Effects Of Erythropoietin Treatment Research Articles

Effects of Erythropoietin-Treatment on Wound Healing in Burn Patients. Investigated Using Immunohistochemical and Histological Methods, Analyzed Using AI. Post Hoc Analysis of the Randomized, Placebo-Controlled Clinical Trial “EPO in Burns”

Effects of Erythropoietin-Treatment on Wound Healing in Burn Patients. Investigated Using Immunohistochemical and Histological Methods, Analyzed Using AI. Post Hoc Analysis of the Randomized, Placebo-Controlled Clinical Trial “EPO in Burns”

Effect of erythropoietin on primed leucocyte expression profile

Resistance to erythropoietin (EPO) affects a significant number of anaemic patients with end-stage renal disease. Previous reports suggest that inflammation is one of the major independent predictors of EPO resistance, and the effects of EPO treatment on inflammatory mediators are not well established. The aim of this study was to investigate EPO-induced modification to gene expression in primary cultured leucocytes. Microarray experiments were performed on primed ex vivo peripheral blood mononuclear cells (PBMCs) and treated with human EPO-α. Data suggested that EPO-α modulated genes involved in cell movement and interaction in primed PBMCs. Of note, EPO-α exerts anti-inflammatory effects inhibiting the expression of pro-inflammatory cytokine IL-8 and its receptor CXCR2; by contrast, EPO-α increases expression of genes relating to promotion of inflammation encoding for IL-1β and CCL8, and induces de novo synthesis of IL-1α, CXCL1 and CXCL5 in primed cells. The reduction in MAPK p38-α activity is involved in modulating both IL-1β and IL-8 expression. Unlike the induction of MAPK, Erk1/2 activity leads to upregulation of IL-1β, but does not affect IL-8 expression and release. Furthermore, EPO-α treatment of primed cells induces the activation of caspase-1 upstream higher secretion of IL-1β, and this process is not dependent on caspase-8 activation. In conclusion, our findings highlight new potential molecules involved in EPO resistance and confirm the anti-inflammatory role for EPO, but also suggest a plausible in vivo scenario in which the positive correlation found between EPO resistance and elevated levels of some pro-inflammatory mediators is due to treatment with EPO itself.

Effects of erythropoietin on osteoblast proliferation and function

The purposes of this study were to investigate the effects of erythropoietin (EPO) on the proliferation and function of human osteoblast cells (hFOB 1.19) cultured in vitro and to explore the underlying molecular mechanisms to provide a theoretical foundation for clinical applications of EPO in oral implant and restoration therapies. Cultured hFOB 1.19 cells were treated with high and low doses of EPO. Changes in cell viability after 24 and 48 h of treatment were evaluated with the Mosmann tetrazolium assay. Changes in cell proliferation after 48 h of EPO treatment were measured by bromodeoxyuridine (BrdU) labeling, and changes in alkaline phosphatase (ALP) activity were determined by a specific assay. The effects of EPO on osteocalcin secretion were determined with the enzyme-linked immunosorbent assay, and changes in the protein expression of osteoprotegerin (OPG), osteopontin (OPN) and receptor activator of NF-κB ligand (RANKL) were assayed by western blot. The effects of EPO treatment on the levels of the EPO receptor (EPOR), phosphorylated Jak2 (P-Jak2) and phosphorylated Stat3 (P-Stat3) in hFOB 1.19 cells were evaluated in conjunction with a Jak2/Stat3 inhibitor. After 24 h of EPO treatment, hFOB 1.19 cells showed increased cell viability compared with the blank control group (p < 0.05). After 48 h, cell viability and growth were further improved relative to controls, with a significant increase observed for viability (p < 0.05). A significant increase in the proportion of BrdU-labeled proliferating cells was observed in the high-dose EPO group (p < 0.05), and EPO-treated cells also showed enhanced ALP activity (p < 0.05). There were no statistically significant differences in osteocalcin secretion between groups after 48 h of EPO treatment (p > 0.05); however, increased secretion was observed in EPO-treated cells after 96 h of treatment (p < 0.05). EPO treatment significantly promoted OPG and OPN expression (p < 0.05) while significantly inhibiting RANKL expression (p < 0.01). EPO treatment also significantly upregulated the levels of EPOR, P-Jak2 and P-Stat3 in hFOB 1.19 cells (p < 0.01); these effects were abrogated by co-treatment with a Jak2/Stat3 inhibitor (AG490) (p < 0.01). EPO significantly stimulated osteoblast proliferation and differentiation. The underlying molecular mechanism is associated with the ability of EPO to promote ALP activity, osteocalcin secretion and OPG and OPN expression and to inhibit RANKL expression in osteoblasts. This mechanism appears to be mediated by the Jak2/Stat3 pathway.

