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Erythropoietin is a hypoxia-induced cytokine that stimulates erythropoiesis through the promotion of erythroid precursor cell proliferation and

differentiation. Recent evidence supports that erythropoietin has a broad spectrum of tissue protecting actions affecting other systems than hemopoietic. Lately, research has focused on the nonhemopoietic effects of erythropoietin against tissue ischemia due to the unexpected observations of erythropoietin receptor expression by various cells, such as endothelial cells, neuronal cells, cardiac myocytes, and vascular smooth muscle cells. It has been shown that erythropoietin exerts its cardioprotective action during cardiac ischemic injury through reducing the infract size and enhancing new vessel formation over a longer time frame. Erythropoietin plays a crucial role in neuroprotection in many types of ischemic injury in the central and the peripheral nervous system. It is also strongly believed that erythropoietin exhibits a critical role in many other disorders that are pathogenetically related to acute tissue ischemia. Abstract: Erythropoietin is known as the requisite cytokine for red blood cell production. Its receptor, expressed at a high level on erythroid progenitor/precursor cells, is also found on endothelial, neural, and other cell types. Erythropoietin and erythropoietin receptor expression in the developing and adult brain suggest their possible involvement in neurodevelopment and neuroprotection. During ischemic stress, erythropoietin, which is hypoxia inducible, can contribute to brain homeostasis by increasing red blood cell production to increase the erythropoietin, which is hypoxia inducible, can contribute to brain homeostasis by increasing red blood cell production to increase the blood oxygen carrying capacity, stimulate nitric oxide production to modulate blood flow and contribute to the neurovascular response, or act directly on neural cells to provide neuroprotection as demonstrated in culture and animal models. Clinical studies of erythropoietin treatment in stroke and other diseases provide insight on safety and potential adverse effects and underscore the potential pleiotropic of erythropoietin. Herein, we summarize the roles of EPO and its receptor in the developing and adult brain during health and disease, providing first a brief overview of the well-established EPO biology and signaling, its hypoxic regulation, and role in erythropoiesis Erythropoietin is a 165 amino acid glycoprotein hormone with approximately 30 kD molecular weight. It is synthesized primarily by kidneys in adults and by kidneys and liver in the fetus. The ratio between kidney and liver erythropoietin in the adult is 9:1. Its primary role involves prevention of programmed cell death (apoptosis) of erythrocyte precursors. Erythropoietin induces erythropoiesis by promoting proliferation and differentiation of erythroid progenitor cells with the main target cell being the colony-forming unit erythroid (CFU-E). Although erythropoietin is the main regulator of this process, other growth factors, such as granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), interleukins IL-1, IL-3, IL-6 IL-4, IL-9, and IL-11, granulocytemacrophage (GM)-CSF, and insulin growth factor-1 (IGF-1) are believed that contribute in different levels of maturation of the erythrocyte. 1. Erythropoietin gene expression is regulated mainly by hypoxia. . Hypoxia-inducible factors (HIF) 1, 2 and 3, as well as nuclear factor kappa B (NF-kB) are the key regulators of erythropoietin gene expression. Recent data revealed that hypoxia-inducible factor 2a (HIF-2a) has prominent role in controlling erythropoietin gene expression in hepatic cells. According to some investigators this role of HIF-2a may be also applied in other tissues. In addition to its well known effect on red blood cell mass in response to changes in tissue oxygenation, many investigations have shown that erythropoietin also exerts protective role against tissue ischemia. It is believed that this is achieved both directly by activating multiple biochemical mechanisms that provide antiapoptotic, antioxidative, and anti-inflammatory response to hypoxia/anoxia and indirectly via its angiogenic potential by inducing oxygen systematic supply to the ischemic tissue. 