Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sickle-cell anemia is a congenital hemolytic anemia characterized by sickle-shaped RBCs. The deformed RBCs become distorted and rigid and may occlude small arterioles and capillaries leading to tissue ischemia and infarction. Sickled RBCs are too fragile to withstand the trauma of circulation, and hemolysis occurs after they enter the circulation. RBCs with a high level of Hb F are resistant to sickling. Hydroxyurea has been shown to stimulate Hb F synthesis, leading to a reduction in the incidence of hemolytic and vaso-occlusive manifestations; however, hydroxyurea has no role in the treatment of crises already in progress. The National Heart, Lung, and Blood Institute announced in January 1995 that treatment with hydroxyurea leads to an increase in Hb F production within RBCs and a reduction in the frequency of painful crises in patients with sickle-cell anemia. Although the mechanism by which hydroxyurea increases Hb F is not known, one possible explanation is that hydroxyurea is cytotoxic to the more rapidly dividing late erythroid precursors, leading to the recruitment of early erythroid precursors that have demonstrated increased capacities to produce Hb F. Clinical trials have demonstrated that hydroxyurea results in an increase in Hb F concentrations; however, this increase may not dramatically affect the progressive vascular changes associated with sickle-cell anemia; thus, patients may still experience complications related to sickle-cell anemia. At North Carolina Baptist Hospital in Winston-Salem, NC, compliant patients with sickle-cell anemia are started on hydroxyurea. There are no specific criteria for patient selection or monitoring. The dosage is started at 10-15 mg/kg/d. Platelet count, complete blood count, and Hb F are monitored and hydroxyurea dosages are adjusted accordingly. Although hydroxyurea has been effective in the treatment of sickle-cell anemia, large double-blind, placebo-controlled clinical trials are needed to determine whether the risks of long-term administration outweight the risk of vaso-occlusive disease in untreated patients.
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PMID:Hydroxyurea in the treatment of sickle-cell anemia. 939 97

Extramedullary hematopoiesis (EMH) after fetal development is uncommon and is most often seen in patients who have hematologic disorders. EMH unassociated with hematologic disease is rare. After the recent observation of EMH in a myocardial infarct, we sought to determine the frequency and clinicopathologic setting of EMH in myocardial tissues submitted for pathologic examination. Hematoxylin and eosin (H&E)-stained sections from 805 consecutive myocardial samples (207 surgical specimens, 598 autopsy specimens) were examined retrospectively. The presence of immature erythroid or myeloid cell clusters in intramyocardial capillaries or stroma was considered sufficient for the diagnosis of EMH. Immunoperoxidase studies confirming the nature of the hematopoietic cell infiltrate were performed in selected cases. Foci of EMH (often multiple) were identified in 15 of 207 surgical hearts (7.2%) and in 22 of 598 autopsy hearts (3.7%). Patient ages (exclusive of premature infants) ranged from 2 weeks to 73 years (median, 13 years). Twenty-four of 37 (65%) EMH-positive cases were associated with infarcts in various stages of repair (accounting for 11 of 68 [16.2%] of all infarcts in surgical specimens and 13 of 86 [15.1%] of infarcts in autopsy specimens). Acute infarcts less than 72 hours old, excluding those with acute extension, were not associated with EMH. Viral myocarditis and myocardial hypertrophy with fibrosis accounted for primary diagnoses in the nonischemic, EMH-positive surgical cases, whereas seven of nine nonischemic, EMH-positive autopsy cases involved premature or term infants with no obvious myocardial disease. Another autopsy patient had sarcoidosis with myelophthisic involvement of her bone marrow and represented one of only two cases overall in which a hematopoietic disorder was coexistent or suspected. Myocardial EMH is relatively common after myocardial infarct but is rarely encountered in normal or nonischemic myocardium. Its presence in healing but not early acute stages of infarct suggests that EMH results from inflammation- or repair-associated trophic factors, not from ischemia itself.
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PMID:Myocardial extramedullary hematopoiesis: a clinicopathologic study. 1091 38

Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.
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PMID:Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. 1528 11

