intervillous space. In LPS-exposed fetuses this index was greater than in control or rhEPO alone fetuses (p < 0.02). Treatment of LPS-exposed fetuses with rhEPO resulted in a reduction in the index (p < 0.05) and in the extent of liver necrosis. We conclude that rhEPO offers protection to the placenta and fetal liver in the presence of acute inflammation.

Topics: Animals; Erythropoietin; Female; Fetus; Humans; Inflammation; Lipopolysaccharides; Liver; Necrosis; Placenta; Pregnancy; Recombinant Proteins; Sheep

The erythropoietic response in hemodialysis patients depends on several physiologic factors. Most epidemiologic studies include the effect of these factors by representing them as confounders. This study tested the hypothesis that iron stores, inflammation, dialysis adequacy, nutritional status, and hyperparathyroidism act as nonlinear effect modifiers of the erythropoietic response and quantified the magnitude of those effects over clinically relevant ranges.. The following retrospective data from 209 hemodialysis patients receiving Epoetin alfa (Epo) were collected: monthly: predialysis hemoglobin (Hgb), transferrin saturation, serum albumin, dialysis adequacy (Kt/V); quarterly: predialysis serum ferritin and intact parathyroid hormone over a period of 13 to 69 months. The study analyzed the dynamic relationship between hemoglobin and Epo, considering nonlinear effect modification by ferritin, transferrin saturation, Kt/V, albumin, and parathyroid hormone individually.. Maximum Hgb response to Epo was achieved for serum ferritin between 350 and 500 ng/ml, transferrin saturation greater than 30%, Kt/V greater than 1.4, and albumin greater than 3.8 g/dl. Hgb sensitivity to Epo decreases by about 30% as parathyroid hormone increases from 0 through 1000 pg/ml.. Serum ferritin, transferrin saturation, Kt/V, serum albumin, and intact parathyroid hormone are markers of nonlinear effect modification of the erythropoietic response in hemodialysis patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Confounding Factors, Epidemiologic; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Humans; Hyperparathyroidism; Inflammation; Iron; Kidney Diseases; Likelihood Functions; Logistic Models; Male; Middle Aged; Nonlinear Dynamics; Nutritional Status; Parathyroid Hormone; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Serum Albumin; Time Factors; Transferrin; Treatment Outcome; Young Adult

We hypothesized that donor treatment of deceased brain dead donors would lead to a decrease in inflammatory responses seen in brain death and lead to a restoration of kidney function.. A standardized slow-induction rat brain death model followed by evaluation of kidney function in an isolated perfused kidney model.. Surgery Research Laboratory, University Medical Center Groningen, the Netherlands.. Male Fisher rats.. Donor treatment with erythropoietin, carbamylated erythropoietin, which lacks erythropoietic activity, or vehicle.. In brain death, carbamylated erythropoietin and, to a lesser extent, erythropoietin were able to decrease the expression of several proinflammatory genes and to decrease the infiltration of polymorphonuclear cells in the kidney. No effect on tubular injury parameters was seen. Kidney function decreased almost by 50% after brain death but was fully restored after treatment with both carbamylated erythropoietin and erythropoietin.. Carbamylated erythropoietin can inhibit the inflammatory response caused by brain death more effectively than erythropoietin, whereas both substances can restore kidney function after brain death.

Topics: Animals; Brain Death; Creatinine; Disease Models, Animal; Erythropoietin; Glomerular Filtration Rate; Inflammation; Kidney; Male; Rats; Rats, Inbred F344; Tissue Donors

Recombinant human erythropoetin beta; (rHuEPO) has not only an erythropoietic effect but also appears to affect production of cytokines and may improve nutritional status of dialysis patients. Darbepoetin alpha; is a new erythropoiesis-stimulating protein with a threefold longer serum half-life when compared with rHuEPO. The objective of this prospective study was to assess oxidative stress, inflammation, nutrition and hematological response in peritoneal dialysis (PD) patients who were switched from rHuEPO beta to darbepoetin alpha. 12 stable PD patients (6 M, 6 F; mean age 56.2 +/- 15.1 yr.) were evaluated during this study together with 22 healthy volunteers serving as a control group. All patients had been receiving erythropoetin beta subcutaneously once a week before they were reassigned to darbepoetin. The new drug was administered every other week for 6 months, in a dose equivalent to a weekly dose of previously taken rHuEPO. Hematology, iron status and biochemical profiles were evaluated monthly. Markers of oxidative stress: malondialdehyde/ 4-hydroxynoneal (MDA/4HNE), carbonyl groups (CG), oxyLDL and AGEs and markers of inflammation: CRP, TNF alpha, IL-6 were measured on rHuEPO beta before the switch to darbepoetin, and after 1st and 6th month of darbepoetin treatment. The assessment of nutritional status was determined by body mass index (BMI), serum albumin concentration and Subjective Global Assessment (SGA).. Mean levels of Hb and Hct were stable during 6 months of observation and not significantly different from the data observed for on rHuEPO. Nutritional status was good in 9 patients, 3 patients were malnourished at the beginning of this study as assessed by SGA and this status persisted to the end of observation. The levels of markers of oxidative stress and inflammation were statistically higher than in the control group (p < 0.05).. Darbepoetin alpha given subcutaneously once every 2 weeks is effective for the treatment of anemia in PD patients. Less frequent administration of darbepoetin has a biological response similar to weekly administration of rHuEPO.

Topics: Adult; Aldehydes; Anemia; Biomarkers; C-Reactive Protein; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Inflammation; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Nutritional Status; Oxidative Stress; Peritoneal Dialysis; Prospective Studies; Recombinant Proteins; Serum Albumin; Time Factors; Treatment Outcome

Topics: Animals; Brain Death; Disease Models, Animal; Erythropoietin; Humans; Inflammation; Kidney; Rats; Tissue Donors

Erythropoietin (EPO) has a neuroprotective effect in the animal model of ischemia/hypoxia, but the mechanisms underlying the EPO effect in traumatic brain injury (TBI) are not well understood. This study examined the potential neuroprotective mechanisms of recombinant human EPO (rhEPO) in rats after TBI. Sixty healthy adult male Sprague-Dawley rats were randomly divided into 5 groups: 1000 U/kg rhEPO-treated, 3000 U/kg rhEPO-treated, 5000 U/kg rhEPO-treated, citicoline, and normal saline (control) groups. The TBI model was based on the modified Feeney's free falling model. Serum samples were collected at 6 hours, 24 hours, 3 days, 5 days, and 7 days after trauma. The serum S100B protein and interleukin-6 (IL-6) levels were measured after treatment in each group with double antibody sandwich enzyme-linked immunosorbent assay. Both serum S100B protein and IL-6 levels were significantly lower in 3000 U/kg rhEPO-treated and 5000 U/kg rhEPO-treated groups (p < 0.001). The decrease in serum S100B protein level was correlated with the dosage of rhEPO. Medium doses of rhEPO achieved the optimum decreases in the serum IL-6 level. Therefore, inhibition of the composition and secretion of S100B protein and IL-6 levels by EPO might be one of the mechanisms involved in decreasing inflammatory reaction in the brain, and may be responsible for the neuroprotective effect after TBI.

Topics: Animals; Brain Injuries; Cytidine Diphosphate Choline; Dose-Response Relationship, Drug; Erythropoietin; Humans; Inflammation; Interleukin-6; Male; Nerve Growth Factors; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Time Factors

Biliary obstruction and cholestasis result in hepatocellular necro-inflammation and lead to the development of liver fibrosis. The objective of this study was to analyze whether the multiple tissue-protective properties of erythropoietin are salutary in an experimental model of liver fibrosis. For this purpose, C57BL/6J mice underwent common bile duct ligation (BDL) and were treated with either darbepoetin-α (10 μg/kg i.p.) or physiological saline every third day, beginning 24 h after BDL. Mice were killed at 2, 5, 14, and 28 days after BDL. Beside hematological parameters, markers of inflammation and fibrosis were assessed histomorphometrically and immunohistochemically as well as by quantitative real-time PCR. In addition, a 7-week survival study was performed. BDL provoked cholestatic hepatitis characterized by biliary infarcts with accumulation of macrophages followed by marked collagen deposition and increased expression of profibrotic gene transcripts. Darbepoetin-α treatment significantly diminished the area of focal necrosis, reduced the infiltration of macrophages, decreased levels of profibrotic genes, and lowered collagen deposition. Moreover, darbepoetin-α significantly reduced systemic anemia caused by BDL. Finally, darbepoetin-α treatment significantly prolonged the survival time after BDL. This study suggests that darbepoetin-α, which is a clinically well-established substance, might be used as an efficient therapeutic option for patients with chronic cholestatic liver disease.

Topics: Alanine Transaminase; Anemia; Animals; Cholestasis, Extrahepatic; Collagen; Common Bile Duct; Cytophotometry; Darbepoetin alfa; Disease Models, Animal; Erythropoietin; Hematinics; Immunohistochemistry; Inflammation; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Necrosis

Ischemia-reperfusion (I/R) injury may influence graft function after transplantation. Erythropoietin (EPO) attenuates I/R injury in various animal organs such as intestine, brain, and kidney.. To evaluate the effects of pretreatment with recombinant human EPO (rhEPO) on I/R-induced heart injury.. A rat model of I/R injury was established by ligating the left descending coronary artery for 30 minutes, followed by reperfusion for 4 hours. Fifty Sprague-Dawley rats were divided into 5 groups: sham operation; I/R; I/R+rhEPO, 100 U/kg; I/R+rhEPO, 1000 U/kg; and I/R+rhEPO, 5000 U/kg. Electrocardiograms were assessed continuously to note arrhythmia caused by reperfusion. Serum concentrations of interleukin (IL)-6 and IL-8, and tumor necrosis factor-alpha were measured at 2 and 4 hours after reperfusion.. The rhEPO-treated animals exhibited dosage-dependent significant reduction in the incidence of ventricular arrhythmia caused by reperfusion, and markedly decreased serum concentrations of IL-6, IL-8, and tumor necrosis factor-alpha (P < .05) compared with the I/R group (P < .05).. The rhEPO attenuates myocardial I/R injury in rats, at least in part related to inhibition of the system inflammatory response.

Topics: Animals; Erythropoietin; Humans; Inflammation; Interleukin-6; Interleukin-8; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reperfusion Injury; Tumor Necrosis Factor-alpha

Dysregulated production of hepcidin is implicated in anemia of inflammation, whereas interleukin-6 (IL-6) is a major inducer of hepcidin production. Overproduction of IL-6 is responsible for pathogenesis of multicentric Castleman disease (MCD), a rare lymphoproliferative disorder accompanied by systemic inflammatory responses and anemia. In this study, we investigated the roles of hepcidin and IL-6 in anemia of inflammation and the long-term effects of anti-IL-6 receptor antibody (tocilizumab) treatment on serum hepcidin and iron-related parameters in MCD patients. We found that tocilizumab treatment resulted in a rapid reduction of serum hepcidin-25 in 5 of 6 MCD patients. Long-term reductions, accompanied by progressive normalization of iron-related parameters and symptom improvement, were observed in 9 of 9 cases 1.5, 3, 6, and 12 months after the start of tocilizumab treatment. In in vitro experiments, IL-6-induced up-regulation of hepcidin mRNA in hepatoma cell lines was completely inhibited by tocilizumab but increased in the presence of patients' sera. Our results suggest that, although multiple factors affect serum hepcidin levels, IL-6 plays an essential role in the induction of hepcidin in MCD. This accounts for the long-term ameliorative effect of IL-6 blockage with tocilizumab on anemia by inhibiting hepcidin production in MCD patients.

Topics: Anemia; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimicrobial Cationic Peptides; Castleman Disease; Cell Line; Down-Regulation; Erythropoietin; Hepatocytes; Hepcidins; Humans; Inflammation; Interleukin-6; Iron; Receptors, Interleukin-6

Accumulating data suggest potential clinical relevant relationships between hepcidin-25 levels, iron stores, erythropoiesis effectiveness, and epoetin dose. The immunometric methods and mass spectroscopy are currently used to measure hepcidin-25, but no standard exists, and values, although similar in trends, differ in absolute value.. To investigate hepcidin levels and their relationship with peripheral iron indices, inflammation, and anemia therapy in patients on hemodialysis (HD).. A cross-sectional study in 78 patients from a single HD center. Hepcidin-25 was measured with enzyme-linked immunosorbent assay (ELISA), using a commercial kit (Bachem, UK).. Hepcidin-25 levels were similar to those previously reported in studies using the same antibody (median 113 [95% CI; 107-122 ng/mL]) and significant but weak correlations of hepcidin with transferrin (R2=0.06; p<0.04) and ferritin (R2=0.09; p<0.01) were found. A model of multiple regression analysis explained 57% of variation along hepcidin quartiles. Lower hepcidin levels were associated with higher transferrin levels (odds ratio 1.05 [1.01-1.09]), bigger iron doses (odds ratio 1.09 [1.02-1.15]), and an increased darbepoetin resistance index (odds ratio 4.3E+15 [11.15-1.6E+30]). An elevated serum C reactive protein was associated with increased hepcidin levels (odds ratio 0.70 [0.49-0.99]), while a higher ultrafiltration volume (odds ratio 4.30 [1.28-14.51]) and the male sex (odds ratio 0.04 [0.00-0.80]) were related to lower hepcidin levels.. Cohort number and composition. Hepcidin-25 ELISA assay.. A low hepcidin level in hemodialysis patients with high epoetin resistance index could be a useful marker of iron-restricted erythropoiesis, but confirmation by a therapeutical trial is necessary.

Topics: Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; C-Reactive Protein; Cross-Sectional Studies; Darbepoetin alfa; Drug Resistance; Enzyme-Linked Immunosorbent Assay; Erythropoiesis; Erythropoietin; Female; Hepcidins; Humans; Inflammation; Iron; Iron Deficiencies; Iron Overload; Male; Middle Aged; Renal Dialysis; Transferrin

Mouse bone marrow erythropoiesis is homeostatic, whereas after acute anemia, bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis develops in the spleen. The aim of this work was to compare spleen stress erythropoiesis and bone marrow erythropoiesis in a mouse model of zymosan-induced generalized inflammation, which induces long-lasting anemia and to evaluate the ability of erythropoietin (Epo) injections to correct anemia in this setting. The effects of zymosan and/or Epo injections on erythroid precursor maturation and apoptosis, serum interferon-γ levels, hematologic parameters, and spleen BMP4 expression were analyzed, as well as the effect of zymosan on red blood cell half-life. We found that bone marrow erythropoiesis is suppressed by inflammation and does not respond to Epo administration, despite repression of erythroblast apoptosis. On the contrary, a robust erythropoietic response takes place in the spleen after Epo injections in both control and zymosan-induced generalized inflammation mice. This specific response implies Epo-mediated induction of BMP4 expression by F4/80(+) spleen macrophages, proliferation of stress burst-forming units-erythroid, and increased number of spleen erythroblasts. It allows only partial recovery of anemia, probably because of peripheral destruction of mature red cells. It is not clear whether similar BMP4-dependent stress erythropoiesis can occur in human bone marrow after Epo injections.

Topics: Anemia; Animals; Apoptosis; Blotting, Western; Bone Marrow; Bone Morphogenetic Protein 4; Disease Models, Animal; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Receptors, Erythropoietin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Spleen; Zymosan

Expanded endothelial progenitor cells (eEPC) improve global left ventricular function in experimental myocardial infarction (MI). Erythropoietin beta (EPO) applied together with eEPC may improve regional myocardial function even further by anti-apoptotic and cardioprotective effects. Aim of this study was to evaluate intramyocardial application of eEPCs and EPO as compared to eEPCs or EPO alone in experimental MI.. In vitro experiments revealed that EPO dosed-dependently decreased eEPC and leukocyte apoptosis. Moreover, in the presence of EPO mRNA expression in eEPC of proangiogenic and proinflammatory mediators measured by TaqMan PCR was enhanced. Experimental MI was induced by ligation and reperfusion of the left anterior descending coronary artery of nude rats (n = 8-9). After myocardial transplantation of eEPC and EPO CD68+ leukocyte count and vessel density were enhanced in the border zone of the infarct area. Moreover, apoptosis of transplanted CD31 + TUNEL + eEPC was decreased as compared to transplantation of eEPCs alone. Regional wall motion of the left ventricle was measured using Magnetic Resonance Imaging. After injection of eEPC in the presence of EPO regional wall motion significantly improved as compared to injection of eEPCs or EPO alone.. Intramyocardial transplantation of eEPC in the presence of EPO during experimental MI improves regional wall motion. This was associated with an increased local inflammation, vasculogenesis and survival of the transplanted cells. Local application of EPO in addition to cell therapy may prove beneficial in myocardial remodeling.

Topics: Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Endothelium; Erythropoietin; Humans; Inflammation; Male; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rats; Rats, Nude; Recovery of Function; Stem Cell Transplantation; Stem Cells

Iron deficiency anemia (IDA) affects many young women in sub-Saharan Africa. Its etiology is multifactorial, but the major cause is low dietary iron bioavailability exacerbated by parasitic infections such as malaria.. We investigated whether asymptomatic Plasmodium falciparum parasitemia in Beninese women would impair absorption of dietary iron or utilization of circulating iron.. Iron absorption and utilization from an iron-fortified sorghum-based meal were estimated by using oral and intravenous isotope labels in 23 afebrile women with a positive malaria smear (asexual P. falciparum parasitemia; > 500 parasites/μL blood). The women were studied while infected, treated, and then restudied 10 d after treatment. Iron status, hepcidin, and inflammation indexes were measured before and after treatment.. Treatment reduced low-grade inflammation, as reflected by decreases in serum ferritin, C-reactive protein, interleukin-6, interleukin-8, and interleukin-10 (P < 0.05); this was accompanied by a reduction in median serum hepcidin of ≈ 50%, from 2.7 to 1.4 nmol/L (P < 0.005). Treatment decreased serum erythropoietin and growth differentiation factor 15 (P < 0.05). Clearance of parasitemia increased geometric mean dietary iron absorption (from 10.2% to 17.6%; P = 0.008) but did not affect systemic iron utilization (85.0% compared with 83.1%; NS).. Dietary iron absorption is reduced by ≈ 40% in asymptomatic P. falciparum parasitemia, likely because of low-grade inflammation and its modulation of circulating hepcidin. Because asymptomatic parasitemia has a protracted course and is very common in malarial areas, this effect may contribute to IDA and blunt the efficacy of iron supplementation and fortification programs. This trial was registered at clinicaltrials.gov as NCT01108939.

Topics: Adolescent; Adult; Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; Benin; Erythropoietin; Female; Ferritins; Food, Fortified; Growth Differentiation Factor 15; Hepcidins; Humans; Inflammation; Inflammation Mediators; Intestinal Absorption; Iron, Dietary; Isotope Labeling; Malaria, Falciparum; Parasitemia; Plasmodium falciparum; Sorghum; Young Adult

Anemia is a significant problem in elderly patients. Although many anemic elderly patients can be diagnosed with nutritional deficiency, anemia of chronic inflammation or comorbid diseases that explain their decreased hematocrit, the etiology of anemia in a significant fraction remains obscure. There is evidence to suggest that the hematopoietic stem cell displays increasing erythropoietin (EPO) resistance with age. EPO levels rise in elderly, nonanemic patients, and it is hypothesized that there is an interplay between this rising demand for EPO and the decreasing ability of the aging kidney to produce adequate hormone to meet that need. There is further considerable evidence that aging is associated with increased proinflammatory cytokine expression and that many of these cytokines can contribute to EPO insensitivity. Consequently, genetic variation in the expression of these proinflammatory cytokines may influence the development of anemia in elderly patients, both through induction of hepcidin expression (anemia of inflammation) and through cytokine suppression of erythroid colony formation. The impact of inflammatory mediators, EPO insensitivity, and other factors that may act on the hematopoietic stem cell to decrease erythropoiesis are under active study and should serve to elucidate the pathophysiology of this important cause of morbidity and mortality in elderly individuals. A better understanding of the pathophysiology of anemia in elderly patients should provide critical entry points for interventions that will improve survival and quality of life in the aging population.