2. Non Erythropoietic Role of Erythropoietin Erythropoietin has a broad spectrum of tissue protecting actions affecting other systems than hemopoietic. Beginning with the unexpected observations of erythropoietin receptor (Epo-R) expression by various cells, such as endothelial cells, neuronal cells, cardiac myocytes, and vascular smooth muscle cells, research lately focused on the nonhemopoietic effects of erythropoietin and its potential use against tissue ischemia. 3. Cardiovascular System Erythropoietin exerts its cardioprotective action during cardiac ischemic injury through reducing the infract size and enhancing new vessel formation over a longer time frame. It is well known that erythropoietin induces vasoconstriction-dependent hypertension and stimulation of angiogenesis in erythropoietin-treated animals and humans. The effect of erythropoietin in blood pressure has been extensively described in the past after the initiation of treating anemia in chronic renal failure patients. The exact mechanism remains unclear, though, different

The antiapoptotic effects of erythropoietin have been associated with the inactivation of Bcl-2 associated death-promoting protein (BAD) through PI3-K/Akt pathway as well as the increased expression of the antiapoptotic proteins Bcl-2 and Bcl-XL. while others have demonstrated that erythropoietin may facilitate nerve regeneration after peripheral nerve injury. . Hypoxia and neurological damage enhance erythropoietin and Epo-R production in the central nervous system . increased NO production. and the retina. the authors demonstrated fail to develop hypertension and myocardial infraction. The presence of Epo-R was demonstrated in rat cardiac myocytes where the administration of erythropoietin prevented apoptosis by activating phosphatidylinositol 3 kinase (PI3-K)/Akt intracellular pathway. during or after ischemia. This was attributed to up-regulation of eNOS expression. recent evidence from randomised trials showed an increased risk of cardiovascular events and increased mortality in the same patient group. Moreover. In a rat isolated. scepticism over the benefits of excessive use of erythropoietin is necessary. Several studies have shown the neuroprotective action of erythropoietin. Bearing in mind the high cost of erythropoietin treatment and the insecure outcome in patient life expectancy. have reported better clinical outcome. the role of nitric oxide (NO). such as hypertension and thromboembolism. This role in neural system appears to resemble the actions of erythropoietin in progenitor cells of the hematopoietic tissue and is thought to be multifactorial. a modulator of vascular tone and inhibitor of processes involved in atherothrombosis.Nervous System It has been shown that special pathways for erythropoietin and its receptor are present not only in the central nervous system but also in the peripheral nerves. the number of circulating EPCs in patients with coronary artery disease was significantly correlated with serum levels of erythropoietin. It has been found that erythropoietin promotes EPC mobilization which in turn was associated with neovascularization of ischemic tissue . and NO-mediated vascular relaxation compared to wild type animals. evaluated the influence of recombinant erythropoietin in patients with chronic cardiac failure and Suggested that erythropoietin usage improves both cardiac and renal function. erythropoietin promotes NO synthesis in EPCs reendothelialization of injured arterial vessels. Further studies showed that specific pathways. a member of the PAS (PER/arylhydrocabon-receptor nuclear translocator/single minded) family of hypoxia-regulated transcription factors is the main factor responsible for hypoxia-mediated induction of erythropoietin expression in the retina. On the contrary. Despite previous evidence it is now believed that erythropoietin crosses the blood-brain barrier in an injured brain .hypotheses involving cyclooxygenase-dependent endothelium