Erythropoietin (EPO), known for its role in erythroid differentiation, has been suggested to have non-hematopoietic functions in the brain, especially during development. In the present study, we investigated the expression of erythropoietin and erythropoietin receptor (EPOR) in the developing rat brain following hypoxia-ischemia. Seven-day-old rats underwent unilateral, permanent carotid artery ligation followed by 1 h of hypoxia, and their brains were examined immediately, 24 h or 4 days after hypoxia-ischemia. RT-PCR and Western blot analysis revealed that hypoxia-ischemia only marginally affected EPO expression. Immunohistochemical study of brains 4 days after hypoxia showed that 60 min of hypoxia (resulting in cortical infarction and severe neuronal loss in other regions) led to the increased EPO immunoreactivity, especially in the boundaries of the damaged cerebral cortex, associated with astrocytosis. In contrast, EPOR was dramatically upregulated within 24 h after hypoxia-ischemia. These results suggest that there is a rapid response of EPOR to the hypoxic-ischemic stimulus, which seems to precede that of EPO, leading to the hypothesis that the EPO/EPOR system is implicated in the processes of neuroprotection from hypoxia-ischemia.
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PMID:Hypoxia-ischemia affects erythropoietin and erythropoietin receptor expression pattern in the neonatal rat brain. 1534 64

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. Previously, activation of this pleiotropic response was neuroprotective in cell culture models that simulate components of stroke damage. However, the role of Nrf2 in limiting stroke damage in vivo remained unclear. We report that Nrf2 activation protects the brain from cerebral ischemia in vivo. Acute (1-3 d) intracerebroventricular or intraperitoneal pretreatment with tert-butylhydroquinone (tBHQ), an Nrf2 activity inducer, reduced cortical damage and sensorimotor deficit at 24 h and even 1 month after ischemia-reperfusion in rats. Cortical glutathione levels robustly increased with tBHQ administration to rats and Nrf2-expressing mice, but not Nrf2(-/-) mice. Basal and inducible activities of antioxidant/detoxification enzymes in Nrf2(-/-) mice were reduced when compared with Nrf2(+/+) controls. Interestingly, larger infarcts were observed in Nrf2(-/-) mice at 7 d after stroke, but not at 24 h, suggesting that Nrf2 may play a role in shaping the penumbra well after the onset of ischemia. Neuronal death caused by a "penumbral" model of stroke, using intracortical endothelin-1 microinjection, was attenuated by tBHQ administration to Nrf2(+/+), but not to Nrf2(-/-) mice, confirming the Nrf2-specific action of tBHQ in vivo. We conclude that Nrf2 plays a role in modulating ischemic injury in vivo. Accordingly, Nrf2 activation by small molecule inducers may be a practical preventative treatment for stroke-prone patients.
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PMID:A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. 1626 40

Bone marrow cell implantation (BMI) has been utilized to treat patients with limb and heart ischemia. BMI provides angiogenic precursors and angiogenic cytokine-producing cells, especially erythroid cells. In this study, we induced in vitro angiogenesis cultures and in vivo BMI simulation using a murine limb ischemia model to examine the role of erythroid cells and the effect of erythropoietin (EPO). Human erythroid colonies (BFU-e) induced capillary networks around the colonies in vitro. Erythroid cells in human bone marrow produced vascular endothelial growth factor and placental growth factor. The angiogenic effects of erythroid cells were further amplified in the presence of EPO. Limb-ischemic mice were treated with BMI +/- EPO, and limb survival, blood flow recovery, and muscle histology were analyzed. Treatment with whole bone marrow cells + EPO significantly improved limb survival and blood flow. The cumulative effects of EPO on BMI induced and increase in capillary number and artery enlargement. Erythroid cells were essential for the in vivo effects of BMI, and CD14-positive cells supported the biological effects. In addition to the direct effect of EPO on angiogenesis, EPO showed indirect effect on angiogenesis through amplifying the angiogenic effects by erythroid cells supported by CD14-positive cells.
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PMID:Erythroid cells play essential roles in angiogenesis by bone marrow cell implantation. 1660 82

Erythropoietin (EPO) is a hypoxia-inducible hormone required for erythroid differentiation. Expression of the EPO receptor is not restricted to hematopoietic cells and exhibits a multi-tissue distribution that includes neural cells, vascular endothelium and muscle progenitor cells. The ability for EPO to stimulate progenitor cell proliferation and prevent apoptosis is critical for maintenance of the erythroid lineage, but is also observed in neural and muscle progenitor cells. Mice lacking the EPO receptor die in utero due to severe anemia. However, even prior to lack of erythroid cell production in the embryo proper, these mice exhibit increased apoptosis in the brain as early as E10.5 and a reduction in the number of neural progenitor cells. Corresponding cultures of primary neural cells exhibit decreased neuron generation and increased sensitivity to reduced oxygen tension, and neurons do not survive after 24 h at low oxygen tension. In contrast, hypoxia induces EPO and EPO receptor in wild-type neuronal cells, and EPO enhances neuron survival at low oxygen tension. In vivo EPO is neuroprotective in adult animal models for brain ischemia. Induction of EPO and its receptor by hypoxia likely contributes to its neuroprotective activity and selective cell survival in the brain during hypoxic stress.
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PMID:Erythropoietin and normal brain development: receptor expression determines multi-tissue response. 1690 40