Topics: Aged; Aging; Anemia; Biomarkers; Erythropoietin; History, 21st Century; HIV Infections; Humans; Inflammation

Human erythropoietin (EPO) is a pleiotropic cytokine with remarkable tissue-protective activities in addition to its well-established role in red blood cell production. Unfortunately, conventional mammalian cell cultures are unlikely to meet the anticipated market demands for recombinant EPO because of limited capacity and high production costs. Plant expression systems may address these limitations to enable practical, cost-effective delivery of EPO in tissue injury prevention therapeutics. In this study, we produced human EPO in tobacco and demonstrated that plant-derived EPO had tissue-protective activity. Our results indicated that targeting to the endoplasmic reticulum (ER) provided the highest accumulation levels of EPO, with a yield approaching 0.05% of total soluble protein in tobacco leaves. The codon optimization of the human EPO gene for plant expression had no clear advantage; furthermore, the human EPO signal peptide performed better than a tobacco signal peptide. In addition, we found that glycosylation was essential for the stability of plant recombinant EPO, whereas the presence of an elastin-like polypeptide fusion had a limited positive impact on the level of EPO accumulation. Confocal microscopy showed that apoplast and ER-targeted EPO were correctly localized, and N-glycan analysis demonstrated that complex plant glycans existed on apoplast-targeted EPO, but not on ER-targeted EPO. Importantly, plant-derived EPO had enhanced receptor-binding affinity and was able to protect kidney epithelial cells from cytokine-induced death in vitro. These findings demonstrate that tobacco plants may be an attractive alternative for the production of large amounts of biologically active EPO.

Topics: Cells, Cultured; Endoplasmic Reticulum; Epithelial Cells; Erythropoietin; Glycosylation; Humans; Inflammation; Kidney; Nicotiana; Plant Leaves; Plants, Genetically Modified; Protein Sorting Signals; Recombinant Proteins

Erythropoietin was recently shown to exert important cytoprotective and anti-apoptotic effects in injury models of the brain, heart and kidney. We examined whether erythropoietin also attenuates renal injury in a rat model of unilateral ureteral obstruction via anti-apoptotic and anti-inflammatory actions.. We divided Sprague-Dawley rats (Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea) into 4 groups, including 1-vehicle treated with sham operation, 2-vehicle treated with unilateral ureteral obstruction for 3 days, 3-erythropoietin treatment with sham operation and 4-erythropoietin treatment for unilateral ureteral obstruction for 3 days. The erythropoietin treatment dose was 3,000 IU/kg per day intraperitoneally, administered daily. We compared competitive reverse transcriptase-polymerase chain reaction data on transforming growth factor-beta, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, osteopontin, Fas and Bcl-2. Furthermore, we examined Western blots for caspase-3 and light microscopy findings with hematoxylin and eosin staining. We applied immunohistochemistry for transforming growth factor-beta, ED-1 and caspase-3, and TUNEL in each group.. Transforming growth factor-beta, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, osteopontin and Fas mRNA levels in the erythropoietin treated, unilateral ureteral obstruction group were significantly lower than in the obstruction only group. The Bcl-2 mRNA level in the erythropoietin treated obstruction group was significantly higher than in the obstruction only group. Caspase-3 activity in the erythropoietin treated obstruction group was significantly lower than in the obstruction only group. On light microscopy interstitially infiltrated inflammatory cells were significantly decreased in the erythropoietin treated obstruction group compared to the obstruction only group. On immunohistochemistry the erythropoietin treated obstruction group showed significantly fewer reactions for transforming growth factor-beta, ED-1 and caspase-3 compared to the obstruction only group. Erythropoietin treatment in rats with unilateral ureteral obstruction significantly decreased the number of TUNEL positive cells.. Erythropoietin exerts renoprotective effects in an experimental unilateral ureteral obstruction rat model via anti-apoptotic and anti-inflammatory actions.

Topics: Animals; Apoptosis; Disease Models, Animal; Erythropoietin; Inflammation; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Ureteral Obstruction

Erythropoiesis is considered as a multistep and tightly regulated process under the control of a series of cytokines including erythropoietin (Epo). Epo activates specific signaling pathways and leads to activation of key transcription factors such as GATA-1, in order to ensure erythroid differentiation. Deregulation leads to a decreased number of red blood cells, a hemoglobin deficiency, thus a limited oxygen-carrying capacity in the blood. Anemia represents a frequent complication in various diseases such as cancer or inflammatory diseases. It reduces both quality of life and prognosis in patients. Tumor necrosis factor alpha (TNFalpha) was described to be involved in the pathogenesis of inflammation and cancer related anemia. Blood transfusions and erythroid stimulating agents (ESAs) including human recombinant Epo (rhuEpo) are currently used as efficient treatments. Moreover, the recently described conflicting effects of ESAs in distinct studies require further investigations on the molecular mechanisms involved in TNFalpha-caused anemia. The present study aims to evaluate the current knowledge and the importance of the effect of the proinflammatory cytokine TNFalpha on erythropoiesis in inflammatory and malignant conditions.

Topics: Anemia; Animals; Cell Differentiation; Cytokines; Erythroid Cells; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Humans; Inflammation; Neoplasms; Tumor Necrosis Factor-alpha

Our objective was to assess the regulation of the hypoxia response of angiogenic and inflammatory factors from 76 cerebrospinal fluids (CSF) of sporadic amyotrophic lateral sclerosis (ALS) patients with different respiratory status. We first analysed the hypoxia response capacity by measuring CSF levels of angiogenin (ANG), VEGF, angiopoietin-2 (ANG-2) and PGE-2 in 40 ALS patients according to their hypoxaemia level and compared it with 40 neurological controls. We then compared the ANG, VEGF, EPO and ANG-2 CSF levels of 36 other ALS patients, divided into three groups with either 1) normoxaemia, 2) intermittent desaturation in the absence of hypoxaemia, or 3) chronic hypoxaemia with or without desaturation. We demonstrated a lack of up-regulation of both ANG and VEGF during hypoxaemia in ALS, compared with hypoxaemic controls. In contrast, PGE-2 and ANG-2 levels were increased in both hypoxaemic ALS patients and controls. ANG and VEGF levels did not increase in patients with long disease durations and with intermittent or chronic hypoxaemia. ANG-2 and EPO levels were up-regulated early in intermittent hypoxaemia and late in chronic hypoxaemia, respectively. Our results suggest alteration of the HIF-1alpha-mediated response to hypoxia during sporadic ALS, whereas the NFK-B pathway seems early activated.

Topics: Aged; Amyotrophic Lateral Sclerosis; Angiopoietin-2; Dinoprostone; Erythropoietin; Humans; Hypoxia; Inflammation; Middle Aged; Oxygen; Respiration; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A

Recombinant human erythropoietin (rEpo) is neuroprotective in neonatal models of brain injury. Proposed mechanisms of neuroprotection include activation of gene pathways that decrease oxidative injury, inflammation, and apoptosis, while increasing vasculogenesis and neurogenesis. To determine the effects of rEpo on gene expression in 10-d-old BALB-c mice with unilateral brain injury, we compared microarrays from the hippocampi of brain-injured pups treated with saline or rEpo to similarly treated sham animals. Total RNA was extracted 24 h after brain injury and analyzed using Affymetrix GeneChip Mouse Exon 1.0 ST Arrays. We identified sex-specific differences in hippocampal gene expression after brain injury and after high-dose rEpo treatment using single-gene and gene set analysis. Although high-dose rEpo had minimal effects on hippocampal gene expression in shams, at 24-h post brain injury, high-dose rEpo treatment significantly decreased the proinflammatory and antiapoptotic response noted in saline-treated brain-injured comparison animals.

Topics: Animals; Animals, Newborn; Apoptosis; Disease Models, Animal; Erythropoietin; Female; Gene Expression Profiling; Gene Expression Regulation; Hippocampus; Humans; Hypoxia-Ischemia, Brain; Inflammation; Male; Mice; Mice, Inbred BALB C; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Recombinant Proteins; Sex Factors; Time Factors

Hepcidin, a key iron-regulator secreted from the liver, consists of 25 amino acids (hepcidin-25), blocks iron release from macrophages via internalization and degradation of cellular iron exporter ferroportin, and restrains the use of iron in organs. Hepcidin mRNA and protein are also expressed in the human heart. A short form of hepcidin that lacks 5 amino-acid residues in the N-terminus (hepcidin-20) has been found in human serum, although its physiological role is unknown. Here, we successfully measured the serum levels of hepcidin-25 and hepcidin-20 in 12 patients with acute myocardial infarction (AMI) using surface-enhanced laser desorption ionization time of flight mass spectrometry. Among the selected 10 patients, whose blood samples were taken within 4 hours after a heart attack, all the patients showed elevated serum levels of hepcidin-20 [between 31.7 and 285.1 arbitrary unit (AU); normal level < 9.3 AU], while 8 patients showed high levels of hepcidin-25 (9.3-271.4; normal < 25.5 AU). The hepcidin-20 level was decreased to nearly the normal level on day 7 (range of 2.9 to 12.5 AU) in the 12 patients, whereas the hepcidin-25 level remained high on day 7 in 8 patients. Furthermore, the elevated levels of hepcidin-25 and hepcidin-20 were not correlated with the serum levels of markers for inflammation, interleukin-6 and C-reactive protein, in the patients with AMI. In conclusion, the serum hepcidin-20 is transiently elevated in response to acute cardiac ischemia. Measurement of serum hepcidin-20, rather than hepcidin-25, is helpful for diagnosis of acute myocardial infarction.

Topics: Acute Disease; Adult; Aged; Amino Acid Sequence; Antimicrobial Cationic Peptides; Biomarkers; C-Reactive Protein; Creatine Kinase; Erythropoietin; Female; Hepcidins; Humans; Inflammation; Insulin; Interleukin-6; Male; Middle Aged; Molecular Sequence Data; Myocardial Infarction; Peptide Fragments; Sequence Homology, Amino Acid; Time Factors

Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo.At 12 weeks, EPO expression resulted in a 23% weight reduction (P<0.01) in EPO transfected obese mice; thus the mice weighed 21.9+/-0.8 g (control, normal diet,) 21.9+/-1.4 g (EPO, normal diet), 35.3+/-3.3 g (control, high-fat diet) and 28.8+/-2.6 g (EPO, high-fat diet). Correspondingly, DXA scanning revealed that this was due to a 28% reduction in adipose tissue mass.The decrease in adipose tissue mass was accompanied by a complete normalisation of fasting insulin levels and glucose tolerance in the high-fat fed mice. EPO expression also induced a 14% increase in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles.In conclusion, we have shown that EPO when expressed in supra-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles.

Topics: Adipose Tissue; Animals; Erythropoietin; Female; Gene Expression Regulation; Glucose; Glucose Tolerance Test; Inflammation; Lipid Metabolism; Mice; Mice, Inbred C57BL; Models, Biological; Muscles; Obesity; Oxygen

Hepcidin is the key regulator of iron metabolism. Iron supplementation is often introduced in dialyzed patients to replete or to maintain iron stores, particularly in patients treated with erythropoietic-stimulating agents. The present study was aimed to assess possible relation between hepcidin and erythropoietin therapy, with particular attention being paid to erythropoietin-hyporesponsiveness in hemodialyzed patients. Prohepcidin and hepcidin were studied using commercially available kits from DRG Instruments GmbH, Germany (ELISA method) and Bachem, UK (RIA method). TNFalpha and IL-6 were studied using kits from and R&D (Abington, UK), and hsCRP was studied using kits from American Diagnostica, USA. Hyporesponsive patients to erythropoietin therapy had significantly lower serum albumin, cholesterol, LDL, hemoglobin, hematocrit, and residual renal function, and significantly higher serum ferritin, hsCRP, IL-6, TNFalpha, and erythropoietin dose. The difference in serum prohepcidin and hepcidin did not reach statistical significance; however, there was a tendency toward higher values of both prohepcidin and hepcidin in hyporesponsive patients. In conclusion, though hyporesponsiveness to erythropoietin therapy occur in dialyzed patients, it is mainly associated with subclinical inflammation than with hepcidin excess. Further studies are needed to develop a reliable and reproducible assay to elucidate the potential contribution of hepcidin to hyporesponsiveness during erythropoietin therapy.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; Blood Chemical Analysis; Cohort Studies; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Ferritins; Follow-Up Studies; Hepcidins; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Probability; Protein Precursors; Radioimmunoassay; Recombinant Proteins; Renal Dialysis; Statistics, Nonparametric; Treatment Outcome; Tumor Necrosis Factor-alpha

To determine the correlation of histological chorioamnionitis (CA) with and without clinical CA with umbilical cord blood gases, erythropoietin (EPO), and interleukin-6 (IL-6) levels.. Umbilical artery blood gas analysis (pH, pO(2), pCO(2), BE) and umbilical vein EPO and IL-6 levels were measured in 202 infants from normal, histological, and no clinical CA and histological plus clinical CA pregnancies.. Umbilical artery blood gas analyses were not different between normal controls and histological and clinical CA groups. Blanc Stage 1 histological CA had no abnormal EPO or IL-6 umbilical blood results. EPO in umbilical venous blood was elevated only in those infants with both histological and clinical CA. Umbilical vein IL-6 levels were elevated in all advanced microscopic and clinical CA. High and low EPO groups also have corresponding high and low IL-6 levels suggesting a common stimulus for these substances.. Blanc stage I histological CA is probably clinically insignificant. CA is infrequently associated with abnormal umbilical artery blood gas levels. Advanced histological and clinical CA can elevate both EPO and IL-6 in umbilical blood and these may be key elements of mechanisms that effect fetal brain function.

Topics: Blood Gas Analysis; Carbon Dioxide; Case-Control Studies; Chorioamnionitis; Cohort Studies; Erythropoietin; Female; Fetal Blood; Humans; Hydrogen-Ion Concentration; Inflammation; Interleukin-6; Oxygen; Pregnancy; Statistics, Nonparametric

The aim of this work was to evaluate the neutrophil activation state in chronic kidney disease (CKD) patients under hemodialysis, and its linkage with resistance to recombinant human erythropoietin (rhEPO) therapy.. We studied 63 CKD patients under hemodialysis and rhEPO treatment (32 responders and 31 non-responders to rhEPO therapy). In 20 of the CKD patients (10 responders and 10 non-responders to rhEPO therapy), blood samples were also collected immediately after dialysis. Twenty-six healthy volunteers were included in a control group. Hemoglobin levels, total and differential leukocyte counts, and circulating levels of C-reactive protein (CRP), elastase and lactoferrin were measured in all patients and controls.. Compared with controls, CKD patients presented with significantly higher CRP, neutrophil and elastase levels. When we compared the 2 groups of patients, we found that non-responders presented statistically significantly higher elastase plasma levels. A positive significant correlation was found between elastase levels and weekly rhEPO dose and CRP serum levels. After the hemodialysis procedure, a statistically significant rise in elastase, lactoferrin and, elastase/neutrophil and lactoferrin/neutrophil ratios were found.. Our data show that CKD patients under hemodialysis present higher elastase levels (particularly in non-responding patients), which could be related to the rise in neutrophils, and to be part of the enhanced inflammatory process found in these patients.

Topics: Aged; C-Reactive Protein; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Lactoferrin; Lymphocyte Activation; Male; Middle Aged; Models, Statistical; Neutrophils; Pancreatic Elastase; Recombinant Proteins; Renal Dialysis

Aging is associated with increased incidence and prevalence of anemia, leading to a number of adverse health outcomes. These include death, functional dependence, increased risk of therapeutic complications, falls, and dementia. In approximately 30% of cases, anemia in older individuals is due to either relative or absolute erythropoietin (EPO) deficiency. Absolute EPO deficiency may be primary or secondary to declining renal function. Relative EPO deficiency is due to an age-related pro-inflammatory status that reduces the sensitivity of erythropoietic precursors to EPO. Despite this condition of EPO deficiency, the management of anemia of aging with erythropoiesis-stimulating agents (ESAs) is controversial, unless the anemia is due to renal insufficiency. The main concern related to this treatment arises from eight studies of ESAs in cancer, suggesting that ESAs may reduce patient survival in addition to increasing the risk of deep vein thrombosis. The results of these studies contrast with a host of other trials showing the safety of ESAs. The discrepancy may be explained in part by the fact that, in the trials suggesting a detrimental effect of ESAs, the goal was to obtain hemoglobin (Hb) levels higher than 12 g/dL. Because of this concern, correction of anemia in elderly individuals with relative EPO insufficiency should not be attempted outside clinical trials.

Topics: Aged; Anemia; Drug Therapy; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Inflammation; Neoplasms; Radiotherapy

Although hepcidin, a recently discovered peptide hormone, is considered a major regulator of iron metabolism and anemia in chronic inflammation, its role in anemia during pregnancy has not been characterized. Our objective was to characterize the role of hepcidin in anemia during pregnancy. We examined the relationships between urinary hepcidin, iron status indicators, hemoglobin, erythropoietin, alpha-1 acid glycoprotein, and C-reactive protein in a cross-sectional study conducted among 149 pregnant rural Bangladeshi women with biospecimens obtained during home visits. Urinary hepcidin was measured using surface-enhanced laser desorption/ ionization time-of-flight mass spectrometry. Urinary hepcidin, as log(intensity per mmol/L creatinine), was correlated with log ferritin (r = 0.33, p <0.001), the transferrin receptor index (r = -0.22, p = 0.007), and log alpha-1 acid glycoprotein (r = 0.20, p = 0.01), but not hemoglobin (r = 0.07, p= 0.40), log transferrin receptor (r = -0.07, p = 0.41), log erythropoietin (r = -0.01, p = 0.88) or log C-reactive protein (r = 0.06, p = 0.48). The strength of the relationship between hepcidin and ferritin was maintained in multiple linear regression analyses after enhancing the sample with data from women selected for low iron stores (n = 41). Among pregnant women in a community-based study in rural Bangladesh, urinary hepcidin levels were related to iron status and AGP but not hemoglobin, erythropoietin, or C-reactive protein.