derived contracting factors (EDCFs). mitogen-activated protein kinase (MAPK) pathways and protein kinase C (PKC) are implicated in erythropoietin cardioprotective action before. In a transgenic mice model overexpressing human erythropoietin. and a direct angioconstrictive action of erythropoietin have been described. Erythropoietin exerts both acute and long term cardioprotective effects through its receptor. cerebrospinal fluid. In vitro studies have shown that Epo-R is expressed in various cell lines originated from the cardiovascular system. should also be considered. Inhibition of apoptosis has been strongly correlated with erythropoietin-mediated cardioprotection against acute ischemic injury. Erythropoietin is suggested to be a cytokine with a neurotrophic and a neuroprotective role in the central and peripheral nervous system. endogenous vasodilatory factors. Although apoptosis prevention is a main mechanism for erythropoietin acute cardioprotection. Apoptotic mechanisms are considered to be associated with crucial cardiac cell death following myocardial infraction that potentially is complicated with cardiac failure . High-dose chronic erythropoietin treatment may result to increased hematocrit associated side effects.heart model. Silverberg et al. Similar observational studies in the past. 3. HIF-1. such as PI3-K/Akt. Enhancement of erythropoietin cardiac tissue protective activity without increasing the number of red blood cells is the key in the management of heart disorders. Endothelial nitric oxide synthase (eNOS) is activated by the signal transducer and activator of transcription-5 (STAT-5) and RAS/MAPK ignalling molecules. while it decreases mortality rates and Hospitalization due to heart failure. the expression of Epo-R was confirmed in ventricular myocytes and endothelial cells in adult human heart. stimulation of vascular cell growth. pre-treatment with erythropoietin increased the functional recovery of hearts during ischemia/reperfusion injury. improvement of survival and lower complication rate when erythropoietin is administrated to patients undergoing hemodialysis in order to normalize haemoglobin levels. Interestingly. According to Depping et al. Erythropoietin effect on heart disorders has been showed that involves a mechanism with greater immediacy than that of direct oxygen supply due to haemoglobin levels increase.The endothelial isoform of NO is the prevailing form in the cardiovascular system. Long–term protection of ischemic myocardium by erythropoietin is attributed to both new vascular formations by directly enhancing angiogenesis and increased vasculogenesis from endothelial progenitor cells (EPCs).

Epo (0. Some authors . as suggested by its size and glycoprotein structure. The results available on this aspect are contradictory. is an inflammatory reaction genes regulator.This evolution confirms the importance of erythropoietin role in the initial treatment of the acutely injured nervous tissue. In conclusion. Epo may contribute to improving the uptake and availability of oxygen in the neural cells by means of this mechanism. and retinopathy of prematurity have been etiologically related to hypoxia. anti-inflammatory. NF-kB. Erythropoietin exhibits neurotrophic. it offers an effective treatment for these conditions. Studies have been undertaken to ascertain whether CSF Epo concentrations change in conditions of neural injury. STAT-5 enters the nucleus and induce transcription of genes involved with inhibition of apoptosis. such as granulocyte colony-stimulating factor and granulocyte}macrophage colony. The neuroproperties of Epomay then result fromthe activation of signal-transduction pathways. such as hypoxia.Erythropoietin reduces nitric oxide-mediated injury. Disorders such as early brain injury. such us BclxL genes . which in turn activates NF-kB resulting in increased expression of apoptosis inhibiting genes. A recent study proposed potential benefit by erythropoietin administration in patients with various psychiatric disorders. new vessel formation both in vitro and in vivo. such as XIAP and c-IAP2.Several hypotheses have been proposed in order to explicate