Acute renal failure--characterized by a sudden loss of the ability of the kidneys to excrete nitrogenous waste, and to maintain electrolyte homeostasis and fluid balance--is a frequently encountered clinical problem, particularly in the intensive care unit. Unfortunately, advances in supportive interventions have done little to reduce the high mortality associated with this condition. Might erythropoietin (EPO) have utility as a therapeutic agent in acute renal failure? This hormone mediates anti-apoptotic effects in the bone marrow, facilitating maturation and differentiation of erythroid progenitors. New evidence indicates that EPO also exerts anti-apoptotic effects in the brain, heart and vasculature, which can limit the degree of organ damage. Here, we review the emerging biological role of EPO in the kidney and the pathophysiology of ischemia-reperfusion injury in an attempt to understand the therapeutic potential of EPO in acute renal failure.
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PMID:Mechanisms of disease: Cell death in acute renal failure and emerging evidence for a protective role of erythropoietin. 1693 74

Recent reports have demonstrated that erythroid progenitor cells contain and secrete various angiogenic cytokines. Here, the impact of erythroid colony-forming cell (ECFC) implantation on therapeutic angiogenesis was investigated in murine models of hindlimb ischemia. During the in vitro differentiation, vascular endothelial growth factor (VEGF) secretion by ECFCs was observed from day 3 (burst-forming unit erythroid cells) to day 10 (erythroblasts). ECFCs from day 5 to day 7 (colony-forming unit erythroid cells) showed the highest VEGF productivity, and day 6 ECFCs were used for the experiments. ECFCs contained larger amounts of VEGF and fibroblast growth factor-2 (FGF-2) than peripheral blood mononuclear cells (PBMNCs). In tubule formation assays with human umbilical vein endothelial cells, ECFCs stimulated 1.5-fold more capillary growth than PBMNCs, and this effect was suppressed by antibodies against VEGF and FGF-2. Using an immunodeficient hindlimb ischemia model and laser-Doppler imaging, we evaluated the limb salvage rate and blood perfusion after intramuscular implantation of ECFCs. ECFC implantation increased both the salvage rate (38% vs. 0%, P < 0.05) and the blood perfusion (82.8% vs. 65.6%, P < 0.01). In addition, ECFCs implantation also significantly increased capillaries with recruitment of vascular smooth muscle cells and the capillary density was 1.6-fold higher than in the control group. Continuous production of human VEGF from ECFCs in the skeletal muscle was confirmed at least 7 days after the implantation. Implantation of ECFCs promoted angiogenesis in ischemic limbs by supplying angiogenic cytokines (VEGF and FGF-2), suggesting a possible novel strategy for therapeutic angiogenesis.
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PMID:Therapeutic angiogenesis by ex vivo expanded erythroid progenitor cells. 1699 94

Erythropoietin (EPO), already known as the stimulating hormone for erythropoiesis, has shown different and interesting pleiotropic actions. It does not only affect erythroid cells, but also myeloid cells, lymphocytes and megakaryocytes. This hormone can also enhance phagocytic function of the polymorphonuclear cells and reduce the activation of macrophages, thus modulating the inflammatory process.Moreover, hematopoietic and endothelial cells probably have the same cellular origin, and the discovery of erythropoietin receptors (EPO-R) also on mesangial and myocardial cells, smooth muscle fibrocells and neurons has prompted the study of the non-erythropoietic functions of this hormone.The interaction between EPO and VEGF may be of particular importance in neovascularization and wound healing. Different studies have demonstrated that EPO has an important direct hemodynamic and vasoactive action, which does not depend exclusively on any increase in hematocrit and viscosity. Moreover EPO showed protective effects on myocardial cells against apoptosis induced by ischemia/repefusion injury, but it could negatively affect pulmonary hypertension in patient with chronic cor pulmonale.This review aims to stress the importance of the increasing interest in EPO applications and the necessity of further studies to gain a deeper knowledge of this hormone and its pleiotropic and complex actions.
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PMID:From the oxygen to the organ protection: erythropoietin as protagonist in internal medicine. 1707 7


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