Topics: Adolescent; Adult; Anemia; Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; Bangladesh; Biomarkers; Cross-Sectional Studies; Erythropoietin; Female; Hemoglobins; Hepcidins; Humans; Inflammation; Iron; Linear Models; Nutritional Status; Pregnancy; Pregnancy Complications; Young Adult

Topics: Antibodies, Monoclonal; Biomedical Research; Biotechnology; Drug Industry; Erythropoietin; Humans; Inflammation; Insulin; Neoplasms; Pharmaceutical Preparations; Time Factors; United States

To investigate the anti-inflammatory effect of erythropoietin (EPO) pretreatment on cardiomyocytes exposed to hypoxia/reoxygenation injury (H/R) and explore the possible mechanism.. The cultured neonatal rats?ventricular cardiomyocytes were divided randomly into 4 groups, control group (C group), EPO pretreatment group (E group), EPO and pyrrolidine dithiocarbamate (PDTC) pretreatment group (EP group) and PDTC pretreatment group (P group). After 24 hours?pretreatment, the cardiomyocytes were exposed to H/R. After pretreatment and H/R, the expression of tumor necrosis factor-alpha(TNF-alpha) gene in all the groups was detected by RT-PCR and Western blot. The nuclear factor-kappa B (NF-kappa B) activity was detected by electrophoretic mobility shift assay (EMSA) and the inhibitor-kappa B alpha (I-kappa B alpha) protein level was detected by Western blot.. The decrement of I-kappa B alpha protein and the increasing NF-kappa B activity were found in cardiomyocytes pretreated with EPO before H/R compared to other groups (t equal to 3.321, 4.183, P less than 0.01). However, after H/R, NF-kappa B activity and expression of TNF-alphagene were significantly reduced, I-kappa B alpha protein expression was increased in cardiomyocytes of E group compared to other groups (t=3.425, 3.687, 3.454, P less than 0.01). All theses changes caused by EPO pretreatment were eliminated by the intervention of PDTC (an antagonist to NF-kappa B) during pretreatment.. EPO pretreatment can inhibit the activation of NF-kappa B and upregulation of TNF-alpha gene in cardiomyocytes exposed to H/R through a negative feedback of NF-kappa B signaling pathway, and thus produces the anti-inflammatory effect. This might be one of the ways EPO produces the anti-inflammatory effect.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antioxidants; Blotting, Western; Cells, Cultured; Electrophoretic Mobility Shift Assay; Erythropoietin; Hypoxia; Inflammation; Myocytes, Cardiac; NF-kappa B; Pyrrolidines; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Thiocarbamates; Tumor Necrosis Factor-alpha

Anemia is a common complication in patients with inflammatory diseases of many kinds, including cancer. The mechanisms that have captured the most attention include cytokine-mediated changes in both the production of and the response to erythropoietin (Epo), as well as important alterations in iron metabolism. The last is brought about by the relatively recently recognized peptide hormone, hepcidin. The availability of recombinant human Epo and its derivatives (known by class as Erythropoietic Stimulating Agents, ESAs) has dramatically changed anemia management in patients with cancer but, in the process, has raised as many issues as have been answered. This chapter reviews the mechanisms resulting in anemia in inflammation, including cancer, and focuses on the controversies around management with the ESAs and the adjuvant use of iron in anemia management.

Topics: Anemia; Antimicrobial Cationic Peptides; Cell Line; Erythropoiesis; Erythropoietin; Hepcidins; Humans; Inflammation; Interleukin-1alpha; Interleukin-6; Iron; Neoplasms; Recombinant Proteins; Tumor Necrosis Factor-alpha

Although multifactorial anemia is common following orthotopic liver transplantation (OLT), the late introduction of sirolimus (SRL) has been associated with high rates of anemia, whose pathogenic mechanisms have not been fully studied. Herein we have described a case of severe anemia in an HIV+ OLT patient who was switched from calcineurin inhibitors (CNI) to SRL due to severe nephrotoxicity. After 22 weeks of SRL, hemoglobin levels dropped 4 g/dL to a nadir of 6.5 g/dL. After discarding other causes for anemia, we concluded that it displayed the features of anemia of a chronic inflammatory state (ACIS): decreased mean corpuscular volume (MCV), low serum iron despite high ferritinemia, and elevated fibrinogen and C-reactive protein (CRP) levels. SRL trough levels were never above the therapeutic range. After blood transfusions and erythropoietin (EPO) use, SRL was maintained within the lower range of therapeutic levels, with significant improvement in renal function. As described among kidney transplant recipients, SRL-related anemia in this HIV+ patient with CNI nephrotoxicity after OLT showed features of ACIS. Blood transfusions and EPO use allowed SRL maintenance.

Topics: Adaptor Proteins, Signal Transducing; Anemia; Blood Transfusion; C-Reactive Protein; Calcineurin; Erythropoietin; HIV Seropositivity; Humans; Immunosuppressive Agents; Inflammation; Iron; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus; Transferrin

The repair of the endothelium after inflammatory injury is essential to maintaining homeostasis. The link between inflammation-induced endothelial damage and repair has not been fully characterized in vivo. We have developed a rat model to evaluate the coupling of lipopolysaccharide (LPS)-induced endothelial injury and repair. Aortic endothelium injury was analyzed by both inmunohistochemistry and flow cytometry to quantify the number of endothelial cells and the percentage of apoptotic endothelial cells. We have also identified the percentage of circulating angiogenic cells capable of repairing the damaged endothelium. Erythropoietin was administered to inhibit LPS-induced endothelial apoptosis. Loss of the normal endothelial structure was observed in the aorta of the animals treated with LPS. Eight hours after LPS administration, the number of endothelial cells decreased by 40%, returning to normal after 24 h. There was a threefold increase in the percentage of circulating angiogenic cells, which did not return to normal levels until 48 h after LPS administration. Circulating angiogenic cell levels did not change when LPS-induced endothelial damage was prevented by erythropoietin. The endothelial injury caused by inflammation activates the mobilization of circulating angiogenic cells, thus completing endothelial repair. Inflammation without endothelial injury does not trigger the mobilization of circulating angiogenic cells.

Topics: Animals; Annexin A5; Aorta; Apoptosis; Endothelium, Vascular; Erythropoietin; Flow Cytometry; Immunohistochemistry; Inflammation; Lipopolysaccharides; Male; Neovascularization, Physiologic; Rats; Rats, Wistar; von Willebrand Factor

Intravenous iron supplementation is a recognized therapy for anemia in chronic hemodialysis patients, especially in those treated with erythropoietin. The vast majority of patients with chronic kidney disease (CKD) seem to be iron-deficient, as evaluated by the usual parameters and by iron staining on bone marrow biopsy, because of multiple forms of interference with all phases of iron metabolism. The need for iron supplementation in CKD patients becomes obvious. Intravenous iron was demonstrated to be superior to oral iron in hemodialysis patients. There is also evidence for the superiority of intravenous iron in peritoneal dialysis and in nondialysis-dependent CKD patients. On the other hand, intravenous iron could promote cytotoxicity and tissue injury, and exacerbate oxidative stress and thus endothelial dysfunction, as well as inflammation and the progression of both CKD and cardiovascular disease. Nevertheless, correction of anemia is effective in reducing oxidative stress and, consequently, cardiovascular risk. The overall risk-benefit ratio favors the use of intravenous iron alone or with an erythropoietic stimulating agent in the management of renal anemia. Clinical judgment is necessary in each individual case to diagnose iron deficiency and effectively use intravenous iron.

Topics: Anemia, Iron-Deficiency; Disease Progression; Erythropoietin; Humans; Inflammation; Injections, Intravenous; Iron; Kidney Failure, Chronic; Oxidative Stress; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Risk Assessment; Uremia

Resistance to recombinant human erythropoietin (rhEPO) occurs in some chronic kidney disease (CKD) patients, which may be due to enhanced systemic inflammatory response and to the erythropoiesis-suppressing effect of pro-inflammatory cytokines, some of which are produced by T cells.. The aim of this study was to investigate the relationship between resistance to rhEPO therapy in hemodialysis CKD patients and inflammatory markers [C-reactive protein (CRP), soluble interleukin (IL)-2 receptor (sIL2R), and serum albumin levels], blood cell counts, T-cell phenotype, cytokine production by T cells, and serum cytokine levels.. We studied 50 hemodialysis CKD patients, 25 responders and 25 nonresponders to rhEPO, and compared them to each other and with 25 healthy controls. When compared to controls, CKD patients showed increased serum levels of CRP, IL-6, and sIL2R and a T-cell lymphopenia, due to decreased numbers of both CD4+ and CD8+ T cells. T cells from CKD patients had an immunophenotype compatible with chronic T-cell stimulation as shown by the increased percentage of CD28-, CD57+, HLA-DR+, CD28-HLA-DR+, and CD57+ HLA-DR+ T cells and produce higher levels of IL-2, INF-gamma, and TNF-alpha after short-term in vitro stimulation, although Th1 cytokines were not detectable in serum. Statistically significant differences were found between responders and nonresponders to rhEPO therapy for total lymphocyte and CD4+ T-lymphocyte counts, albumin (lower in nonresponders) and CRP (higher in nonresponders) levels.. CKD patients under hemodialysis present with raised inflammatory markers and decrease of total lymphocyte and CD4+ T-lymphocyte counts when compared with controls. Some of those markers are even further enhanced in nonresponders to rhEPO therapy patients, but resistance to this therapy cannot be justified by a Th1 polarized T-cell response.

Topics: Cytokines; Drug Resistance; Erythropoietin; Humans; Immunophenotyping; Inflammation; Inflammation Mediators; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; T-Lymphocyte Subsets

Numerous studies using erythropoietin (EPO) gene delivery vectors, either viral or nonviral, have shown uncontrolled EPO expression leading to transient or sustained erythrocytosis and, more recently, severe autoimmune anemia. Therefore, there is a need to develop other EPO gene delivery systems that allow sustained and adjustable expression of EPO. We have examined a new approach of delivering plasmid encoding mouse EPO cDNA into mouse skeletal muscle, using an amphiphilic block copolymer. Repeated injections of low doses of block copolymer-EPOcDNA formulations increased hematocrit in a dose-dependent manner for more than 9 months, without any initial overshoot. Low doses of block copolymer-EPOcDNA formulations prevented autoimmune anemia in immunocompetent Swiss mice and prevented or reversed chronic anemia in an acquired mouse model of renal failure. We conclude that repeated injections of low doses of block copolymer-DNA formulations that do not induce (1) inflammation at the injection site, (2) overexpression of EPO, or (3) the production of anti-EPO neutralizing auto-antibodies hold promise for in vivo expression of therapeutic proteins, in particular for systemic delivery.

Topics: Anemia; Animals; Creatinine; Disease Models, Animal; Erythropoietin; Female; Genetic Therapy; Inflammation; Injections, Intramuscular; Kidney; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Plasmids; Polyethylene Glycols; Renal Insufficiency; Reticulocyte Count; Urea

Beneficial effects of short-term erythropoietin (EPO) therapy have been demonstrated in several animal models of acute neurologic injury, including experimental autoimmune encephalomyelitis (EAE)--the animal model of multiple sclerosis. We have found that EPO treatment substantially reduces the acute clinical paralysis seen in EAE mice and this improvement is accompanied by a large reduction in the mononuclear cell infiltration and downregulation of glial MHC class II expression within the inflamed CNS. Other reports have recently indicated that peripherally generated anti-inflammatory CD4(+)Foxp3(+) regulatory T cells (Tregs) and the IL17-producing CD4+ T helper cell (Th17) subpopulations play key antagonistic roles in EAE pathogenesis. However, no information regarding the effects of EPO therapy on the behavior of the general mononuclear-lymphocyte population, Tregs or Th17 cells in EAE has emerged.. We first determined in vivo that EPO therapy markedly suppressed MOG specific T cell proliferation and sharply reduced the number of reactive dendritic cells (CD11c positive) in EAE lymph nodes during both inductive and later symptomatic phases of MOG(35-55) induced EAE. We then determined the effect in vivo of EPO on numbers of peripheral Treg cells and Th17 cells. We found that EPO treatment modulated immune balance in both the periphery and the inflamed spinal cord by promoting a large expansion in Treg cells, inhibiting Th17 polarization and abrogating proliferation of the antigen presenting dendritic cell population. Finally we utilized tissue culture assays to show that exposure to EPO in vitro similarly downregulated MOG-specific T cell proliferation and also greatly suppressed T cell production of pro-inflammatory cytokines.. Taken together, our findings reveal an important new locus whereby EPO induces substantial long-term tissue protection in the host through signaling to several critical subsets of immune cells that reside in the peripheral lymphatic system.

Topics: Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Central Nervous System; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Forkhead Transcription Factors; Genes, MHC Class II; Inflammation; Interleukin-17; Leukocytes, Mononuclear; Lymph Nodes; Mice; Mice, Inbred C57BL

Topics: Acute Kidney Injury; Amlodipine; Epoetin Alfa; Erythropoietin; Female; Fibrosis; Humans; Inflammation; Middle Aged; Prednisone; Recombinant Proteins; Sarcoidosis; Treatment Outcome

Neutrophilic disease is characterized by aseptic visceral infiltration by normal polymorphonuclear leukocytes that can occur in any organ. Association with an underlying systemic disease, particularly haematological malignancy or inflammatory bowel disease, is frequent. This may produce a multisystem disorder, but diagnosis is usually based on skin lesions because of their clinical and histological accessibility. Pulmonary manifestations are the most common extracutaneous symptoms but may be misdiagnosed, as in our case report.. A 77-year-old woman with IgA myeloma presented with an inflammatory bullous plaque of the leg coupled with fever lasting one week. The clinical and histological examinations were evocative of a neutrophilic dermatosis such as Sweet's syndrome. Significant improvement was initially obtained with systemic corticosteroids and colchicine. The course became complicated by necrotic neutrophilic papulopustular lesions of the upper limbs and pulmonary manifestations, with fever and decline in overall condition occurring the day after administration of erythropoietin. A hypothesis of septic aetiology prompted antibiotic and antifungal therapy, which remained ineffective. The patient died the day after the second erythropoietin injection.. This case involved late identification of the aseptic neutrophilic aetiology of pulmonary manifestations. Several factors favouring their appearance and the fatal outcome may be suggested: the existence of a myeloma, association with myelodysplastic syndrome and the possible iatrogenic action of erythropoietin. To the best of our knowledge, this is the first reported case of extracutaneous neutrophilic infiltrate occurring in a patient treated with this haematopoietic hormone.

Topics: Aged; Erythropoietin; Fatal Outcome; Female; Humans; Inflammation; Lung Diseases; Multiple Myeloma; Sweet Syndrome

A few small-scale studies have shown that high levels of various parameters of inflammation were associated with a less efficient response to erythropoetin. The responsiveness to EPO in haemodialysis (HD) patients with relative risk of cardiovascular disease (CVD) remains undetermined. In a retrospective study of HD patients, we compared causes of CV morbidity and mortality in relation to various weekly EPO doses needed for stable hemoglobin (Hb) levels, according to the definition currently suggested by international guidelines.. On the basis of distribution of the weekly EPO doses (lower or higher than the minimally recommended), eighteen HD patients, aged 55.8+/-14.8 years, were divided into two groups with higher (A) and lower (B) EPO doses. We correlated EPO doses with positive (C reactive protein-CRP, fibrinogen, feritin) and negative (albumin, LDL, TIBC) acute phase reactans, BMI, the quality (Kt/V) and duration of HD.. We also found a significantly positive corelation between CRP levels on the start of EPO therapy and weekly EPO dose in the univariate linear regression analysis (p-0.290). Higher EPO doses were associated with a lower levels of Kt/V, BMI, residual diuresis and higher levels of CRP, LDL, feritin, age and duration of HD. CRP levels were decreasing in the group with higher EPO doses. This important result can be explained the know EPO effect of endothelial cells apoptosis and inhibiting inflammation induced by HD.. Chronic inflammation is a common cause of CVD, hyporesponsiveness to EPO and endothelial dysfuncton in HD patients. Our results suggest a new protective function of EPO.

Topics: Anemia; C-Reactive Protein; Erythropoietin; Female; Humans; Inflammation; Inflammation Mediators; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Recombinant Proteins; Renal Dialysis

Carbamylerythropoietin (CEPO) does not bind to the classical erythropoietin (EPO) receptor. Nevertheless, similarly to EPO, CEPO promotes neuroprotection on the histologic level in short-term stroke models. In the present study, we investigated whether CEPO and other nonerythropoietic EPO analogs could enhance functional recovery and promote long-term histologic protection after experimental focal cerebral ischemia. Rats were treated with the compounds after focal cerebral ischemia. Animals survived 1, 7, or 60 days and underwent behavioral testing (sensorimotor and foot-fault tests). Brain sections were stained and analyzed for Iba-1, myeloperoxidase, Tau-1, CD68 (ED1), glial fibrillary acidic protein (GFAP), Fluoro-Jade B staining, and overall infarct volumes. Treatment with CEPO reduced perifocal microglial activation (P<0.05), polymorphomonuclear cell infiltration (P<0.05), and white matter damage (P<0.01) at 1 day after occlusion. Carbamylerythropoietin-treated rats showed better functional recovery relative to vehicle-treated animals as assessed 1, 7, 14, 28, and 50 days after stroke. Both GFAP and CD68 were decreased within the ipsilateral thalamus of CEPO-treated animals 60 days postoperatively (P<0.01 and P<0.05, respectively). Furthermore, behavioral analysis showed efficacy of CEPO treatment even if administered 24 h after the stroke. Other nonerythropoietic derivatives such as carbamylated darbepoetin alfa and the mutant EPO-S100E were also found to protect against ischemic damage and to improve postischemic neurologic function. In conclusion, these results show that postischemic intravenous treatment with nonerythropoietic EPO derivatives leads to improved functional recovery, which may be linked to their long-term effects against neuroinflammation and secondary tissue damage.

Topics: Animals; Brain; Brain Ischemia; Erythropoietin; Humans; Immunohistochemistry; Inflammation; Male; Neuroprotective Agents; Rats; Recovery of Function

Topics: Adult; Anemia; Erythropoietin; Hematocrit; Hemoglobins; Humans; Inflammation; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Male; Renal Dialysis

The anemia of inflammation is an acquired disorder affecting patients with a variety of medical conditions, and it is characterized by changes in iron homeostasis and erythropoiesis. Mounting evidence suggests that hepcidin antimicrobial peptide plays a primary role in the pathogenesis of the anemia of inflammation. To evaluate which features of this anemia can be attributed to hepcidin, we have generated mice carrying a tetracycline-regulated hepcidin transgene. Expression of the hepcidin transgene resulted in down-regulation of endogenous hepcidin mRNA. The transgenic mice developed a mild-to-moderate anemia associated with iron deficiency and iron-restricted erythropoiesis. Similar to the anemia of inflammation, iron accumulated in tissue macrophages, whereas a relative paucity of iron was found in the liver. Circulating erythrocytes in transgenic animals had normal survival rates, but transgenic animals had an impaired response to erythropoietin. Thus, hepcidin transgenic mice recapitulate each of the key features of anemia of inflammation in human patients and serve as a useful model of this prevalent disorder.

Topics: Anemia, Iron-Deficiency; Animals; Antimicrobial Cationic Peptides; Cell Survival; Disease Models, Animal; Erythrocytes; Erythropoiesis; Erythropoietin; Hepcidins; Inflammation; Iron; Macrophages; Mice; Mice, Transgenic

Possible interactions between inflammatory and nutritional markers and their impact on recombinant human erythropoietin (rHuEPO) hyporesponsiveness are not well understood. We investigated the role of nutritional status in rHuEPO requirement in maintenance hemodialysis (MHD) patients without evidence of inflammation. This cross-sectional study included 88 MHD patients. The associations between required rHuEPO dose and malnutrition-inflammation score (MIS) and several laboratory values known to be related to nutrition and/or inflammation were analyzed. Anthropometric measures including body mass index, triceps skinfold thickness, and midarm circumferences were also measured. Twenty-three patients with serum C-reactive protein levels >10 mg/L were excluded from the analysis. The remaining 65 patients (male/female, 41/24; age 49.1+/-11.4 years; dialysis duration 99.7+/-63.0 months) were studied. These patients had moderate malnutrition and the average MIS was 7.4 (range 3-17). The average weekly dose of administered rHuEPO was 69.1+/-63.1 U/kg. Malnutrition-inflammation score had a positive correlation with the serum concentration of tumor necrosis factor-alpha, whereas it had a negative correlation with anthropometric measures, total iron-binding capacity, prealbumin, phosphorus, creatinine, and triglyceride. According to Pearson's correlation analysis, significant relationships of increased MIS with increased required rHuEPO dose and rHuEPO responsiveness index (EPO divided by hematocrit) were observed (p=0.008, r=-0.326; p=0.017, r=-0.306, respectively). Recombinant human erythropoietin dose requirement is correlated with MIS and adverse nutritional status in MHD patients without evidence of inflammation. Further research should focus on reversing the undergoing microinflammation for a better outcome in dialysis patients.