the neuroprotective role of erythropoietin. Furthermore. Furthermore. and antioxidant action. the discovery of the production of Epo by neuronal cells in man was made only 10 years ago.tidylinositol 3-kinase}protein kinase Akt [39]. It has been shown that it decreases susceptibility to glutamate toxicity and promotes apoptosis through induction of apoptotic agents. Previously. caspase-9. This suggests that Epo does not cross the intact BBB. Because it is the primary site of CSF production. Finally. When a single molecule of erythropoietin binds its receptor enzymic phosphorylation of PI3-K and the nuclear factor NF-kB occurs. in turn. Erythropoietin activates JAK2. a new identified globin expressed mainly in the brain. Moreover. which is activated by erythropoietin after oxidotic stress. despite significantly increased plasma Epo concentrations. attention deficit hyperactivity disorder. since its intravenously or subcutaneous administration provides effective and targeted therapy. etc [73]. In a study conducted on 50 human newborns . related to BAD. 25 of whom were treated with human recombinant Epo (rHuEpo). such as those which are related to glycogen synthetase kinase 3β (GSK3β). Such an ischemic etiological profile may alternate not only the treatment approach used so far. Sire ' n et al.stimulating factor. Epowas found in the CSF of normal pre-term and full-term infants. 24 h after intraperitoneal administration at 5000 units}kg of body mass. Erythropoietin actions seem to reverse this hypoxia-induced sequelae.In the recent years. Low concentrations of Epo are also found in the CSF of normal human adults.3 units}ml) inhibits the apoptosis of hippocampal neurons. decreasing proportionately according to gestational age. In a recent study. No differences were found between the CSF Epo concentrations of neonates treated with rHuEpo and controls. Ras}MAPK or phospha. Epo may control the synthesis of neuroglobin. but could also develop a new dynamic in the research of pathogenetic factors of vague disorders. thus improving the blood flow and tissue oxygenation in the border zone of the ischaemic area. and whether this change reflects loss of BBB integrity or increased CNS Epo production. Yet. rHuEpo dramatically reduces the infarction area. thus opening new frontiers in the treatment of diseases of the CNS. the results from the administration of recombinant human erythropoietin (rhEpo) in acute stroke patients confirmed exultantly both its safety and effectiveness in protecting cerebral tissue from ischemia. It has been observed that Epo. can stimulate endothelial proliferation and. such as those employing JAK2}signal transduction and acti-vators of transcription-5a}5b. Activation of Akt by erythropoietin inhibits various metabolic paths that are connected to cell death. Treatment with rHuEpo has perhaps de®nitively underscored the neurotrophic and protective effect of the hormone. now an important body of evidences demonstrates the impact of this hormone in the pathophysiology of the brain. The improvement of blood flow to the injured tissue is a further potential mechanism of erythropoietin's protective role in the nervous system. similar to other growth factors. EPO IN THE CEREBROSPINAL FLUID (CSF) The choroid plexus is immunoreactive for both Epo and EpoR during development and after birth. Bernaudin et al. Epo may modulate angiogenesis in the ischaemic brain. several authors have investigated whether Epo is present in the spinal ¯uid. meningitis or intraventricular haemorrhage. have shown that Epo may reduce the brain ischaemic area by protecting endothelial and neural cells fromapoptotic cell death. increasing knowledge of the nervous system physiology allowed the analysis of the pathogenetic mechanisms involved in various abnormal conditions. In addition. JAK2 induces activation by phosphorylation of Jun kinase (JNK) and signal transducers and activators of transcription-5 (STAT5). the activation of extracellular signalregulated kinases and protein kinase Akt-1}protein kinase B. with its protective role on glia. such as Alzheimer's disease. showed in rats with middle cerebral artery occlusion that.