Erythropoietin Levels in Cardiac Resynchronization Patients

Cardiac resynchronization therapy (CRT) is indicated in patients with advanced heart failure secondary to severe systolic impairment and refractory symptoms despite optimized medical treatment and evidence of electro- mechanical dyssynchrony with a QRS complex greater than 120 milliseconds (msec). Approximately 20%-30% of patients who receive CRT fail to respond with little improvement in subjective symptoms, functional capacity, and left ventricular indices. To date, there fails to be a serologic marker to adequately assess the degree of ventricular dyssynchrony and electro-mechanical dissociation. Increased levels of erythropoietin (EPO), a hematopoietic cytokine, has been demonstrated in patients with more advanced stages of heart failure and is associated with an increase in mortality and hospital re-admission. A recent study demonstrated a significant response to CRT in patients with higher baseline EPO levels (> 25mU/mL) with improvements in cardiac function and reduced heart failure symptoms. The presence of elevated EPO levels in addition to traditional determinants of cardiac dyssynchrony may effectively predict those that will benefit from CRT. LETTER TO THE EDITOR Cardiac resynchronization therapy (CRT) is indicated in patients with advanced heart failure secondary to severe systolic impairment and refractory symptoms despite optimized medical treatment and evidence of electro- mechanical dyssynchrony with an ECG QRS complex greater than 120 msec. Simultaneous pacing of both the right and left ventricle (BiV pacing) has been shown to restore electro-mechanical synchrony, improve overall cardiac function, reduce hospitalizations, and confer a mortality benefit (1). Despite the cardiovascular benefits of BiV pacing demonstrated in recent trials, approximately 20%- 30% of patients who receive CRT fail to respond with little improvement in subjective symptoms, functional capacity, and left ventricular functional indices (2). Absence of electro-mechanical dyssynchrony despite prolonged QRS duration (>120ms), pre-existing right bundle branch block (RBBB), inappropriate lead placement and continued disease progression have been shown as causes for non-response to CRT. To date, there fails to be a serologic marker to adequately assess the degree of ventricular dyssynchrony and electro-mechanical dissociation. Erythropoietin (EPO), a hematopoietic cytokine, has traditionally been associated with erythropoiesis in response to anemic stress. Several studies have indicated the positive effects of EPO treatment in heart failure patients with concomitant anemia resulting in reductions in hospital re- admission, improved cardiac and renal function, as well as

Introduction: anemia in heart failure

During the last two decades, advances in our understanding of the role of neurohormonal activation in the pathogenesis of chronic heart failure have led to rational therapies with a remarkable improvement in survival. In spite of this, the prognosis of heart failure still remains dismal. One of the factors that contribute to worse prognosis in patients with heart failure is the presence of several comorbidities. Over the last few years, anemia has come to be recognized as an important comorbidity that is common in patients with heart failure and is strongly associated with poor clinical status and worse outcomes. Therefore, correcting anemia could become an important and novel therapeutic target to improve long-term outcomes in such patients. In 2000 Silverberg and his colleagues from Israel were the first to report the effects of erythropoietin treatment on anemic patients with heart failure [1]. This landmark report was responsible for raising worldwide interest in anemia in heart failure, and the potential therapeutic implications of treating anemia. Several small-sized studies have shown beneficial effects of empirically treating anemia in heart failure patients with recombinant erythropoietin and intravenous iron [2]. However, little is known about the pathophysiological basis of the remarkable association of anemia with heart failure outcomes [3]. It is unclear whether anemia is just a marker or a mediator of poor outcomes. If anemia is a mediator, there may be potential benefits of correcting anemia. 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 needs 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 [4], and may worsen cancer in patients receiving chemotherapy to treat various types of cancer [5]. In this special issue of Heart Failure Reviews, seven international experts discuss various aspects of anemia in heart failure. In the first section, I point out that although the reasons for anemia in heart failure may be multifactorial, anemia of chronic disease appears to be the most frequent cause. Therefore, if correction of anemia is important, use of erythropoiesis stimulating agents (ESA) may be the only rational approach that works. Whether anemia worsens heart failure due to reduced LV function is not known. It is clear, however, that chronic severe anemia leads to a vasodilated state, and in patients with normal LV function can cause fluid retention and high output heart failure, through neurohormonal activation, identical to that seen in low output heart failure [6]. In patients with LV dysfunction, increased myocardial workload to compensate for reduced tissue oxygen delivery and volume overload can worsen LV remodeling and contribute to adverse outcomes. I argue, however, that because increase in hemoglobin (by any means) is associated with an elevation in the systemic vascular resistance, it is unlikely that correction of anemia will improve impaired LV function. Therefore, nonhemodynamic mechanisms may play a more important if therapy with ESA to increase hemoglobin is found to be beneficial. Roberto Latini, Michael Brines, and Fabio Fiordaliso examine this exciting area of the nonhemopoietic effects of ESAs and review the studies showing

Effects of erythropoietin treatment on cell-mediated immune responses in predialysis patients