Topics: Adult; Anthropometry; Erythropoietin; Female; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Nutrition Assessment; Protein-Energy Malnutrition; Recombinant Proteins; Renal Dialysis

Sepsis has a high mortality (50-80%) when associated with acute renal failure (ARF). Oxidant injury and proinflammatory cytokines and chemokines have been shown to increase with endotoxaemia-related ARF. Since erythropoietin (EPO) has been demonstrated to possess anti-oxidant and anti-inflammatory properties, EPO may have therapeutic efficacy for treating ARF associated with endotoxaemia.. Wild-type mice were given 2.5 mg/kg of intraperitoneal (i.p.) endotoxin, lipopolysaccharide (LPS), and studied 16 h later. Thirty minutes prior to LPS, the mice were given either EPO or vehicle.. During endotoxaemia, EPO was found to significantly attenuate the renal dysfunction, as assessed by glomerular filtration rate (48.1 +/- 12.4 microl/min vs 136.7 +/- 30.2, P < 0.05). Renal blood flow and mean arterial pressure were not significantly different between the two groups. The renal dysfunction during endotoxaemia was associated with a decrease in renal superoxide dismutase (SOD). The EPO-related renal protection was associated with reversal of the effects of endotoxin on renal SOD.. This is the first demonstration of a renal protective effect of EPO on endotoxin-related renal dysfunction.

Topics: Animals; Cytokines; Endotoxemia; Erythropoietin; Glomerular Filtration Rate; Inflammation; Kidney; Kidney Diseases; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Sepsis; Tumor Necrosis Factor-alpha

Multifactorial pathogenic mechanisms, including inflammation, attenuated survival signals and enhanced death signals, are involved in amyotrophic lateral sclerosis (ALS). Erythropoietin (EPO) has recently been highlighted as a cytokine with various potent neuroprotective effects, including reduction of inflammation, enhancement of survival signals and prevention of neuronal cell death. This study was undertaken to evaluate the effect of recombinant human EPO (rhEPO) on ALS model mice. We treated 96 ALS model mice with vehicle only, or 1, 2.5 or 5 imu of rhEPO/g of mouse once every other week after they were 60 days old. The treatment significantly prolonged symptom onset and life span, preserved more motor neurons, enhanced survival signals, and attenuated inflammatory signals in a dose-dependent manner. These data suggest that treatment with rhEPO represents a potential therapeutic strategy for ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Dinoprostone; Disease Models, Animal; Disease Progression; Erythropoietin; Humans; Inflammation; Mice; Mice, Transgenic; Motor Neurons; Recombinant Proteins; Rotarod Performance Test; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1; Survival Rate

Topics: Animals; Axons; Brain; Calcium; Calcium Channels; Cell Proliferation; Diffuse Axonal Injury; Erythropoietin; Humans; Inflammation; Nimodipine; Sodium; Spinal Cord

In many liver disorders inflammation and apoptosis are important pathogenic components, finally leading to acute liver failure. Erythropoietin and its analogues are known to affect the interaction between apoptosis and inflammation in brain, kidney, and myocardium. The present study aimed to determine whether these pleiotropic actions also exert hepatoprotection in a model of acute liver injury. C57BL/6J mice were challenged with d-galactosamine (Gal) and Escherichia coli lipopolysaccharide (LPS) and studied 6 hours thereafter. Animals were either pretreated (24 hours before Gal-LPS exposure) or posttreated (30 minutes after Gal-LPS exposure) with darbepoetin-alpha (DPO, 10 mug/kg i.v.). Control mice received physiological saline. Administration of Gal-LPS caused systemic cytokine release and provoked marked hepatic damage, characterized by leukocyte recruitment and microvascular perfusion failure, caspase-3 activation, and hepatocellular apoptosis as well as enzyme release and necrotic cell death. DPO-pretreated and -posttreated mice showed diminished systemic cytokine concentrations, intrahepatic leukocyte accumulation, and hepatic perfusion failure. Hepatocellular apoptosis was significantly reduced by 50 to 75% after DPO pretreatment as well as posttreatment. In addition, treatment with DPO also significantly abrogated necrotic cell death and liver enzyme release. In conclusion, these observations may stimulate the evaluation of DPO as hepatoprotective therapy in patients with acute liver injury.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Caspase 3; Cytokines; Darbepoetin alfa; Erythropoietin; Galactosamine; Hematinics; Inflammation; Lipopolysaccharides; Liver; Liver Failure, Acute; Male; Mice; Mice, Inbred C57BL; Proliferating Cell Nuclear Antigen

Testicular torsion is an important clinical urgency. Similar mechanisms occurred after detorsion of the affected testis as in the ischemia reperfusion (I/R) damage. This study was designed to investigate the effects of erythropoietin (EPO) treatment after unilateral testicular torsion. Fifty male Sprague-Dawley rats were divided into five groups. Group 1 underwent a sham operation of the right testis under general anesthesia. Group 2 was same as sham, and EPO (3,000 IU/kg) infused i.p., group 3 underwent a similar operation but the right testis was rotated 720 degrees clockwise for 1 h, maintained by fixing the testis to the scrotum, and saline infused during the procedure. Group 4 underwent similar torsion but EPO was infused half an hour before the detorsion procedure, and in group 5, EPO was infused after detorsion procedure. Four hours after detorsion, ipsilateral and contralateral testes were taken out for evaluation. Treatment with EPO improved testicular structures in the ipsilateral testis but improvement was less in the contralateral testis histologically, but EPO treatment decreased germ cell apoptosis in both testes following testicular IR. TNF-alpha, IL-1beta, IL-6 and nitrite levels decreased after EPO treatment especially in the ipsilateral testis. We conclude that testicular I/R causes an increase in germ cell apoptosis both in the ipsilateral and contralateral testes. Erythropoietin has antiapoptotic and anti-inflammatory effects following testicular torsion.

Topics: Animals; Apoptosis; Disease Models, Animal; Erythropoietin; Hematinics; Inflammation; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Seminiferous Tubules; Spermatic Cord Torsion

We sought to evaluate influences of oxidative stress (OS) on rHuEPO requirements in hemodialysis patients without chronic inflammation.. Sixty-eight hemodialysis patients and 46 healthy controls underwent measurements plasma levels of antioxidative agents, such as glutathione peroxidase (GPX), superoxide dismutase (SOD), and oxidative compounds including malonyldialdehyde (MDA). We retrospectively analyzed the last 3 months' rHuEPO requirements, iron indices, and CRP levels.. Plasma levels for SOD, GPX, and MDA were 974.4+/-216.4 U/gHb, 44.4+/-13.6 U/gHb, 10.0+/-2.0 nmol/mL, respectively yielding results that were different from healthy controls (P<.0001). Increased OS negatively correlated with hemoglobin levels (P<.0001) and positively correlated with rHuEPO requirements (P<.01). Increased antioxidative capacity positively correlated with hemoglobin levels (P<.0001) and negatively correlated with rHuEPO requirements (P<.0001). For further analyses, hemodialysis patients were subgrouped according to rHuEPO requirements as group I (lowest 1/3, n=23), group II (moderate 1/3, n=23) and group III (highest 1/3, n=22). Group III displayed the highest MDA (P<.05), the lowest SOD (P<.0001), and comparable GPX (P<.05) levels. Group III also had the highest CRP and the lowest albumin levels compared with the others (P<.01).. OS has strong adverse influences on rHuEPO responses of HD patients with "normal" CRP levels, but it should not be forgotten that CRP levels in the "normal" range may still reflect ongoing microinflammation.

Topics: Adult; Aged; C-Reactive Protein; Cross-Sectional Studies; Erythropoietin; Female; Glutathione Peroxidase; Humans; Inflammation; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Recombinant Proteins; Reference Values; Renal Dialysis; Retrospective Studies; Superoxide Dismutase

Erythropoietin is traditionally known to regulate erythropoiesis, but recently its protective effect against ischemia-reperfusion injury has been studied in cardiovascular and neuronal systems. This study investigated the effect of recombinant human erythropoietin on ischemia-reperfusion injury in a rat transverse rectus abdominis musculocutaneous (TRAM) flap model.. Twenty-four Sprague-Dawley rats were divided into a control group (n = 12) and a group treated with erythropoietin (n = 12). A superiorly based TRAM flap was elevated and ischemic insult was given for 4 hours. Thirty minutes before reperfusion, single-dose recombinant human erythropoietin (5000 IU/kg) was injected through the intraperitoneal route in the treatment group. At 24 hours postoperatively, systemic neutrophil count, tissue myeloperoxidase activity, amount of malondialdehyde, nitric oxide content, tissue water content, and histologic finding of inflammation were evaluated. At day 10 postoperatively, flap survival rate, angiogenesis, and change in hematocrit level were evaluated.. The myeloperoxidase activity and tissue water content were significantly lower (p < 0.01 and p < 0.005, respectively), and the tissue nitric oxide level was significantly higher (p < 0.005) in the treatment group 24 hours after reperfusion. Perivascular neutrophil infiltration and intravascular adhesion were marked in the control group. Mean flap survival after 10 days was 69 percent in the treatment group and 47 percent in the control group, demonstrating a significant difference (p < 0.005). Neovascularization in the treatment group was also greater than that in the control group. No significant hematocrit rise was noted 10 days after erythropoietin administration.. Recombinant human erythropoietin improved flap survival in ischemia-reperfusion-injured rat TRAM flaps by the possible mechanism of suppressed inflammation, decreased infiltration of neutrophils, increased nitric oxide, and enhanced angiogenesis.

Topics: Animals; Apoptosis; Chemotaxis, Leukocyte; Drug Evaluation, Preclinical; Erythropoietin; Hematocrit; Humans; Inflammation; Malondialdehyde; Neovascularization, Physiologic; Neutrophils; Nitric Oxide; Peroxidase; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Rectus Abdominis; Reperfusion Injury; Surgical Flaps

This study was done to determine whether recombinant human erythropoietin (rhEPO) treatment could attenuate hyperoxia-induced lung injury, and if so, whether this protective effect is mediated by the down-modulation of inflammation in neonatal rats. Newborn Sprague Dawley rat pups were subjected to 14 days of hyperoxia (>95% oxygen) within 10 hr after birth. Treatment with rhEPO significantly attenuated the mortality and reduced body weight gain caused by hyperoxia. With rhEPO treatment, given 3 unit/gm intraperitoneally at 4th, 5th, and 6th postnatal day, hyperoxia- induced alterations in lung pathology such as decreased radial alveolar count, increased mean linear intercept, and fibrosis were significantly improved, and the inflammatory changes such as myeloperoxidase activity and tumor necrosis factor-alpha expression were also significantly attenuated. In summary, rhEPO treatment significantly attenuated hyperoxia-induced lung injury by down-modulating the inflammatory responses in neonatal rats.

Topics: Animals; Animals, Newborn; Cytoprotection; Disease Models, Animal; Erythropoietin; Female; Hyperoxia; Inflammation; Lung; Peroxidase; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Survival Rate; Tumor Necrosis Factor-alpha

With use of recombinant erythropoietin (EPO) and intravenous iron, the majority of hemodialysis patients can achieve target hemoglobin concentrations. EPO resistance arises as a consequence of inflammation and other processes that can adversely affect survival. We hypothesized that the EPO dose-hematocrit (EPO/Hct) ratio, also known as the EPO index, may be a surrogate for inflammation and that greater EPO/Hct ratios would be associated with decreased survival.. We used proportional hazards regression models and time-varying logistic models to analyze the association between EPO index and survival in US hemodialysis patients initiating hemodialysis therapy between January 1, 1999, and December 31, 2000, and followed up for up to 3 years until December 31, 2001.. We found an unexpected and consistent association between greater EPO index and survival in all models. The associations of EPO/Hct ratio were most prominent at intermediate Hct values and with longer dialysis vintage. Iron administration was associated with a lower risk for death independent of Hct. Conversely, greater average prior EPO dose was associated with a greater risk for death.. EPO resistance may be reflected better by total cumulative EPO dose than the EPO/Hct ratio. The mechanism(s) responsible for the association between a greater EPO/Hct ratio and survival remains to be established, but may be a result of nonerythrogenic effects of EPO.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Cohort Studies; Cross-Sectional Studies; Drug Resistance; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Humans; Inflammation; Iron; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Proportional Hazards Models; Recombinant Proteins; Renal Dialysis; Reproducibility of Results; Survival Analysis; Time Factors; United States

Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation.. In a cross-sectional study of haemodialysis patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation [BMI, albumin and C reactive protein (CRP)] by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders.. Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3+/-3.8 vs 24.4+/-4.7 kg/m(2), P<0.001; and 3.8+/-0.6 vs 4.1+/-0.4 g/dl, P<0.001), whereas the median CRP level was higher (1.9 vs 0.8 mg/dl, P = 0.004). The median weekly EPO dose ranged from 30 IU/kg/week in the hyper-responsive group to 263 IU/kg/week in the hypo-responsive group. Transferrin saturation linearly decreased from the hyper- to hypo-responsive group (37+/-15 to 25+/-10%, P = 0.003), without any differences in transferrin levels. Ferritin levels were lower in the hypo-responsive than in the other patients (median 318 vs 445 ng/ml, P = 0.01). At multiple linear regression analysis, haemoglobin, BMI, albumin, CRP and serum iron levels were independently associated with the natural logarithm of the weekly EPO dose (R(2) = 0.22).. Our findings support a clear association between EPO responsiveness and nutritional and inflammation variables in haemodialysis patients; iron deficiency is still a major cause of hypo-responsiveness.

Topics: Aged; Body Weight; C-Reactive Protein; Cross-Sectional Studies; Erythropoietin; Female; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Status; Renal Dialysis

Normal and malignant hematopoietic cells are shown to express and secrete various cytokines and chemokines, some of which are believed to play an important role in normal and abnormal hematopoiesis in an autocrine/paracrine manner. To explore the possibility of a cytokine/chemokine network participating in the pathophysiology of anemic disorders, we evaluated the ability of inflammatory cytokines to induce chemokine expression using erythroid progenitor cells.. Erythropoietin-dependent human leukemia cell line AS-E2 was used as a model of erythroid colony-forming unit (CFU-E) cells. The expression of mRNA of 8 chemokines was examined using RT-PCR, before and after TNF-alpha, IFN-gamma, and IL-1beta stimulation. For MIP-3alpha, the promoter activity was analyzed by luciferase assay and secretion was confirmed by ELISA. The expression of CCR6, the specific receptor for MIP-3alpha, was analyzed by RT-PCR and flow cytometry.. Unstimulated AS-E2 cells constitutively expressed transcripts for MCP-4, IP-10, PF-4, IL-8, and MIP-3alpha. Stimulation with TNF-alpha, IFN-gamma, and IL-1beta upregulated MIP-3alpha mRNA expression and induced its protein secretion. Luciferase assay revealed that these cytokines could upregulate promoter activity of the MIP-3alpha gene, possibly through the NF-kappaB pathway. CCR6 mRNA was detected and its intracellular expression was confirmed.. These data suggest that inflammatory cytokine-stimulated erythroid progenitors secrete MIP-3alpha, which may function in an autocrine/paracrine manner. Furthermore, the existence of intracellular CCR6 suggests the involvement in cytokine signaling of a MIP-3alpha-dependent internal autocrine mechanism. These mechanisms may play a role in pathophysiology of anemic disorders, such as secondary anemia and bone marrow failure syndromes.

Topics: Cell Line, Tumor; Chemokine CCL20; Chemokines; Chemokines, CC; Cytokines; Enzyme-Linked Immunosorbent Assay; Erythroid Precursor Cells; Erythropoietin; Gene Expression Regulation; Humans; Inflammation; Interleukin-1; Leukemia, Erythroblastic, Acute; Macrophage Inflammatory Proteins; Promoter Regions, Genetic; Receptors, CCR6; Receptors, Chemokine; RNA, Messenger; Tumor Necrosis Factor-alpha

Topics: Antimicrobial Cationic Peptides; Erythropoietin; Hematocrit; Hepcidins; Humans; Inflammation; Iron; Protein Precursors; Renal Dialysis

Studies on living donor kidney transplantation primarily address the recipients; few publications focus on kidney donors. The aim of the present study was to detect changes in and compensations of defined parameters of anemia and inflammation in the immediate postnephrectomy period. We included six living kidney donors who underwent an open anterior-extraperitoneal nephrectomy. We excluded donors with complications, such as significant blood loss or infection. Blood samples were taken before nephrectomy as well as on postoperative days 1, 3, 5, and 7, and at discharge for measurements of hemoglobin (Hb), serum erythropoietin (Epo), reticulocytes (Reti), pentraxin 3 (PTX3), and C-reactive protein (CRP). There was a significant decrease in Hb (>3 g/dL), reaching a maximum on day 3 followed by a significant threefold increase in Epo levels on day 5 and a nonsignificant elevation of Reti count. CRP increased approximately 80-fold on day 3. PTX3 showed a similar course, peaking on day 3 with an approximate 70-fold increase. After living donor nephrectomy, there was an unexpectedly pronounced inflammatory reaction in the absence of any signs of bacterial infection simultaneous with a significant decrease in Hb. These parameters improved during the hospital stay, in some cases they achieved the prenephrectomy level at discharge. These data may assist in interpreting laboratory results after nephrectomy among living kidney donors.

Topics: Aged; C-Reactive Protein; Creatinine; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Kidney; Living Donors; Male; Middle Aged; Nephrectomy; Postoperative Complications; Postoperative Period; Tissue and Organ Procurement; Treatment Outcome

Arteriovenous grafts (AVG) and tunneled permanent catheters (TPC) are increasingly being used in hemodialysis (HD) patients. However, their role in baseline inflammatory status has not been fully evaluated. Aim of the study was to evaluate the influence of the current kind of vascular access on the baseline inflammatory status, marked by serum C-reactive protein (CRP), and the response to epoetin therapy in a group of iron-replete HD patients, under steady clinical conditions, without evidence of acute infections and/or inflammatory diseases.. We studied 79 patients who had been on bicarbonate HD for 8-410 months and were receiving epoetin therapy. They all had adequate iron stores and stable hemoglobin (Hb) levels. Exclusion criteria were fever, signs of infection, white blood cell count (WBC) > 10 x 1,000/microl, for at least 4 weeks before study. 48 patients (group A) had arteriovenous fistula (AVF), 18 patients (group B) AVG, 13 patients (group C) TPC. CRP, Hb, transferrin saturation, serum ferritin, WBC, serum albumin, protein catabolic rate, Kt/V, and epoetin dose (U/kg body weight/week) were measured. CRP values were log-transformed to normalize the distribution.. Log-transformed CRP values among the 3 groups were significantly different: group A 1.81 +/- 0.48; group B 2.12 +/- 0.50, and group C 3.00 +/- 0.25 (group A vs. B p < 0.003; group B vs. C p < 0.001; group A vs. C p < 0.0001). CRP and the epoetin dose were directly correlated (r = 0.519; p < 0.0001). The epoetin doses among the 3 groups were significantly different. Multiple regression analysis confirmed AVG and TPC as factors independently influencing CRP levels.. AVG and TPC have a higher degree of chronic inflammation than AVF. The epoetin requirement is increased in TPC and AVG compared with AVF.