and found no correlation between the concentration of Epo in serum and that in CSF. The protective role of erythropoietin in tissue ischemia extended the investigation of the potential role of erythropoietin in other conditions related with ischemia. Studies suggesting the role of . However. they make the need for further research in this field essential. which is a Na+-dependent process. demonstrated that Epo concentration in the CSF was significantly higher in newborns with asphyxia or intraventricular haemorrhage than in controls. providing protection against brain injury. observed that Epo was present in the CSF of ®ve patients with traumatic brain injuries. a single nucleotide polymorphism in the human EPO gene promoter is associated with increased EPO in the vitreous and severe microvascular complications in diabetes. Although these reports are not debating the positive affects of erythropoietin. Brines et al. variations in the CSF pH after acute infusion of rHuEpo may play an important part in the neuroprotective effects identi®ed in vitro. Juul et al. During human development. Indeed. Hamadmad and Holh demonstrated that erythropoietin induces chemotaxis of cancer cells via MAPK/Erk and Rho/RhoA kinase pathways. erythropoietin has been proposed as an ameliorator of the clinical outcome. and this increase was related to an increased CNS synthesis of Epo. the expression of erythropoietin receptor in neoplasmatic cells initially raised the question whether erythropoietin promotes tumour growth. proliferative diabetic retinopathy. significantly higher than the control group.for example. EPO mRNA in the retina and EPO protein in the vitreous at levels greater than in serum were observed between 12 and 24 weeks gestation and increased with gestational age . because localmodi®cations in the acid±base balance may interfere with communication and cellular neurotransmission. In the same study. Although the BBB is considered impermeable to large molecules.believe that the production of Epo inCSF is stimulated in conditions of neural injury. Understanding the mechanism of the exact role of erythropoietin in neoplasmatic cells would possibly clarify these issues and potentially indicate alternative therapeutic measures against cancer. followed by translocation into the brain. which are present on the luminal surfaces of the endothelial cells. However. the neuroprotective effect of EPO extends to the retina and provides protection to mouse photoreceptor cells against UV light damage. Two different types of EpoR have been found in the cerebral capillary endothelium. Finally. However. Recently. the treatment outcome of both radiotherapy and chemotherapy in cancer patients receiving erythropoietin seems to be superior based on the beneficial effects of erythropoietin to tumour hypoxia. There is also evidence that Epo induces indirect biohumoral variations in the CSF. EPO was found to be more strongly associated with diabetic retinopathy than VEGF. Also. it has been shown that CSF Epo concentrations in patients with depression are higher than those in healthy controls. concerns about the angiogenic properties of EPO remain. this passage increasing in conditions of neural injury. rather than any passage through the BBB. Marti et al. and the level of EPO in the vitreous did not correlate with plasma level. A recent meta-analysis confirmed the increased risk of venous thromboembolism and increased mortality rates after erythropoietin administration.It has therefore been suggested that circulating Epo could bind to these receptors. it is strongly believed that erythropoietin plays a critical role in disorders that are pathogenetically related to acute tissue ischemia. suggesting local production of EPO. The signi®cance of these endings is unclear. which induces Epo production. These reports are in accordance with the finding from a trial conducted by Leyland-Jones et al. reported that rHuEpo may cross the BBB. the diminished Na+ concentrations found in the CSF suggest that Epo can directly or indirectly interfere with the mechanism of CSF production. This would initiate endocytosis. where the usage of erythropoietin for the treatment of anemia in metastatic breast cancer patients resulted in decreased survival. If so. this difference being resolved following antidepressant therapy. recent studies clearly demonstrate that some high-molecular-mass molecules can be specifically transported into the brain across the capillary endothelium. In critical ill patients. the primary cause of death in erythropoietin group was disease progression. Furthermore. EPO and Retinopathy As previously mentioned. Erythropoietin has been used in the past for correcting both cancer and chemotherapy induced anemia. One hypothesis put forward is that the brain of patients with depression may be in a state of hypoxia. systemically administered rHuEpo could directly reach the brain. and endstage renal disease Other Roles Proposed for Erythropoietin Based on observations on the role of erythropoietin in other tissues. Nor did the intravenous administration of rHuEpo increase Epo levels in the CSF of patients with cerebral tumours. Association between elevated EPO in the vitreous and proliferative retinopathy was observed in adult diabetic patients exhibiting increased levels of VEGF and EPO in the vitreous fluid compared with nondiabetic patients with ocular disease. Safety concerns over the usage of erythropoiesis stimulating agents in treating anemia in patients with cancer are well established.