The effects of erythropoietin (EPO) treatment on the immune functions of dialysis patients have been shown to be controversial and there are only limited data concerning predialysis patients. Twenty-four predialysis patients with renal anemia were assigned to subcutaneous EPO treatment, and those in need (n=19) were additionally treated with i.v. iron every other week. We analyzed the effect of the start of EPO treatment on (i) lymphocyte and lymphocyte subclass counts, (ii) lymphocyte stimulation functions and (iii) persisting IgG-class antibody levels to the viral antigens of Epstein-Barr virus and cytomegalovirus. Our main findings were a decrease in the absolute lymphocyte count, combined with decreases in all the main lymphocyte subclass counts. The absolute number of cells with activation and memory markers remained constant, and therefore their proportion slightly increased. The proliferation responses to phytohemagglutinin, tuberculin and tetanus declined significantly, while the amount of IgG-class viral antibodies remained unchanged, meaning that the humoral side of immunity was not affected by the start of the EPO treatment. Similarly, the proliferation response to pokeweed mitogen, a B-cell mitogen, was unchanged. EPO treatment has a suppressive effect on cellular immune functions of predialysis patients. This suppression does not correlate with erythropoiesis, kidney function or iron status.

Effects of Erythropoietin Treatment on Thyroid Dysfunction in Hemodialysis Patients with Renal Anemia

The thyroid function was evaluated before and after 6 months of recombinant human erythropoietin (rhEPO) treatment (1,500-9,000 U/week) in 22 hemodialysis patients with hematocrit levels < 25%. Based upon the changes in hematocrit following rhEPO treatment, the patients were divided into two groups: 11 patients with an increase of the hematocrit level > 5% (group I) and 11 patients with an increase < 5% (group II). Before rhEPO administration, the levels of thyroid hormones, especially free thyroxine (T4) and free triiodothyronine (T3), were below the normal range despite normal thyrotropin values in most of the patients (low T4:7 cases in group I and 9 in group II; low T3:10 cases in group I and 10 in group II). RhEPO treatment significantly increased both total amount and free fractions of thyroid hormones in group I, whereas it did not affect these values in group II. Consequently, the pretreatment low T4 or low T3 status was resolved in a substantial number of the patients in group I (low T4:5 cases, low T3:4 cases). In addition, there was a significant correlation between the increases in hematocrit and free T3 in all studied subjects (r = 0.603; p < 0.05). These results suggest that anemia may participate to some extent in the pathogenesis of thyroid dysfunction in hemodialysis patients with renal anemia.

Clinical and biological effects of erythropoietin treatment of myelodysplastic syndrome.

To evaluate its clinical efficacy as well as its biologic safety, human recombinant Erythropoietin (rh-Epo) was given to 19 patients with myelodysplastic syndromes (MDS) in an open non-randomized study. Among the seventeen evaluable patients only two showed an apparent hematologic response to rh-Epo treatment. In these patients hemoglobin levels increased from a mean pretreatment value of 8.5 and 8.4 g/dl up to 11.7 and 11.3 g/dl respectively and remained relatively stable for several weeks. In one of these patients the transfusion requirement decreased from 4 to 1.5 units per month whereas the other had no transfusion requirement during the whole period of rh-Epo treatment. Interestingly, when the responding patients, after a "wash-out" period of at least ten weeks, received an additional course of rh-Epo results were less impressive. Before treatment the serum level of endogenous Epo was 18 and 110 mU/ml in the two responding patients, whereas a mean value of 532 mU/ml (range 17-2797 mU/ml) was observed in non responders. The treatment of MDS patients with rh-Epo was clinically well tolerated since no relevant side effects were registered. Moreover, no evidence of harmful cytogenetic changes nor activation of myeloid growth factor genes, as determined by Northern blot analysis of GM-CSF and G-CSF gene expression, could be related to rh-Epo treatment. Overall, it appears that administration of rh-Epo is well tolerated but the therapeutic effects appear to be restricted to a minority of patients and a limited period of time.

Erythropoietin, aluminium, and anaemia in patients on haemodialysis

Effects of erythropoietin treatment on haem synthesis in peripheral blood were evaluated in 11 patients on haemodialysis. After 2 weeks of erythropoietin, mean (SEM) uroporphyrinogen-l synthase activity increased significantly from 88 (10) to 116 (9) pmol/h per mg protein. Haem synthase activity, thought to be the rate-limiting step in erythroid haem synthesis, also showed a significant increase from 4.5 (0.8) to 8.4 (1.8) pmol/h per 10(6) reticulocytes. 4 patients, who showed only a partial response to erythropoietin, had significantly higher serum aluminium concentrations than the 7 who responded fully (225 [44] vs 55 [23] micrograms/l); erythrocyte protoporphyrin concentrations in partial responders were also much higher than in responders (973 [120] vs 388 [29] nmol/l). Aluminium intoxication may cause resistance to erythropoietin by interference with haem synthesis, with accumulation of protoporphyrin.