Topics: Aged; Analysis of Variance; Arteriovenous Shunt, Surgical; Blood Vessel Prosthesis; C-Reactive Protein; Chi-Square Distribution; Chronic Disease; Erythropoietin; Female; Humans; Inflammation; Linear Models; Male; Middle Aged; Renal Dialysis; Statistics, Nonparametric

To evaluate the association between C-reactive protein (CRP) levels and the periodontal status of hemodialysis (HD) patients.. 41 HD patients on rHuEPO therapy were enrolled in the study. Hematologic and biochemical parameters and CRP levels were recorded. The plaque index, gingival index, probing pocket depth and periodontal disease index were used to identify periodontal disease. The patients were divided into 2 groups: group 1 (n = 21), high CRP, and group 2 (n = 20), normal CRP.. After periodontal therapy, while the mean CRP level and erythrocyte sedimentation rate declined from 30.46 to 10.36 (p = 0.001) and from 93.4 to 35.8 mg/l (p = 0.001), respectively, the hemoglobin level increased from 9.4 to 10.6 g/dl (p = 0.009) and hematocrit level from 28.2 to 32.0% (p = 0.008) in group 1.. Periodontitis is an important and occult source of chronic inflammation and increases the CRP levels in HD patients. Periodontitis can cause hyporesponsiveness to rHuEPO treatment and decrease the hemoglobin levels.

Topics: Adult; Biomarkers; C-Reactive Protein; Erythropoietin; Female; Humans; Inflammation; Male; Middle Aged; Periodontitis; Recombinant Proteins; Renal Dialysis; Statistics, Nonparametric

To investigate the effect of EPO on hepcidin mRNA expression in normal mice, acute inflammatory mice and ACD mice, the acute phase model and ACD model of mouse was produced by subcutaneous injection of turpentine oil. Hepatic hepcidin mRNA expression levels of normal mice, acute inflammatory mice and ACD mice were detected by semi-quantitative retro-transcriptase polymerase chain reaction (RT-PCR) after intra-peritoneal injection of EPO. The results showed that prolonged chronic inflammation did not significantly increase mouse hepatic hepcidin mRNA expression, but a single injection of turpentine oil increased mouse hepatic hepcidin mRNA expression transiently. Intra-peritoneal injection of EPO down-regulated hepatic hepcidin mRNA expression in normal mice, ACD mice and acute inflammatory mice. Hb levels had a negative correlation with hepatic hepcidin mRNA expression levels in ACD mice treated with EPO. It is concluded that the ACD model can be produced by repeated subcutaneous injection of turpentine oil. Hepatic hepcidin mRNA expression increased during the early period of ACD process and then fall to normal level. EPO down-regulate hepcidin mRNA expression under the normal, acute inflammation and chronic inflammation conditions.

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; Erythropoietin; Hepcidins; Inflammation; Iron; Liver; Male; Mice; Mice, Inbred C57BL; Random Allocation; RNA, Messenger

The aim of this study was to analyze the effects of elevated parathyroid hormone (iPTH) and C-reactive protein (CRP) on rHuEPO requirements and associated clinical and biochemical parameters of hemodialysis patients.. A total of 127 hemodialysis patients were included. Laboratory values from the previous 3 months (monthly measured CRP, iPTH, albumin, prealbumin, calcium, phosphorus, and hemoglobin) and clinical findings (rHuEPO requirements, iron supplements, Kt/V) were recorded retrospectively. Patients were subgrouped according to presence of hyperparathyroidism (mean iPTH > 350 pg/mL) and chronic inflammation (mean CRP > 8.5 mg/L) as group I (low iPTH, low CRP, n = 32), group II (high iPTH, low CRP, n = 32), group III (low iPTH, high CRP, n = 32), and group IV (high iPTH, high CRP, n = 31).. We found that group IV had lowest hemoglobin (P < .0001, .0001, .01, respectively), albumin (P < .0001), prealbumin (P < .0001, .0001, .02, respectively), and highest rHuEPO requirements (P < .0001, .0001, .01, respectively) compared to other groups despite of similar iron indices. Group III also had lower albumin (P < .002, .0001, respectively), prealbumin (P < .001, .01, respectively), hemoglobin (P < .001, .005, respectively), but higher rHuEPO requirements (P < .01) compared to group I and group II.. We propose that hyperparathyroidism increases rHuEPO requirements and aggravates the negative effects of chronic inflammation in hemodialysis patients.

Topics: Adult; Aged; Albuminuria; C-Reactive Protein; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Hyperparathyroidism; Inflammation; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Topics: Adult; Aged; Aged, 80 and over; Antimicrobial Cationic Peptides; Enzyme-Linked Immunosorbent Assay; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hepcidins; Humans; Inflammation; Injections, Subcutaneous; Interleukin-6; Iron; Male; Middle Aged; Predictive Value of Tests; Protein Precursors; Renal Dialysis

Anaemia is a common finding in elderly patients particularly in those with chronic kidney disease. Effective correction of anaemia improves survival and quality of life. The association between anaemia and a poor nutritional status as well as the presence of inflammation has already been documented. The aim of our study was to assess the impact of the nutritional and inflammatory status on darbepoetin dose requirements of elderly patients followed in a "Chronic Kidney Disease" outpatient clinic. We included 71 elderly patients (age>or=65 years) in a "Chronic Kidney Disease" outpatient clinic. Creatinine Clearance (CrCl) was estimated according to the Cockroft-Gault equation. Nutritional status was evaluated by biochemical and anthropometric parameters. Tumour Necrosis Factor-alpha (TNF-alpha), Interleukin-6 (IL-6) and high sensitivity C-reactive protein (hs-CRP) were used as biomarkers of inflammation. Our patients (56% males) with a mean age of 76.2+/-6.6 years were followed for 33.1+/-43.6 months. Mean eCrCl was 13.5+/-7.2 ml/mn/1.73 m2. All patients were under supplemental iron therapy and 74.7% needed darbepoietin (0.762+/-0.6 (microg/kg/week) to correct anaemia. Among the several variables regressed on darbepoietin dose, in a multiple regression model, only Hb, IL-6 and TNF-alpha levels and SGA score predicted the need for higher doses of darbepoietin. (r=0.677; r2=0.459). In Conclusion, in our pre-dialysis elderly patients, markers of a poor nutritional status (SGA and albumin) and inflammation (IL-6 and TNF-alpha) independently predicted the use of higher doses of darbepoietin to correct anaemia.

Topics: Aged; Aged, 80 and over; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Inflammation; Male; Nutritional Status; Renal Dialysis

Incidents of heart and renal failure (HF, RF) together, are increasing in our country and all over the world, so a great attention has been dedicated to this problem recently. These diseases together have shown bad results because of the process of accelerated arteriosclerosis, structural changes of myocardium, oxidative stress, inflammation, increased activities of sympathetic nervous system (SNS), increased activities of a renin-angiotensin-aldosterone system (RAAS) (1). These factors are crucial in the development of patho-physiological process and consequential development of anemia, that together with heart and renal failure through interaction, cause serious disorder that we call the cardio-renal anemia syndrome (2). We examined effects of erythropoietin (Epoetin beta) at 90 (60 men and 30 women) pre-dialysed and dialysed patients with HF signs during a period of three years in individual dozes of 2000-6000 units subcutaneous (sc) weekly. Using computer S PLUS and SAS multiple variant analysis we have got correlations by Pearson. Epoetin beta significantly develops anemia parameters: number of erythrocytes (r=0.51779; p<0.0001), hemoglobin (r=0.38811; p<0.0002), MCV (r=0.59876; p<0.0001) at patients with HF. Positive effects are seen at NYHA class (r=0.59906; p<0.0001), on quality of life before and after prescribing medicine. Parameters of renal functions are improving: more urea (r =0.45557; p<0.0001) than creatinine (r=0.26397; p<0.00119) and potassium values K(+)) are not changed significantly (r=0.02060; p<0.8471). Epoetin beta has been useful in treatment of pre-dialysed and dialysed patients with HF and anemia by improving functional ability of myocardium and quality of life.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Blood Glucose; Blood Urea Nitrogen; Creatinine; Cytokinins; Erythrocyte Count; Erythropoietin; Female; Heart Diseases; Hematopoiesis; Hemoglobins; Humans; Inflammation; Kidney Failure, Chronic; Male; Malnutrition; Middle Aged; Potassium; Recombinant Proteins; Renal Dialysis; Syndrome; Tumor Necrosis Factor-alpha

In medicine a considerable amount of resources are used in research, but very little attention is paid to ensuring that the findings of research are implemented in routine clinical practice. This prospective study has the aim to evaluate the efficiency of some clinical management strategies (feedback, benchmarking and improving plans) on haemodialysis treatment results in 4 different dialysis centres. We collected consensus data related to haemodialysis results every 6-8 months and informed each centre about its own results (feedback) and how these related to the others(benchmarking). We designed improving plans for any bad result detected. By the end of two years of follow up, 294 patients had been included in the study. The results obtained at the end of the study had improved in comparison with those obtained at the beginning (statistically significant) for the following indicators: % of patients with Hb< 11 g/dl, % patients with Kt/v < 1.2, mean Kt/v, mean albumin, % patients with albumin< 3.5 g/dl y % patients with C reactive protein (CRP) > 5 mg/dl. No statistical changes were found in: mean erythropoietin (EPO) doses, blood pressure (BP), phosphorus plasmatic,calcium-phosphorus product, parathormone (PTHi) and vascular access distribution. We explained the absence of any improvement because of adequate start indicators in some areas (BP and vascular access), therapy with limited efficiency (calcitriol, calcium carbonate and others), lack of support resources (dietetic unit) or inadequate design/implementation of improving plans.In conclusion, our intervention illustrates that combined clinical management strategies(feedback, benchmarking and improving plans) are efficiency in improving some areas of haemodialysis treatment (anaemia, dialysis dose, nutrition and inflammation), although it does not improve calcium phosphate metabolism related indicators.

Topics: Aged; Aged, 80 and over; Anemia; Benchmarking; Blood Pressure; C-Reactive Protein; Calcium; Cardiovascular Diseases; Catheters, Indwelling; Comorbidity; Erythropoietin; Feedback; Female; Follow-Up Studies; Hemodialysis Units, Hospital; Humans; Inflammation; Kidney Failure, Chronic; Male; Malnutrition; Middle Aged; Parathyroid Hormone; Phosphorus; Prospective Studies; Quality Assurance, Health Care; Renal Dialysis; Spain

Recombinant human erythropoietin (rHuEPO) has transformed the management chronic renal failure (CKD) and considerably improved the outcome of patients on regular chronic dialysis. However, a significant number of patients fail to respond to high of Erythropoiesis-stimulating agents (ESAs) and several causes of inadequate response to epoetin therapy have been identified. Some factors, such as gender, age, length of time on dialysis, type of dialysis and co-morbidities such as hemoglobinopathy, are not susceptible to clinical intervention. However, many other factors can be adjusted. Iron deficiency, whether functional or absolute, is the most common factor that limits the response to rHuEPO. Monitoring of iron parameters and a large use of iron supplementation result in an efficient epoetin response. Infection and inflammation have been shown to reduce responsiveness to ESAs by disrupting iron metabolism and increasing the release of pro-inflammatory cytokines that inhibit erythropoiesis. Increase dialysis dose is associated with improvements in anemia correction and reduced requirements for ESAs. Severe hyperparathyroidism and aluminum overload lead to a reduced number of responsive erythroid progenitor cells. Finally, a number of nutritional factors, such as deficiencies of carnitine, vitamin B12, folic acid, and vitamin C, are susceptible to alter erythropoiesis. Optimizing patient response to ESAs therefore requires consideration of many of well-established factors and is important for both patient outcomes and cost of treatment.

Topics: Anemia; Cytokines; Erythropoiesis; Erythropoietin; Humans; Inflammation; Iron Deficiencies; Kidney Failure, Chronic; Recombinant Proteins; Sarcoma Virus, Woolly Monkey; Vitamins

Despite an increase in the use and average dose of recombinant human EPO (rh-EPO) over the last 15 years, a substantial percentage of patients still do not achieve hemoglobin targets recommended by international guidelines. The definition of rh-EPO resistance has been introduced to identify those patients in whom the target hemoglobin level is not attained despite a greater-than-usual dose of erythropoietin-stimulating agent (ESA). In recent years, increasing attention has been paid to the relationship between dialysis, increased inflammatory stimulus, malnutrition, and ESA response. About 35% to 65% of hemodialysis patients show signs of inflammation that could be a cause of anemia through the suppression of bone marrow erythropoiesis by a number of cytokines. A large proportion of chronic kidney disease patients also have protein-energy malnutrition and wasting; low serum albumin levels, together with other more specific nutritional markers, are predictors of rh-EPO response. A diminished nutritional state could then be a feature of patients who are resistant to ESA treatment, with malnutrition probably being a consequence of a chronic inflammatory state. Starting from the hypothesis that anemia, partially attributable to a reduced response to ESA, could be the link among malnutrition, inflammation, and the poor outcome of chronic kidney disease patients, we designed a multicenter observational study, the Malnutrition-Inflammation-Resistance-Treatment Outcome Study (MIRTOS), aimed at evaluating the impact and possible causes of resistance to ESA in a large sample of hemodialysis patients. We hope the results of MIRTOS will represent a step forward toward a better understanding of the factors influencing the response to ESA in hemodialysis patients.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Drug Resistance; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Malnutrition; Protein-Energy Malnutrition; Recombinant Proteins; Renal Dialysis

Anemia in patients with COPD and its pathophysiology is an understudied issue.. In a group of 101 COPD patients (FEV(1) percentage of predicted, 37 +/- 2% [mean +/- SEM]; mean age, 61 +/- 1 years; 35% female gender), the prevalence of anemia and its relationship to body mass and weight loss, inflammatory parameters, and erythropoietin levels was determined. Data were compared to a control group (healthy persons with matched age) in order to identify potential factors that may influence the development of anemia in patients with COPD.. Anemia was diagnosed in 13 patients (hemoglobin levels < 13.5 mg/dL in male patients and < 12.0 mg/dL in female patients), which represents a prevalence of 13%. Anemic COPD patients showed elevated erythropoietin levels (41.8 +/- 25.4 U/L vs 16.3 +/- 2.9 U/L) and an increased inflammatory response compared to nonanemic patients. A significant inverse correlation of hemoglobin vs erythropoietin (r = - 0.84, p < 0.01) was observed in anemic COPD patients, but not in the nonanemic group.. Anemic COPD patients show high erythropoietin levels, which may indicate presence of erythropoietin resistance. The latter may be mediated through inflammatory mechanisms, which is typical for anemia of chronic illness.

Topics: Anemia; Body Mass Index; Erythropoietin; Female; Forced Expiratory Volume; Hemoglobins; Humans; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Vital Capacity; Weight Loss

Gene therapy holds a major promise. However, until now, this promise was fulfilled only in few cases, in rare genetic diseases. One very common clinical condition is anemia. Patients with anemia of chronic renal failure are treated with erythropoietin. The objective of this study was to develop a therapeutic platform for serum-secreted proteins like erythropoietin. We developed a tissue protein factory based on dermal cores (Biopump) harvested and implanted autologously. In this study, an adenovector was designed to express the human erythropoietin under the control of the cytomegalovirus (CMV) promoter. This vector transduced the harvested dermal cores ex vivo. The transduced cores were implanted, and erythropoietin and reticulocyte counts were measured. Dermal cores were harvested from 13 patients with chronic renal failure, and implantation was performed in 10. There were no significant drug-related side effects to this procedure. Erythropoietin serum levels increased significantly to therapeutic levels from day 1 after implantation reaching a peak during the first week of follow-up. The expression period was transient for up to 14 days. The rise of erythropoietin was followed by a transient significant increase in reticulocyte counts. The decrease of erythropoietin expression coincided with a significant dermal infiltrate of CD8 cytotoxic T cells. Antierythropoietin antibodies were not detected until day 90 following implantation. Implantation of dermal cores ex vivo transduced with human genes could eventually be used in the clinical setting to express therapeutic serum proteins. However, nonimmunogenic delivery system should be tested as gene vehicles.

Topics: Adenoviridae; Adult; Aged; Anemia; CD8-Positive T-Lymphocytes; Cytomegalovirus; Erythropoietin; Genetic Therapy; Genetic Vectors; Humans; Immunohistochemistry; Inflammation; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Reticulocytes; Skin; Time Factors

Mechanical circulatory assist devices (MCADs) are increasingly utilized independently of cardiac transplantation in the management of heart failure. Though MCAD use incorporates inherent mechanical risks, the inevitable onset of chronic anemia, with its associated morbidity and mortality, is also a significant concern. MCAD support has been correlated with elevated plasma levels of inflammatory cytokines TNF-alpha, IL-1beta, and IL-6, which have separately been found to inhibit erythropoietin (Epo)-induced erythrocyte (RBC) maturation. Previous analysis of hematological parameters for MCAD-supported patients concluded that an amplified inflammatory response impedes RBC proliferation and recovery from hemolytic anemia. Additional analysis may bolster this assertion. Hemoglobin concentration (HC), RBC distribution width (RDW), mean cell volume (MCV), and cardiac index were retrospectively analysed for 78 MCAD-supported patients implanted for greater than 30 days at the University of Arizona Health Sciences Center from 1996 to 2002. Analysis confirms that the HC, a conventional marker for anemia, declines with MCAD placement and remains below the clinically defined, minimum normal value. Inversely, the RDW rises above maximum normal measure, signifying an increased fraction of juvenile RBCs. The MCV remains unchanged and within normal limits, demonstrating adequate substrate for RBC formation. MCAD performance also stabilizes as adequate perfusion returns. These results further support our previously published conclusion that a sufficient response of erythropoiesis occurs in reaction to the onset of anemia by an increased production of immature RBCs. However, the cells never fully mature and join circulation. The patient's inflammatory cytokine response to the implanted device most likely mediates the chronic MCAD-induced anemia by inhibition of Epo effects.

Topics: Adult; Aged; Anemia; Cytokines; Erythropoiesis; Erythropoietin; Female; Heart, Artificial; Humans; Inflammation; Male; Middle Aged

Erythropoietin (EPO), a hematopoietic growth factor, has been shown to be neuroprotective when administered as either a pretreatment or posttreatment. This study tested the hypothesis that one of the mechanisms of protection afforded by posttreatment with recombinant human EPO (rh-EPO) is an anti-inflammatory effect via inhibition of interleukin (IL)-1beta.. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 90 minutes of hypoxia (8% O2 at 37 degrees C). Pups were divided into the following groups: control, hypoxia/ischemia, and hypoxia/ischemia plus rh-EPO. In the rh-EPO-treated pups, rh-EPO (5 U/g body weight IP) was administered starting 24 hours after the insult and then for 2 additional days. Samples were collected at 3, 7, 14, and 21 days after the insult. IL-1beta mRNA and protein levels were determined by quantitative real-time reverse transcription-polymerase chain reaction and ELISA. Tumor necrosis factor (TNF)-alpha mRNA levels were determined by colorimetric microplate assay.. rhEPO attenuated brain injury, as assessed by brain weight, and attenuated both the hypoxia/ischemia-induced increases in IL-1beta mRNA and protein levels. TNF-alpha mRNA levels did not increase at 3 to 14 days after the hypoxic/ischemic insult.. Administration of exogenous rh-EPO starting 24 hours after a hypoxic/ischemic insult is neuroprotective in the neonatal rat. This neuroprotective activity prevented the secondary, delayed rise in IL-1beta and attenuated the infiltration of leukocytes into the ipsilateral hemisphere.