It is known that erythropoietin results in neovascularization and increased healing through stimulation of endothelial cell mitosis. Further study is needed before establishing the exact role of both erythropoietic inducing factors in tissue ischemia. Further study is needed in order to clarify the role of this ischemia protective cytokine in conditions. erythropoietin found to have equal angiogenic potential with vascular endothelial growth factor (VEGF) which was confirmed by histologic evaluation on flaps. retina. It has a different pharmacokinetic profile from erythropoietin that allows less frequent administration in order to maintain similar haemoglobin levels. According to Brimes and Gerami. and antiiflammatory properties. such as ischemia/reperfusion injury. Moreover. results in tissue dysfunction. The injury is attributed to a complex interaction between neutrophils and endothelial cells when the formers release enzymes. and finally to impairment of oxygen supply to the tissue. This cascade usually leads to endothelium destruction. and intestine. such as catalase (CAT). mainly through its antiapoptotic action. free radicals. significant alterations were obtained in the level of CAT activity. the potential benefit of interfering in erythropoietin gene expression through HIF-2 mechanisms emerges as an alternative for the treatment of certain types of anemia. Kim et al. Despite the discouraging results reported in non randomised trials exploring the results of erythropoietin in retinopathy. antioxidative. 3. and glutathione peroxidase (GSH-Px). Novel erythropoiesis stimulating protein (NESP) or darbepoetin alfa has been introduced for the treatment of anemia in several conditions with comparable results with those of erythropoietin. including brain. capillary obstruction. induction of programmed cell death in pathologic conditions. This erythropoietin mediated protective effect against ischemia/reperfusion injury has been related to its antiapoptotic. The presence of erythropoietin receptor in retina establishes a major role to erythropoietin in the treatment of pathologic conditions etiological related to ischemia in these highly oxygen dependent tissue. lung. the decrease in the mortality rate is not considered as a consequence of blood transfusion. it finally declined mortality in this group of patients with a higher decrease applied in trauma patients. In an intestinal ischemia/reperfusion injury model in rats.erythropoietin in survivor of skin and muscular flaps in animal studies magnify the significance of this cytokine in trauma patients. such as diabetic retinopathy and retinopathy of prematurity. revealed that although enzymatic activity of SOD and GSH-Px was not significantly changed after intraperitoneal administration of erythropoietin. its role in other tissues remains to be explored. Guneli et al. The role of angiogenic potential on survival of various flaps after erythropoietin administration has been extensively investigated. Since the mechanism of action of NESP is relevant to the one of erythropoietin. Based on the disadvantages of high cost and potential low safety profile of recombinant erythropoiesis-stimulating agents in some patient groups. kidney. Erythropoietin by . The contribution of a nonhematopoietic mechanism in the superior mortality rate in erythropoietin treated patients is believed by the authors to be logical explanation to this contradictory event. liver. However. the mechanism mediating the antiapoptotic effects of erythropoietin probably incudes the JAK2-STAT-Bcl-2 pathway. Although erythropoietin failed to reduce red blood cell transfusions in critically ill patients. exogenous administration of erythropoietin stimulated angiogenesis by day 3 in a genetically diabetic mouse model by increasing VEGF mRNA and protein expression. Previous studies have shown that rhEpo protects against the ischemia/reperfusion injury. Erythropoietin in Ischemia/Reperfusion Injury Reperfusion injury is defined as the tissue injury following restoration of blood flow to an ischemic region. Bcl-2 may also be responsible for the antioxidant activity of erythropoietin. a new dynamic has been developed as knowledge on erythropoietin and nervous system advances. Oxidative stress is an important determinant in the pathogenesis of ischemia/reperfusion injury. superoxide dismutase (SOD). Although apoptosis serves to eliminate dying cells in proliferating or differentiating cell populations. Since there was no difference in blood transfusion rate. The authors concluded that erythropoietin may be capable to increase the activity of the antioxidant system via the increase or restoration of CAT levels which decreases due to ischemia/reperfusion injury. According to Jaquet et al. Ischemia/reperfusion-induced injury is characterized by a greater rate of tissue damage than the original ischemic insult itself and it is thought to be the result of the acute interruption of blood flow within the microcirculation. It is believed that erythropoietin exhibits its antioxidant action either directly through the scavenging action of its sugar-moiety or indirectly by activating antioxidant enzymes. cardiac. and cytokines. Accumulation of activated neutrophils at the injury site triggers the inflammatory cascade through the production of various cytotoxic proteins which in turn promote the radical induced ischemia/reperfusion injury. Many studies have demonstrated that erythropoietin has a protective effect on tissue injury associated with ischemia/reperfusion injury in many tissues. supported that the angiogenic potential of erythropoietin is unlikely to occur in the first 24 hours and therefore is not sufficient enough to explain the protective effect of erythropoietin on ischemia/reperfusion injury in their rat transverse rectus abdominis musculocutaneous (TRAM) flap model.