Topics: Animals; Animals, Newborn; Brain; Carotid Arteries; Erythropoietin; Growth Substances; Humans; Hypoxia; Hypoxia-Ischemia, Brain; Inflammation; Interleukin-1; Ischemia; Leukocytes; Organ Size; Oxygen; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Temperature; Time Factors

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in young people in industrialized countries. Although various anti-inflammatory and antiapoptotic modalities have shown neuroprotective effects in experimental models of TBI, to date, no specific pharmacological agent aimed at blocking the progression of secondary brain damage has been approved for clinical use. Erythropoietin (Epo) belongs to the cytokine superfamily and has traditionally been viewed as a hematopoiesis-regulating hormone. The newly discovered neuroprotective properties of Epo lead us to investigate its effect in TBI in a mouse model of closed head injury. Recombinant human erythropoietin (rhEpo) was injected at 1 and 24 h after TBI, and the effect on recovery of motor and cognitive functions, tissue inflammation, axonal degeneration, and apoptosis was evaluated up to 14 days. Motor deficits were lower, cognitive function was restored faster, and less apoptotic neurons and caspase-3 expression were found in rhEpo-treated as compared with vehicle-treated animals (P<0.05). Axons at the trauma area in rhEpo-treated mice were relatively well preserved compared with controls (shown by their density; P<0.01). Immunohistochemical analysis revealed a reduced activation of glial cells by staining for GFAP and complement receptor type 3 (CD11b/CD18) in the injured hemisphere of Epo- vs. vehicle-treated animals. We propose that further studies on Epo in TBI should be conducted in order to consider it as a novel therapy for TBI.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Axons; Brain; Caspase 3; Caspases; CD11b Antigen; CD18 Antigens; Cytokines; Disease Models, Animal; Erythropoietin; Glial Fibrillary Acidic Protein; Head Injuries, Closed; Hematopoiesis; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Male; Mice; Neurons; Rats; Recombinant Proteins; Time Factors

Dose requirements of epoetin vary considerably among patients with end-stage renal disease (ESRD), whereas determinants of epoetin sensitivity are poorly understood. Fat mass is an important source of adipokines, including interleukin 6 (IL-6), which is associated with decreased epoetin sensitivity. Furthermore, the adipokine leptin stimulates human erythroid development in vitro. In the present study, we investigate the impact of fat mass and leptin level on epoetin sensitivity in patients with ESRD.. One hundred sixty-six patients with ESRD (107 men; 64%) with a mean age of 56.9 +/- 0.9 years were studied in a post hoc cross-sectional analysis. Body composition was analyzed by dual-energy X-ray absorptiometry and correlated with serum markers of inflammation and leptin (analyzed by enzyme-linked immunosorbent assays), as well as with epoetin dose, in international units administered per week (IU/wk). To correct for differences in body mass and hemoglobin (Hb) levels, epoetin sensitivity was approximated as epoetin/Hb ratio, ie, epoetin dose per unit of Hb (IU/wk/g/dL) and epoetin/Hb/kg ratio, ie, epoetin dose per unit of Hb and kilogram of patient body weight (IU/wk/Hb/kg).. Patients were divided into 3 groups according to epoetin/Hb/kg ratio (no-epoetin group, low-epoetin group, and high-epoetin group). The 3 groups had significantly different serum levels of high-sensitivity C-reactive protein (hsCRP; median, 8.6 versus 3.1 and 8.0 mg/L, respectively; P < 0.05), neopterin (median, 112.4 versus 94.3 and 96.1 ng/L, respectively; P < 0.05), and IL-6 (median, 6.8 versus 4.1 and 6.5 ng/mL, respectively; P < 0.05). Significant between-group differences also were found in fat mass and leptin levels (median, 14.8 versus 10.5 and 7.9 ng/mL, respectively; P = 0.02). In univariate analyses, significant relationships between epoetin sensitivity indices, leptin levels, and levels of the inflammatory markers hsCRP and IL-6 were found. In a multivariate stepwise regression model, log ferritin, parathyroid hormone, log leptin, log IL-6, and polycystic kidney disease were significantly associated with the epoetin/Hb ratio.. The present study shows that leptin level may be a predictor of epoetin sensitivity. The effect could be either direct stimulation of erythropoiesis or indirect stimulation by associated adipokines. Although truncal fat is associated with secretion of proinflammatory cytokines, this secretion appears not to have inhibitory effects on epoetin sensitivity in the presence of high leptin levels.

Topics: Adipose Tissue; Anemia; Body Composition; C-Reactive Protein; Cross-Sectional Studies; Darbepoetin alfa; Drug Resistance; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Inflammation; Interleukin-6; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Organ Size; Polycystic Kidney Diseases; Renal Dialysis; Sweden

rHuEPO (recombinant human erythropoietin) is a haemopoietic growth factor and a primary regulator of erythropoiesis that is used for the treatment of chronic anaemia associated with RA (rheumatoid arthritis). Erythropoietin also appears to modulate a broad array of cellular processes, including progenitor stem-cell development, cellular integrity, angiogenesis and oxidative damage. These diverse activities suggest the exciting possibility of multiple roles for rHuEPO therapy in a variety of disorders other than RA, including cerebral ischaemia, myocardial infarction, chronic congestive heart failure and cancer. Thus it appears that rHuEPO may be a pleiotropic agent, capable of influencing tissue remodelling independently of its established erythropoietic role. Whereas these effects may be largely beneficial, dose-related side effects could have implications for the safe therapeutic use of rHuEPO and its illegal use as a performance-enhancing agent in endurance sports.

Topics: 3T3 Cells; Anemia; Animals; Arthritis, Rheumatoid; Erythropoietin; Extracellular Matrix; Humans; Inflammation; Mice; Nitric Oxide; Recombinant Proteins

High circulating levels of proinflammatory cytokines cause anemia, perhaps by interacting with erythropoietin production or biological activity. We characterize the relationships of systemic inflammation, erythropoietin, and hemoglobin.. Data are from the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study population. A sample of 1270 persons aged 65 years or older and 30 men and 30 women from each age-decade 20 to 70 years were randomly selected from the residents in the Chianti, Italy, geographic area. Of the 1714 eligible persons, 1235 had complete data on inflammatory markers, erythropoietin, hemoglobin, potential causes of anemia, and other relevant covariates. Anemia was defined as hemoglobin less than 12 g/dL in women and less than 13 g/dL in men.. Independent of age, sex, and hemoglobin, the number of elevated inflammatory markers (C-reactive protein, interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha) was associated with progressively higher erythropoietin in non-anemic participants but lower erythropoietin in anemic participants. Findings were consistent across different causes of anemia. The threshold at which the effect of inflammation on erythropoietin reversed was close to 13.0 g/dL of hemoglobin.. Our findings suggest that anemia of inflammation evolves from a "pre-anemic" stage characterized by a compensatory increment of erythropoietin that maintains normal hemoglobin levels to a stage of clinically evident anemia in which erythropoietin levels are not high enough to maintain normal hemoglobin, possibly because of the inhibitory effect of inflammation on erythropoietin production. This hypothesis requires testing in a longitudinal study.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Comorbidity; Cytokines; Erythropoietin; Female; Folic Acid; Health Surveys; Hemoglobins; Humans; Inflammation; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Interleukins; Italy; Male; Middle Aged; Models, Biological; Receptors, Transferrin; Sampling Studies; Sialoglycoproteins; Transferrin

Although a known cardiovascular risk factor, anemia in the renal transplant recipients has only recently been receiving an increasing attention.. In a cross-sectional study, data was obtained from 959 patients followed at a single outpatient transplant clinic. Based on the guideline of the American Society of Transplantation, anemia was defined as hemoglobin (Hb) < or =130 g/L in males and < or =120 g/L in females.. About one-third (34%) of the patients were anemic. The prevalence of anemia was comparable in males and females. Serum Hb concentration was significantly correlated with the estimated glomerular filtration rate (eGFR) (abbreviated modification of diet in renal disease formula) (r = 0.266, p < 0.001), serum transferrin (r = 0.268, p < 0.001) and serum albumin (r = 0.196, p < 0.001). None of the immunosuppressive medications or the use of angiotensin converting enzyme inhibitors was associated with a higher likelihood of anemia. In multivariate analysis the eGFR, serum albumin and serum transferrin, potential markers of nutritional status and/or chronic inflammation, and also iron deficiency were independently and significantly associated with anemia. Erythropoietin was administered only to 63 (19%) anemic patients.. Post-transplant anemia is a prevalent and under-treated condition. Based on our results we suggest that, besides other factors, protein/energy malnutrition and/or chronic inflammation may be independently associated with anemia. Further studies are needed to determine whether the presence of anemia and its treatment will have an impact on long-term outcomes of this population.

Topics: Adult; Anemia, Iron-Deficiency; Angiotensin-Converting Enzyme Inhibitors; Comorbidity; Cross-Sectional Studies; Erythropoietin; Female; Humans; Inflammation; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Protein-Energy Malnutrition; Recombinant Proteins; Transferrin

Maternal diabetes increases the risk of intrauterine hypoxia. Inflammation may play a role in the pathogenesis of hypoxia-related neonatal complications. We studied correlations between levels of cord serum C-reactive protein (CRP), measured by a highly sensitive immunofluorometric assay, and indices of fetal hypoxia in diabetic pregnancies. Cord serum CRP correlated positively with amniotic fluid erythropoietin and umbilical artery pCO2. A negative correlation existed between cord serum CRP and umbilical artery pH and pO2. Amniotic fluid erythropoietin showed an independent effect on cord serum CRP in multiple regression analysis. These data suggest that the fetus responds to hypoxia by an inflammatory reaction.

Topics: Adult; Amniotic Fluid; Body Mass Index; C-Reactive Protein; Carbon Dioxide; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Fluoroimmunoassay; Humans; Hydrogen-Ion Concentration; Inflammation; Oxygen; Pregnancy; Pregnancy in Diabetics; Regression Analysis; Umbilical Arteries

It was hypothesized that pentoxifylline might improve the response to recombinant human erythropoietin (rh-Epo) in anemic renal failure patients. Sixteen patients with ESRD and rh-Epo-resistant anemia, defined by a hemoglobin of <10.7 g/dl for 6 mo before treatment and a rh-Epo dose of > or =12,000 IU/wk, were recruited. They were treated with oral pentoxifylline 400 mg o.d. for 4 mo. Ex vivo T cell generation of tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) from the patients was assessed before treatment and 6 to 8 wk after therapy. A total of 12 of 16 patients completed the study. Before therapy, the 12 patients' mean hemoglobin concentration was 9.5 +/- 0.9 g/dl. After 4 mo of pentoxifylline treatment, the mean hemoglobin concentration increased to 11.7 +/- 1.0 g/dl (P = 0.0001). Baseline ex vivo T cell expression of TNF-alpha decreased from 58% +/- 11% to 31% +/- 23% (P = 0.0007) after therapy. Likewise, IFN-gamma expression decreased from 31% +/- 10% to 13% +/- 10% (P = 0.0002). Pentoxifylline therapy may significantly improve the hemoglobin response in patients with previously rh-Epo-resistant anemia in renal failure. This may occur due to inhibition of proinflammatory cytokine production, which could interfere with the effectiveness of rh-Epo.

Topics: Adult; Aged; Anemia; Cytokines; Dose-Response Relationship, Drug; Drug Resistance; Erythropoietin; Female; Flow Cytometry; Free Radical Scavengers; Hemoglobins; Humans; Inflammation; Interferon-gamma; Leukocytes, Mononuclear; Male; Middle Aged; Pentoxifylline; Recombinant Proteins; Renal Insufficiency; T-Lymphocytes; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Chronic inflammation is a major cause of morbidity and mortality in end-stage renal disease. The associated anemia in these patients due to renal cortical atrophy and erythropoietin deficiency is treated with recombinant erythropoietin. Recent reports suggest a growing incidence of symptomatic venous thrombosis in cancer patients treated with recombinant erythropoietin. Several investigators have reported on different mechanisms of thrombosis in these patients. We hypothesize that thrombosis in patients with end-stage renal disease due to increased expression of C-reactive protein (CRP) as a result of chronic inflammation promotes the release of thrombin activatable fibrinolytic inhibitor causing fibrinolytic deficit and eventually thrombosis. Furthermore, because endothelial nitric oxide is responsible for the maintenance of the normal vascular function, the decreased levels of nitric oxide in chronic inflammation cause endothelial damage and result in thrombosis. To test this hypothesis, blood samples were collected from 106 patients (49 male and 57 female, aged 59.8+/-15.7 years) with end-stage renal disease undergoing hemodialysis and treated with recombinant erythropoietin at a mean dose of 201.8 U/kg/week. Blood samples were drawn in 5-mL tubes containing 3.2% sodium citrate just before the hemodialysis procedure. These blood samples were immediately centrifuged to obtain platelet-poor plasma, which was aliquoted and frozen at -70 degrees C until further analysis. Erytropoietin antibodies were measured using an anti-EPO enzyme-linked immunosorbent assay (ELISA) method developed in our laboratory. Nitric oxide was measured using a NO analyzer (Sievers 280I, Ionics, Boulder, CO). Plasma CRP levels were measured with a highly sensitive ELISA method IMUNOCLONE CRP ELISA (American Diagnostica, Greenwich, CT). TAFI antigen levels in plasma were analyzed with an IMUCLONE TAFI ELISA kit (American Diagnostica, Greenwich, CT). TAFI functional activity was assayed with an ACTICHROME TAFI activity kit. The measured levels of nitric oxide, CRP, TAFI antigen, and TAFI functional were 37.36+/-36.8 (normal value, 37.49+/-18.96; range, 19.3-102 microM), 12.27+/-10.6 (normal value, < 1 microg/mL), 146.9+/-28.4% NHP (normal, 100% NHP), and 102.55+/-37% NHP (normal range, 22.3-165.7; mean, 89.5% NHP), respectively. The erythropoietin antibody was detected in 9.4% of the patient group. While 20% of the erythropoietin antibody-positive and 27.1% of the erythropoietin ant

Topics: Adult; Aged; Aged, 80 and over; Anemia; Autoantibodies; C-Reactive Protein; Carboxypeptidase B2; Chronic Disease; Complement Activation; Cytokines; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Induction; Erythropoietin; Female; Fibrinolysis; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Recombinant Proteins; Renal Dialysis; Thrombin; Thrombophilia; Thrombosis

Mutations of hepcidin (HAMP) and hemo-juvelin (HJV) genes have been recently demonstrated to result in juvenile hemochromatosis. Expression of HAMP is regulated by iron status or infection, whereas regulation of HJV is yet unknown. Using quantitative real-time polymerase chain reaction, we compared expression of Hamp and Rgmc (the murine ortholog of HJV) in livers of mice treated with iron, erythropoietin, or lipopolysaccharide (LPS), as well as during fetal and postnatal development. Iron overload increased Hamp expression without effect on Rgmc mRNA. Erythropoietin decreased Hamp mRNA, but Rgmc expression was unchanged. Hamp mRNA level decreased after birth by 4 orders of magnitude, without significant changes in Rgmc expression. Administration of LPS elevated Hamp mRNA levels, while markedly decreasing hepatic Rgmc mRNA levels (to approximately 5% after 6 hours). The responses of Hamp and Rgmc were quite different and suggested that human HJV expression could be modulated by inflammation.

Topics: Animals; Antimicrobial Cationic Peptides; Erythropoietin; Gene Expression Regulation, Developmental; GPI-Linked Proteins; Hepcidins; Homeostasis; Inflammation; Iron; Liver; Mice; Muscle Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Patients returning to hemodialysis (HD) after failure of their kidney transplant suffer from high morbidity and mortality rates. It is common practice to keep failed kidney transplants in place. It is not known if these failed kidney transplants induce an inflammatory state that contributes to morbidity and mortality. In a single facility, patients starting on HD with failed kidney transplant were identified (Group A) and screened for the presence of chronic inflammatory state. Those with clinical symptoms attributed to the failed allograft (Group A1) were not offered transplant nephrectomy unless deemed necessary during follow-up. Their clinical and laboratory data were followed up for 6 months. Similar data were obtained from a group of incident HD patients (Group B). Forty-three patients had a failed Kidney transplant (Group A). Of these, 29 comprised Group A1 and 14 Group A2. Group B comprised 121 patients. In comparison with Group B, Group A exhibited worse anemia and erythropoietin resistance index (ERI), had lower serum albumin and prealbumin, and higher CRP. Group A1 had lower Hb and higher ferritin, CRP, and ESR in comparison with Group A2. Following transplant nephrectomy, Group A1 had improvement in ERI, serum albumin, prealbumin, ferritin, fibrinogen, CRP, and ESR. At 6 months, Group A1 had higher Hb and serum albumin levels, and lower CRP and ERI in comparison with Group A2. Group B parameters showed no change during follow-up. Patients returning to HD following failure of their kidney transplant suffer from a chronic inflammatory state. Resection of failed transplants in symptomatic patients is associated with amelioration of markers of chronic inflammation. Transplant nephrectomy should be considered a treatment option for patients with failed kidney transplants, especially if they exhibit signs and symptoms of chronic inflammatory state.

Topics: Chronic Disease; Erythropoietin; Female; Humans; Inflammation; Kidney Transplantation; Male; Middle Aged; Nephrectomy; Postoperative Complications; Renal Dialysis; Treatment Failure

Topics: Anemia, Iron-Deficiency; Bone Marrow; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Hematologic Tests; Humans; Inflammation; Iron; Neoplasms

The present study investigates the respective roles of both the host immune response and the metabolic requirements in determining the long-term survival of erythropoietin-secreting myoblasts within encapsulating polymer membranes. Hollow-fiber capsules loaded with a high density of erythropoietin-secreting C(2)C(12) myoblasts survived poorly in the subcutaneous tissue of syngeneic mice, inducing variable hematocrit responses. To determine the role and the nature of the host response, recipients were treated with anti-inflammatory (diclofenac) and immunosuppressive (dexamethasone, FK506) agents. Only immunosuppressive drugs led to improved graft survival after 5 weeks of implantation, indicating an immune process as the cause of cell death. Furthermore, transient blocking of this process allowed long-term preservation of the implanted cells (> 100 days). The formation of necrotic cell cores inside densely packed devices elicited a local chronic inflammatory reaction. Hence, implants were designed to limit early cell death by inserting a supporting matrix and decreasing the number of loaded cells. The most efficient erythropoietin delivery was obtained with matrix-containing capsules that had received the lowest myoblast density. These results highlight the critical role of initial engraftment in the long-term acceptance of encapsulated myoblasts and the need to limit early cell death in the device to prevent subsequent host immuno-inflammatory responses.

Topics: Animals; Capsules; Cell Transplantation; Cells, Cultured; Dexamethasone; Diclofenac; Erythropoietin; Female; Gene Expression; Genetic Engineering; Genetic Vectors; Graft Survival; Hematocrit; Immunosuppressive Agents; Inflammation; Mice; Mice, Inbred C3H; Myoblasts; Plasmids; Tacrolimus; Transplantation Tolerance

Resistance to recombinant human erythropoietin occurs in a small but important proportion of hemodialysis patients. This may be due to increased immune activation because pro-inflammatory cytokines inhibit erythropoiesis in vitro. Using FACScan flow cytometry, the proportion of PMA/ionomycin-stimulated T cells expressing cytokines ex vivo was compared in 18 poor responders to erythropoietin, 14 good responders to erythropoietin, and 14 normal controls. CD4(+) T cells from poor responders expressed more interferon-gamma (IFN-gamma; 19 +/- 6%) compared with good responders (11 +/- 6%, P < 0.001) and controls (12 +/- 6%, P < 0.01). Similarly, CD4+ T cells from poor responders expressed more tumor necrosis factor-alpha (TNF-alpha; poor responders: 51 +/- 19% versus good responders: 27 +/- 15% [P < 0.01] and controls: 30 +/- 19% [P < 0.01]). CD4+ expression of IL-10 was also enhanced (poor responders: 1.6 +/- 1.1% versus good responders: 0.7 +/- 0.6% [P < 0.05] and controls: 0.5 +/- 0.2% [P < 0.01]). Likewise, CD4+ expression of interleukin-13 (IL-13) was increased (poor responders: 4.4 +/- 4.2% versus good responders: 1.6 +/- 1.7% [P < 0.05] and controls: 1.6 +/- 1.5% [P < 0.05]). CD8+ T cells from poor responders also showed enhanced expression of cytokines. For IFN-gamma, poor responder expression was 48 +/- 20% compared with 31 +/- 17% (P < 0.05) for good responders and 23 +/- 15% (P < 0.01) for controls. TNF-alpha expression for poor responders was 41 +/- 21% versus 25 +/- 14% for good responders (P < 0.05) and 21 +/- 15% for controls (P < 0.01). IL-10 expression for poor responders was 2.0 +/- 1.2% (good responders: 0.7 +/- 0.6% [P < 0.01]; controls: 0.5 +/- 0.2% [P < 0.001]). These data indicate that T cells from poor responders are in an enhanced activation state possibly as a result of chronic inflammation. In the absence of any other cause (such as iron deficiency), the overproduction of cytokines may account for hyporesponsiveness to erythropoietic therapy in patients with renal failure.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Division; Cell Separation; Cytokines; Erythropoiesis; Erythropoietin; Female; Flow Cytometry; Humans; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-13; Interleukin-4; Ionomycin; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Models, Biological; Recombinant Proteins; Reproducibility of Results; T-Lymphocytes; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Ischemic brain injury resulting from stroke arises from primary neuronal losses and by inflammatory responses. Previous studies suggest that erythropoietin (EPO) attenuates both processes. Although EPO is clearly antiapoptotic for neurons after experimental stroke, it is unknown whether EPO also directly modulates EPO receptor (EPO-R)-expressing glia, microglia, and other inflammatory cells. In these experiments, we show that recombinant human EPO (rhEPO; 5,000 U/kg body weight, i.p.) markedly reduces astrocyte activation and the recruitment of leukocytes and microglia into an infarction produced by middle cerebral artery occlusion in rats. In addition, ischemia-induced production of the proinflammatory cytokines tumor necrosis factor, interleukin 6, and monocyte chemoattractant protein 1 concentration is reduced by >50% after rhEPO administration. Similar results were also observed in mixed neuronal-glial cocultures exposed to the neuronal-selective toxin trimethyl tin. In contrast, rhEPO did not inhibit cytokine production by astrocyte cultures exposed to neuronal homogenates or modulate the response of human peripheral blood mononuclear cells, rat glial cells, or the brain to lipopolysaccharide. These findings suggest that rhEPO attenuates ischemia-induced inflammation by reducing neuronal death rather than by direct effects upon EPO-R-expressing inflammatory cells.

Topics: Animals; Apoptosis; Brain Ischemia; Cells, Cultured; Coculture Techniques; Cytokines; Erythropoietin; Humans; Infarction, Middle Cerebral Artery; Inflammation; Lipopolysaccharides; Male; Neuroglia; Neurons; Neuroprotective Agents; Rats; Receptors, Erythropoietin; Recombinant Proteins; Tumor Necrosis Factor-alpha

Elements of malnutrition-inflammation complex syndrome (MICS) may blunt the responsiveness of anemia of end-stage renal disease (ESRD) to recombinant human erythropoietin (EPO).. The authors examined cross-sectional associations between the required dose of EPO within a 13-week interval as prescribed by practicing nephrologists who were blind to the study and several laboratory values known to be related to nutrition and/or inflammation, as well as the malnutrition-inflammation score (MIS), which is a fully quantitative assessment tool based on the subjective global assessment of nutrition.. A total of 339 maintenance hemodialysis (MHD) outpatients, including 181 men, who were aged 54.7 +/- 14.5 years (mean +/- SD), who had undergone dialysis for 36.3 +/- 33.2 months, were selected randomly from 7 DaVita dialysis units in Los Angeles South/East Bay area. The average weekly dose of administered recombinant human EPO within a 13-week interval was 217 +/- 187 U/kg. Patients were receiving intravenous iron supplementation (iron gluconate or dextran) averaging 39.5 +/- 47.5 mg/wk. The MIS and serum concentrations of high-sensitivity C-reactive protein, interleukin 6 (IL-6), tumor necrosis factor-alpha, and lactate dehydrogenase had positive correlation with required EPO dose and EPO responsiveness index (EPO divided by hemoglobin), whereas serum total iron binding capacity (TIBC), prealbumin and total cholesterol, as well as blood lymphocyte count had statistically significant but negative correlations with indices of refractory anemia. Most correlations remained significant even after multivariate adjustment for case-mix and anemia factors and other relevant covariates. Similar associations were noticed across EPO per body weight tertiles via analysis of variance and after estimating odds ratio for higher versus lower tertile via logistic regression after same case-mix adjustment.. The existence of elements of MICS as indicated by a high MIS and increased levels of proinflammatory cytokines such as IL-6 as well as decreased nutritional values such as low serum concentrations of total cholesterol, prealbumin, and TIBC correlates with EPO hyporesponsiveness in MHD patients.

Topics: Aged; Anemia; Biomarkers; C-Reactive Protein; Epidemiologic Methods; Erythropoietin; Female; Ferric Compounds; Humans; Inflammation; Interleukin-6; Iron; Iron-Dextran Complex; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Male; Malnutrition; Middle Aged; Recombinant Proteins; Renal Dialysis; Reproducibility of Results; Sex Factors; Syndrome; Tumor Necrosis Factor-alpha

Chronic inflammation is a common cause of severe anemia and hyporesponsiveness to recombinant erythropoietin (EPO) therapy in maintenance hemodialysis (HD) patients. We compared various acute-phase markers and ex vivo platelet aggregation tests in relation to clinical conditions in order to find factors predictive of hemoglobin (Hb) and endogenous EPO levels in a cross-section of clinically stable HD patients.. In 100 subjects, pre-HD blood levels of C-reactive protein (CRP), alpha(1)-acid-glycoprotein (AGP), alpha(1)-antitrypsin (AT), immunoglobulin (Ig) M and G (by nephelometry), antigens of endothelial von Willebrand factor (vWF), type 1 plasminogen activator inhibitor and thrombomodulin, interleukin-6, lipoprotein(a) [Lp(a)] and EPO (by ELISA), and albumin, fibrinogen, iron metabolism indices, thyroid-stimulating hormone, phosphorus, parathormone, total cholesterol, triglycerides, viral hepatitis B/C markers, liver enzyme, and aluminium were determined. Platelet aggregations in response to ristocetin (RIPA), adenosine diphosphate, and collagen were measured in whole blood (electric impedance method) and platelet-rich plasma (optical aggregometry).. Hb levels inversely correlated with IgM, Lp(a), soluble vWF antigen, phosphorus, and all platelet aggregations in whole blood, but not in platelet-rich plasma. HD duration and triglycerides were positive correlates of anemia. In a multivariable analysis, increased IgM, short HD duration, increased Lp(a) and enhanced whole blood RIPA (in descending order of significance) were independent predictors of low Hb levels. In 51 patients not treated with recombinant EPO, serum levels of this hormone inversely correlated with whole blood RIPA, AT, age, vWF antigen, AGP, and positively with viral hepatitis marker. Anemia and EPO levels were not affected by gender, body mass index, cause of renal failure, residual renal function, HD dose, protein catabolic rate, use of different heparins or dialysate buffers, ACE inhibitor therapy, and parathyroid or thyroid function. In additional 10 patients, single HD session resulted in an increase in IgM levels associated with a fall in total lymphocyte counts.. Subclinical inflammation is an important determinant of anemia in maintenance HD patients. Increased serum IgM reflecting a microinflammatory effect of HD procedures, enhanced whole blood RIPA as a surrogate of vascular endothelial damage, and Lp(a) as its promoter could be markers of such impaired erythropoiesis.

Topics: Adolescent; Adult; Aged; Anemia; Biomarkers; Cross-Sectional Studies; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Male; Middle Aged; Platelet Aggregation; Renal Dialysis

Hemodialysis (HD) patients face a 25% annual mortality rate, with 50% of reported deaths attributed to cardiovascular disease. All-cause and cardiovascular mortality correlate with such acute-phase proteins as C-reactive protein (CRP). Hepatic CRP synthesis is upregulated by inflammation; however, elevated CRP values frequently are found in the absence of apparent infection or inflammation. Because destructive periodontal diseases have been associated with elevated CRP levels, we questioned whether destructive periodontal diseases could contribute to elevated CRP values in HD populations.. Sera from 86 consecutive dentate HD patients were assayed for levels of immunoglobulin G (IgG) antibody to six periodontal species by means of an enzyme-linked immunosorbent assay.. CRP values for the subject population ranged from less than 6.9 to 159 mg/L (median, 8.2 mg/L). Univariate comparisons between subjects with or without elevated CRP levels (>10 mg/L) showed that CRP level elevation was associated significantly (P < 0.05) with greater doses of human recombinant erythropoietin and lower levels of hemoglobin, serum iron, transferrin saturation (TSat), albumin averaged over the 3 preceding months, total cholesterol, and triglycerides. Log serum IgG antibody levels to Porphyromonas gingivalis also were significantly greater in the group with elevated CRP levels (P = 0.013). Subsequent multivariate logistic regression showed that log serum antibody levels to P gingivalis remained significant (P = 0.02) after controlling for nonperiodontal sources of elevated CRP, hemoglobin, TSat, and triglyceride values.. These results suggest that elevated levels of IgG antibody to bacterial species associated with destructive periodontal diseases are associated with elevated CRP values in HD populations.

Topics: Actinobacillus Infections; Aggregatibacter actinomycetemcomitans; Antibodies, Bacterial; Bacteroidaceae Infections; Biomarkers; C-Reactive Protein; Campylobacter; Campylobacter Infections; Drug Administration Schedule; Erythropoietin; Female; Humans; Immunoglobulin G; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Periodontitis; Porphyromonas; Recombinant Proteins; Renal Dialysis; Species Specificity

Occult infection of old nonfunctioning arteriovenous grafts (AVGs) is frequent among hemodialysis patients. It is a recognized cause of bacteremia and other infectious complications. Additionally, old nonfunctioning AVGs may be harbingers of other noninfectious complications. The aim of this study was to investigate whether occult infection of old nonfunctioning AVGs is a cause of a chronic inflammatory state in hemodialysis patients.. This study was performed in two phases: In the first phase (study 1), 22 patients with clinically proven occult infection of old nonfunctioning AVG were identified, and data on hemoglobin, weekly erythropoietin dose, and albumin levels were collected retrospectively. Comparisons were made between values obtained pre- and post-AVG resection. In the second phase (study 2), we examined whether the presence of a chronic inflammatory state is associated with occult AVG infection in old nonfunctioning AVGs. Twenty hemodialysis patients were identified with chronic inflammatory state based on erythropoietin dose (units/wk)/hematocrit ratio>470, serum albumin <3.3 g/dL, and CRP>25 mg/L. Among these patients, we found eight with old nonfunctioning AVGs. We then performed indium-labeled white blood cell (WBC) scans on the eight patients to screen for occult infection of old nonfunctioning AVGs. The AVGs with positive indium scan were resected and cultured. Data on hematocrit, erythropoietin dosing, serum albumin, ferritin, and CRP were obtained at 2 months following AVG resection and compared to pre-resection values.. In study 1, the 22 patients with occult infection of old nonfunctioning AVG exhibited profound anemia and hypoalbuminemia. Their mean hemoglobin was 9.2 +/- 1.2 g/dL which improved to 11.6 +/- 0.8 g/dL (P < 0.05) 3 months after AVG resection. Their mean serum albumin was 3.3 +/- 0.5 g/dL which improved to 3.8 +/- 0.2 g/dL (P < 0.05) 3 months after AVG resection. Their mean erythropoietin dosages (units/patient/wk) fell from 14,240 +/- 350 to 6,675 +/- 455 (P < 0.05). In study 2, among the 8 patients with chronic inflammatory state and old nonfunctioning AVG, 6 (75%) had positive indium scans and underwent surgical resection that proved bacterial infection. Upon follow-up, the 2-month data showed a remarkable improvement in the following parameters: weekly erythropoietin dose/hematocrit ratio from 622 +/- 137 to 254 +/- 28 (P < 0.05), plasma ferritin values from 690 +/- 126 ng/mL to 247 +/- 42 ng/mL (P < 0.01), and plasma CRP from 56.7 +/- 9.0 to 14.5 +/- 3.8 mg/L (P < 0.01). Serum albumin values also improved from 3.07 +/- 0.08 g/dL to 3.34 +/- 0.14 g/dL (P = 0.13). Percent plasma iron saturation did not appreciably differ from baseline (20.5% +/- 4.4% to 19.8 +/- 1.9%, P = 0.89).. Occult infection of old nonfunctioning AVG is a common cause of erythropoietin resistance and chronic inflammatory state among hemodialysis patients. Resection of old nonfunctioning AVGs with occult infection is associated with resolution of markers of chronic inflammatory state.

Topics: Algorithms; Anemia; Blood Vessel Prosthesis; Chronic Disease; Drug Resistance; Erythropoietin; Follow-Up Studies; Humans; Inflammation; Prosthesis-Related Infections; Renal Dialysis; Retrospective Studies; Time Factors

A previous study from our laboratory has shown that erythropoietin (EPO), beside its traditional role in erythropoiesis, acts as an alleviator of oxidative stress and inflammation in chronic hemodialysis (HD) patients, conferred in part by activated polymorphonuclear leukocytes (PMNLs). To substantiate this phenomenon, the existence of EPO receptors (EPO-Rs) on PMNL membrane was examined at the transcriptional and translational levels. mRNA for EPO-R was detected in PMNLs using specific primers directed towards the extracellular region of human EPO-R cDNA. The predicted 300-bp fragment was amplified by reverse transcriptase-polymerase chain reaction. Subcloning and sequence analysis revealed 100% homology of this fragment with human EPO-R. The receptor protein was detected on the surface of intact PMNLs using (125)I-EPO. The protein was further demonstrated by flow cytometric analysis using a fluorescent monoclonal anti-EPO-R. The percentage of PMNLs expressing EPO-R showed a strong correlation with the level of EPO in the serum, suggesting an upregulation of the receptor by the hormone. Taken together with our recent findings that EPO attenuates the oxidative stress and inflammation contributed by PMNLs in HD patients, the detection of functional EPO-R expression in PMNLs places these cells among the nonerythroid, EPO-responsive target populations.

Topics: Adult; Base Sequence; Case-Control Studies; Cell Membrane; DNA Primers; Erythropoiesis; Erythropoietin; Female; Humans; Inflammation; Male; Middle Aged; Neutrophils; Oxidative Stress; Receptors, Erythropoietin; Renal Dialysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

The aim of the present study was to examine the association between 4-hour dialysate-to-plasma ratio of creatinine (D/PCr), erythropoietin (EPO) responsiveness [EPO (U/week)/hemoglobin (g/L)], and C-reactive protein (CRP). Subjects were 54 prevalent peritoneal dialysis (PD) patients [mean age: 58 years; 30 women, 24 men; 28 with diabetes; 15 on continuous ambulatory peritoneal dialysis (CAPD); 39 on continuous cycling peritoneal dialysis (CCPD); mean Kt/V: 2.44]. In 17 patients, CRP was elevated (> 15 mg/L), and in 39 patients, 4-hour D/PCr was high or high-average (> or = 0.65). Mean hemoglobin (Hb) was 115.5 +/- 12.9 g/L; median EPO dose was 2800 U/week, and median EPO/Hb was 24.5. A nonsignificant negative correlation was noted between CRP and hemoglobin (r = -0.25, p = 0.07), but no correlations were seen between CRP and 4-hour D/PCr, or hemoglobin and 4-hour D/PCr. No correlation was seen between EPO/Hb and 4-hour D/PCr or CRP. Multiple linear regression (stepwise, alpha = 0.05) was performed with outcome hemoglobin and independent variables EPO [U/week (forced in)], percent transferrin saturation [TSAT (forced in)], age, sex, diabetes mellitus, serum albumin, CRP, time on PD, 4-hour D/PCr, normalized protein catabolic rate (nPCR), ferritin, intact parathyroid hormone (iPTH), aluminum, and angiotensin converting enzyme inhibitor (ACEI) use. Serum albumin (1.27, p < 0.01) and diabetes mellitus (-6.69, p = 0.04) were the only significant predictors of hemoglobin. With serum albumin removed from the model, age (but not CRP) became significant. These results do not support an association between peritoneal transport and EPO responsiveness, mediated by inflammation. The association between serum albumin and hemoglobin appears to be confounded by age more than by inflammation.

Topics: Biological Transport; C-Reactive Protein; Creatinine; Diabetes Mellitus; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Inflammation; Iron; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Proteins; Regression Analysis

We developed a rodent model of noninfectious systemic inflammation to examine the pathogenesis of the associated anemia of chronic disorders (ACD), to evaluate the similarity of this ACD model to human ACD, and to evaluate the potential efficacy of novel erythropoiesis stimulating protein (darbepoetin alfa) as an ACD therapy.. Lewis rats were immunized with peptidoglycan-polysaccharide polymers (PG-APS), the chronic inflammation and associated ACD were characterized, and the effects of darbepoetin alfa treatment on complete blood counts (CBC), red blood cell (RBC) indices, and iron metabolism were analyzed weekly.. Acutely inflamed rats had reduced peripheral blood (PB) RBC counts and hemoglobin (Hb) concentrations and increased reticulocyte counts. PB RBC numbers normalized during chronic inflammation, but RBC remained hypochromic and microcytic. Consequently, the rats remained chronically anemic. Anemic rats had fluctuating serum erythropoietin (EPO) concentrations, but mean EPO concentrations never varied significantly from baseline control levels. Histology of anemic rat spleen sections revealed reticuloendothelial siderosis. Total serum iron concentrations were chronically low. Peritoneal exudate cells (PEC) isolated from anemic rats and stimulated with PG-APS in vitro produced more interleukin (IL)-1alpha and interferon (IFN)-gamma, and significantly more tumor necrosis factor (TNF)-alpha and IL-10 than control cultures. Darbepoetin alfa restored Hb concentrations to baseline levels within 2 to 7 weeks, depending on dosage. A refined treatment strategy restored Hb to baseline and maintained those levels with reduced dosing.. ACD in this rodent model closely replicates human ACD. Darbepoetin alfa treatment reversed ACD in this model by increasing RBC production and RBC hemoglobinization while reducing siderosis and hypoferremia.