iron and erythropoietin shows stem cel ls maturing along the erythroid line to form BFU-E's At this point iron is needed for the production of new hemoglobin. Even when both components are available.g. If one component is absent (e. Hypoxia (low oxygen) of the kidney prompts synthesis and release of erythropoietin. Conclusion Erythropoietin is believed to serve a manifold role in several tissues with the primary target being the protection from ischemia. there is insufficient fuel for red cell production. before direct conclusions can be made. Erythropoiesis involves the close interaction of iron and erythropoietin. Erythropoietin promotes the maturation of BFU-E's into CFU-E's and subsequently into mature erythrocytes. Further research would provide us with evidence that could alter the way erythropoietin is currently used in the clinical practice. The first is the bone marrow which produces red cells. This condition has been termed. Erythropoietin mediated neutropenia reversal following reperfusion is believed to be the underlying mechanism for the inhibition of neutrophil recruitment in the inflamed tissue. The erythropoietin would have spent itself on cells that were unable to respond. Therefore. red cell production will be suboptimal . This is the scenario in subjects with severe iron deficiency. Erythropoietin therefore is part of a finely-tuned feedback circuit that controls red blood cell levels. they must be coordinately delivered to the bone marrow for proper action. the thermostat signals the furnace to cease heat production. It acts both by ensuring adequate oxygen supply through its role to erythropoiesis but also it intervenes directly to the tissue targets with multiple set of actions that reserve cell survivor through its nonhematopoietic effects. Li ttle or none of the erythropoietin would be left when the iron finally arrived. the role of erythropoietin in eNOS expression after ischemia/reperfusion injury should be elucidated. the superoxide anions produced during oxidative stress may react with NO and turn it into oxidant peroxynitrite which is cytotoxic. iron deficiency) anemia results. impaired erythropoiesis also occurs in patients in whom red cell production is suddenly jolted forward by a burst of erythropoietin from an injection of the hormone. For instance. Once the proper temperature is reached. In essence. However. This increases the blood's oxygen carrying capacity and corrects the hypoxia which was the primary stimulus to erythropoietin production.suppressing the inflammatory response after the ischemia/reperfusion injury seems to be a protective agent in tissues subjected to this type of damage. functional iron deficiency 4. It is supported that although eNOS-derived NO may play a protective role at the onset of ischemia/reperfusion injury. The second is the kidney which produces the hormone erythropoietin. If erythropoietin is present without sufficient i ron. Many authors have shown that eNOS Production and eNOS-derived NO overproduction is decreased after erythropoietin administration. erythropoietin is the accelerator that drives erythropoiesis. other investigators have reported increased expression of eNOS after erythropoietin therapy. The thermostat senses the temperature and the furnace produces heat to eliminate the chill. if iron arrives on the scene 6 hours after erythropoietin reaches the bone marrow. . The erythropoietin then travels to the bone marrow via the blood circulation where i t activates new red blood production. However. red cell production moves briskly and efficiently. The best analogy is a thermostat and a furnace.. The role of erythropoietin on eNOS is still controversial. The Interaction of Iron and Erythropoietin: The production of red cells involves the coordinate interaction of two organ systems in the body. Iron is the fuel for the production of new red blood cells. When the two are coupled.