Topics: Anemia; Animals; Ascitic Fluid; Blood Cell Count; Chronic Disease; Disease Models, Animal; Erythrocyte Count; Erythropoietin; Female; Hemoglobins; Inflammation; Mononuclear Phagocyte System; Peptidoglycan; Polysaccharides; Rats; Rats, Inbred Lew; Reticulocyte Count; Siderosis

Inflammation and hypoxia are frequently associated, but their interaction is poorly understood. In vitro studies have shown that hypoxia stimulates the genes of acute phase proteins (APP) and cytokines known to induce APP. We decided to determine kinetics and potential determinants of an acute phase response after cardiac arrest and to assess whether isolated moderate hypoxia can induce APP in humans in vivo.. Prospective, observational study in patients and human experiment.. Tertiary care university hospital.. 22 patients after primarily successful cardiopulmonary resuscitation (CPR) and 7 healthy volunteers.. None in patients; exposure of volunteers to simulated altitude (460 torr/6 h).. Following CPR, type-1 APP (C-reactive protein, alpha 1-acidglycoprotein, serum amyloid A) and type-2 APP (haptoglobin, alpha 1-antitrypsin) increased consistently within 1-2 days and the 'negative' APP transferrin was downregulated. This APP response occurred irrespective of the cause of arrest, the estimated time of anoxia, clinical course or patient outcome and was not different in patients with and without infectious complications. Exposure of healthy volunteers to less severe but more prolonged hypoxia did not induce APP, although a time dependent increase of serum erythropoietin (EPO) was measurable under these conditions, indicating the activation of oxygen dependent gene expression.. (i) A marked acute phase response occurs regularly after cardiac arrest, but within the complexity of this situation the severity of hypoxia is not a predominant determinant of this response. (ii) Despite in vitro evidence for similarities in the oxygen dependent regulation of APP and EPO production, the oxygen sensitivity of these proteins in vivo is different. (iii) Measurements of APP are not revealing regarding infectious complications in the early phase after CPR.

Topics: Acute-Phase Proteins; Acute-Phase Reaction; Adolescent; Adult; Aged; Cardiopulmonary Resuscitation; Erythropoietin; Female; Heart Arrest; Hemoglobins; Humans; Hypoxia; Inflammation; Kinetics; Male; Middle Aged; Prospective Studies

The response to recombinant human erythropoietin (rHuEpo) is determined primarily by the availability of iron. In contrast to i.v., iron, oral iron supplementation is often insufficient for an optimal response.. We studied iron absorption and the effects of iron status, aluminium status and inflammation in 19 chronic haemodialysis patients on maintenance rHuEpo therapy. Iron mucosal uptake after 24 h, iron retention after 2 weeks and mucosal transfer of iron were determined with a whole-body counter using an oral dose 59Fe. Iron absorption was measured once without, and once after the ingestion of 2 g aluminium hydroxide.. On the basis of transferrin saturation, two groups of dialysis patients were distinguished: a group with a functional iron deficiency (n = 9), and an iron-replete group (n = 10). In the iron-deficient dialysis patients group, mucosal uptake, mucosal transfer, and iron retention were 49.9% +/- 29.4, 0.73 +/- 0.29, and 41.6% +/- 32.2, being significantly lower than in a non-uraemic iron deficient population (P < 0.01, P < 0.05, P < 0.01 respectively). In the iron-replete dialysis patients group, mucosal uptake, mucosal transfer, and iron retention were 20.0 +/- 12.3, 0.59 +/- 0.18, and 11.1 +/- 6.7, mucosal uptake and iron retention being lower than in a normal iron-replete population (P < 0.0005 and P < 0.003 respectively). Dialysis patients with high C-reactive protein (CRP) values showed lower iron absorption. Iron absorption data correlated significantly with transferrin saturation and CRP in the iron-deficient group, and with serum ferritin in the iron-replete group. Iron absorption decreased after an aluminium hydroxide challenge in the iron-deficient patients to the lower levels of the iron-replete subjects. Body aluminium stores, estimated by the desferrioxamine test, did not correlate with parameters of iron absorption.. The absorption of iron in dialysis patients is decreased in haemodialysis patients, which may, at least in part, be due to inflammation. Aluminium ingestion further reduces absorption in functional iron-deficient patients.

Topics: Absorption; Adult; Aged; Aged, 80 and over; Aluminum; C-Reactive Protein; Erythropoietin; Female; Ferritins; Humans; Inflammation; Iron; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Many different cell types, coordinated by proinflammatory mediators, take part in the acute inflammatory reaction, but there is a lack of evidence regarding the role of erythroid cells in such conditions. In this study, changes in bone marrow, splenic, and peripheral blood erythroid cells and in erythropoietin (Epo) blood levels were investigated up to 72 hours after polyvinylpyrrolidone (PVP)-induced sterile inflammation in male Wistar rats (two intraperitoneal injections of 15 mL 3.5% PVP at 18-hour intervals). Transient changes within progenitor erythroid cells were observed in the bone marrow. Significant increases in the number of splenic immature erythroid progenitors (BFU-E) 6 hours and mature erythroid progenitors (CFU-E), erythroblasts, and orthochromatic erythroblasts 48 and 72 hours after the induction of inflammation pointed to stimulated splenic erythropoiesis. This was confirmed by semiquantitative assessment of splenic smears, which demonstrated expansion of erythroid cells at hours 48 and 72. The changes observed in the bone marrow and spleen indicated that during acute inflammation erythropoiesis was stimulated and that the spleens of PVP-treated rats were favorable to erythroid development. The significant increase in the percentage of peripheral blood reticulocytes 48 and 72 hours after PVP-induced inflammation provided evidence that effective erythropoiesis occurred. In spite of the stimulated erythropoiesis, serum levels of Epo remained unchanged, implying that other non-Epo regulatory molecules may be responsible for erythroid cellular changes.

Topics: Acute Disease; Animals; Bone Marrow Cells; Cell Differentiation; Erythropoiesis; Erythropoietin; Inflammation; Male; Povidone; Rats; Rats, Wistar; Spleen; Time Factors

Activation of p38 MAP kinase (p38) as well as JNK/SAPK has been described as being induced by a variety of environmental stresses such as osmotic shock, ultraviolet radiation, and heat shock, or the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 (IL-1). We found that the hematopoietic cytokines erythropoietin (Epo) and IL-3, which regulate growth and differentiation of erythroids and hematopoietic progenitors, respectively, also activate a p38 cascade. Immunoblot analyses and in vitro kinase assay clearly showed that Epo and IL-3 rapidly and transiently phosphorylated and activated p38 in Epo- or IL-3-dependent mouse hematopoietic progenitor cells. p38 can generally be activated by the upstream kinase MKK3 or MKK6. However, in vitro kinase assays in the immunoprecipitates with anti-MKK6 antibody and anti-phosphorylated MKK3/MKK6 antibody showed that activation of neither MKK3 nor MKK6 was detected after Epo or IL-3 stimulation, while osmotic shock clearly induced activation of both MKK3/MKK6 and p38. Together with previous observations, these results suggest that both p38 and JNK cascades play an important role not only in stress and proinflammatory cytokine responses but also in hematopoietic cytokine actions.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cell Line; Enzyme Activation; Erythropoietin; Hematopoiesis; Hematopoietic Stem Cells; Inflammation; Interleukin-3; Mice; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Processing, Post-Translational; Signal Transduction; Stress, Physiological

Erythropoietin (Epo) production during acute inflammation induced by s. c. turpentine administration in experimental Long-Evans rats increased in response to reduced erythropoiesis. A close correlation was found between decreased haematocrit (Hct) and increased levels of tumour necrosis factor-alpha (TNF alpha) in this experimental system. The Epo response was not different between rats with acute inflammation and anaemia and control animals with a comparable degree of anaemia. It is concluded that Epo is not an acute phase reactant, and that the Epo response in acute experimental inflammation in rats is explained by the associated development of anaemia.

Topics: Acute Disease; Anemia; Animals; Asepsis; Erythropoiesis; Erythropoietin; Inflammation; Kinetics; Male; Rats

Topics: Anemia; Chronic Disease; Elective Surgical Procedures; Erythropoietin; Humans; Inflammation; Neoplasms; Preoperative Care; Recombinant Proteins

The role of erythropoietin in the pathogenesis of anaemia associated with inflammatory disorders is unclear. We studied serum erythropoietin levels in patients with inflammatory process of varying aetiologies. Serum erythropoietin levels and reticulocyte counts were prospectively measured in 40 patients with inflammatory syndromes and compared with values obtained in 20 patients with myelodysplastic syndromes. Significant inverse correlation between erythropoietin levels and haemoglobin concentration were noted in the 2 groups. The slope of the regression line for patients with inflammatory disorders was lower as compared with that for the myelodysplastic syndromes. In all cases, when the erythropoietin response in relation to degree of anaemia is compared with that which occurs in patients with myelodysplastic syndromes, the inadequate erythropoietin response in patients with chronic inflammatory process becomes evident. In patients with inflammatory process, a relationship between erythropoietin levels and reticulocyte counts were only noted in patients with mildly anaemia (haemoglobin concentration higher than 10.5 g/dl). This study suggests blunted erythropoietin production and impaired marrow response to this hormone in the anaemia which occurs in inflammatory syndromes and supports the hypothesis that these disorders may contribute to the development of the anaemia associated with inflammatory disorders.

Topics: Adult; Aged; Anemia; Chronic Disease; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Inflammation; Male; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Reticulocyte Count

Preoperative autologous donation (PAD) of blood and administration of recombinant human erythropoietin (Epoetin alfa) are two strategies for increasing red blood cell (RBC) mass preoperatively. The success of PAD depends primarily on the patient's ability to manufacture new RBCs before surgery to replace those removed during PAD. Red blood cell manufacture depends in turn on adequate supplies of iron and the increased renal production of endogenous erythropoietin following PAD. Successful PAD also requires adequate time for regeneration of predonated RBCs. Parenteral administration of Epoetin alfa causes a dose-dependent stimulation of RBC production. Its use has been studied as an adjunct to PAD and as a method to enhance endogenous erythropoiesis without PAD. Several studies suggest that administration of Epoetin alfa, begun several days before surgery, may stimulate erythropoiesis and help decrease the number of RBC transfusions required postoperatively. The precise role of Epoetin alfa in the surgical setting is not yet established, and optimal dosage regimens have not been determined.

Topics: Aged; Anemia; Blood Transfusion, Autologous; Drug Administration Schedule; Elective Surgical Procedures; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Female; Ferritins; Humans; Inflammation; Male; Osteoarthritis; Postoperative Complications; Preoperative Care; Recombinant Proteins

Infection and inflammation are common problems in patients with end-stage renal disease. Both conditions can interfere with normal erythropoiesis and lead to a worsening of anemia and a suboptimal response to Epoetin alfa therapy. By understanding the pathophysiologic effects of infection and inflammation, assessing the patient's clinical status, and analyzing relevant laboratory values, nurses can intervene early and minimize the impact of these conditions on hematocrit.

Topics: Adult; Anemia; Diagnosis, Differential; Erythropoietin; Humans; Infections; Inflammation; Kidney Failure, Chronic

In patients with the anemia of chronic diseases, the plasma level of EPO is often low in relation to the blood hemoglobin concentration. Because infectious and inflammatory processes cause activation of cytokine-producing macrophages and lymphocytes, we investigated whether isolated inflammatory cytokines influence the synthesis of EPO in vitro. IL-1 and TNF-alpha were shown to inhibit EPO mRNA levels and EPO formation in the human hepatoma cell cultures HepG2 and Hep3B, and to lower EPO formation in isolated perfused rat kidneys. IFN-alpha and IFN-beta also induced some inhibition of EPO production in HepG2 cultures. IL-3, TGF-beta 2, and IFN-gamma did not inhibit. IL-6 stimulated the production of EPO in Hep3B cells but was ineffective in HepG2 cells and lowered EPO production in isolated perfused rat kidneys. IL-1, TNF-alpha, and possibly other cytokines could contribute to defective EPO production in renal and nonrenal immune responses.

Topics: Anemia; Animals; Carcinoma, Hepatocellular; Cell Line; Chronic Disease; Culture Media, Conditioned; Cytokines; Erythropoietin; Hemoglobins; Humans; Inflammation; Interferon-alpha; Interferon-beta; Kidney; Kinetics; Liver Neoplasms; Macrophages, Peritoneal; Male; Mice; Monokines; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Tumor Cells, Cultured

Topics: Anemia; Anemia, Refractory; Blood Preservation; Blood Transfusion, Autologous; Erythropoiesis; Erythropoietin; Hematologic Diseases; Humans; Inflammation; Neoplasms; Receptors, Erythropoietin; Recombinant Proteins; Renal Dialysis

Varied conditions associated with immune activation (rheumatic, infectious and malignant) are associated with a syndrome characterized by selective erythropoietic suppression. The pathogenesis of this anemia is unknown. We have cultured intact marrows from 11 patients and found decreased erythroid colony forming activity (CFU-E: colony forming unit-erythroid; p < 0.01). We analyzed sera from 23 patients with infectious, rheumatic and malignant disorders for their ability to render normal human T lymphocytes inhibitory to autologous CFU-E and burst forming unit-erythroid in vitro. Following exposure to serum from some anemic patients, normal T cells were observed to inhibit autologous CFU-E when compared to the effect elicited by T cells incubated with heterologous normal serum. Pooled data from 19 (7 not anemic, 12 anemic) serum samples using 8 different normal T cell and marrow donors revealed a significant correlation (r = 0.65, p < 0.01) between each patient's hemoglobin level and the ability of his/her serum to render T cells suppressive to CFU-E in vitro. The suppression mediated by patient serum exposed T cells on autologous CFU-E could be ameliorated by increased concentrations of erythropoietin. The serum factor was heat stable (56 degrees C) and could not be eliminated by neutralizing antibody to either gamma-interferon or tumor necrosis factor-alpha. We conclude that some patients with anemia of inflammation may have a circulating factor(s) which renders normal T lymphocytes suppressive to autologous CFU-E in vitro. The presence of a circulating serum factor in these patients may help explain how inflammatory events distant from the marrow mediate the erythropoietic suppression characteristic of this syndrome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Bone Marrow; Cells, Cultured; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cells; Hemoglobins; Humans; Inflammation; Interleukin-1; Male; Middle Aged; T-Lymphocytes

The effects of the inflammatory cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) on erythropoietin (Epo) production in Hep3B cells were examined. The addition of IL-1 alpha, IL-1 beta, or TNF-alpha resulted in a dose-dependent inhibition of hypoxia-induced Epo production by as much as 89%. IL-1 beta was the most effective cytokine tested, demonstrating half-maximal inhibition at 0.4 U/mL compared with 1.0 and 10.0 U/mL for IL-1 alpha and TNF-alpha, respectively. TGF-beta also inhibited hypoxia-induced Epo production, but only by as much as 56%. In contrast to IL-1 alpha, IL-1 beta, TNF-alpha, and TGF-beta, the addition of IL-6 to hypoxic Hep3B cells resulted in a dose-dependent stimulation of hypoxia-induced Epo production by as much as 81%. However, IL-6 did not stimulate Epo synthesis in the absence of hypoxia, and was thus synergistic with hypoxia in inducing Epo production. Combinations of IL-1 alpha, TNF-alpha, and IL-6 were found to be additive in their effects on hypoxia-induced Epo production. By Northern blot analysis, Epo messenger RNA levels in Hep3B cells grown in 1% O2 were decreased when concurrently exposed to either IL-1 alpha or TNF-alpha. The effects that IL-1 alpha, IL-1 beta, TGF-beta, TNF-alpha, and IL-6 have on hypoxia-induced Epo production may provide new insights into the signal transduction pathway by which hypoxia leads to changes in gene expression. In addition, the effects of these inflammatory cytokines on hypoxia-induced Epo production in vitro suggest that in various inflammatory disorders these cytokines may affect Epo production in vivo and may play a significant role in the pathogenesis of the anemia of chronic disease.

Topics: Blotting, Northern; Cell Hypoxia; Cell Line; Cytokines; Dose-Response Relationship, Drug; Erythropoietin; Humans; Inflammation; Interleukin-1; Interleukin-6; Kinetics; Protein Biosynthesis; Radioimmunoassay; Recombinant Proteins; RNA; Transforming Growth Factor beta; Tritium; Tumor Necrosis Factor-alpha

Topics: Amino Acid Sequence; Anemia; Dialysis; Erythropoietin; Humans; Hypertension; Inflammation; Molecular Sequence Data; Recombinant Proteins

Response to Epoetin alfa can be influenced by several factors, including the presence of inflammation or infection. It is important that nurses monitor patients so that possible undesirable effects of inflammation or infection can be avoided or minimized.

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Infections; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Patient Care Planning

The administration of recombinant human erythropoietin (rHuEPO) to anemic hemodialysis patients is usually followed by a rapid increase in hemoglobin. Initial 'nonresponders' may either respond to higher doses of rHuEPO or rarely may remain totally unresponsive. Schematically, one can distinguish between a state of relative and absolute resistance to the action of the hormone. The most common causes of resistance are iron deficiency, aluminium overload, episodes of infection or other inflammatory processes, probably severe hyperparathyroidism, acute or chronic hemolytic conditions, acute or chronic blood loss, folate deficiency, and hemoglobinopathies in exceptional instances. Antibody formation against rHuEPO or marrow fibrosis secondary to rHuEPO treatment can be discarded as potential causes of resistance.

Topics: Aluminum; Anemia; Drug Resistance; Erythropoietin; Hemoglobins; Humans; Hyperparathyroidism, Secondary; Inflammation; Iron Deficiencies; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Cats with induced sterile abscesses developed a hematologic disorder consistent with anemia of inflammation. Serum iron concentrations decreased while the abscess was present, but erythropoietin concentrations did not change significantly. Cobalt administration to control (healthy) cats resulted in polycythemia, reticulocytosis, and hyperferremia. Cats with abscesses responded to cobalt similarly; however, magnitudes of the polycythemia and reticulocytosis were less. Constant infusion of ferric citrate (IV) into cats with sterile abscesses maintained serum iron concentration in the normal to high range. The iron infusion did not prevent the anemia, but did enable the bone marrow to respond to the anemia.

Topics: Anemia; Animals; Cat Diseases; Cats; Cobalt; Erythrocyte Count; Erythropoiesis; Erythropoietin; Ferric Compounds; Hematocrit; Inflammation; Iron; Reticulocytes; Time Factors; Turpentine

Inflammation, induced in mice by a single intramuscular injection of turpentine, caused a long lasting reduction in the number of morphologically unrecognizable CFU-E in the bone marrow. This resulted in marked decreases in marrow erythroblasts and their iron incorporation into heme. The effect is attributed to blood-borne mediators of inflammation which either caused an emigration of progenitors of CFU-E from the marrow or inhibited their proliferation, possibly as the result of increases in marrow myelopoiesis. CFU-S as well as erythroid and myeloid precursors were markedly increased in the spleen during the inflammatory reaction.

Topics: Animals; Bone Marrow; Cell Count; Erythroblasts; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cells; Inflammation; Mice; Polycythemia; Spleen; Turpentine

Topics: Anemia; Animals; Carcinoma 256, Walker; Chronic Disease; Erythrocyte Aging; Erythropoietin; Inflammation; Iron; Liver; Male; Mononuclear Phagocyte System; Rats; Spleen; Turpentine

Topics: Animals; Erythropoiesis; Erythropoietin; Female; Freund's Adjuvant; Hypoxia; Inflammation; Iron; Iron Radioisotopes; Mice; Polycythemia; Rats

Topics: Animals; Chromium Isotopes; Erythropoiesis; Erythropoietin; Freund's Adjuvant; Hypoxia; Immune System Diseases; Inflammation; Injections, Intraperitoneal; Iron Isotopes; Male; Neutralization Tests; Polycythemia; Rats