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陕西医学杂志 2007年第4期36卷 487-490页

作者：任明强陈琦莫宁萍遵义医学院附属医院血液科遵义563003 遵义医学院中心实验室

目的探讨恶性血液病患者血清红细胞生成素(EPO)、血小板生成素(TPO)水平与血红蛋白,红细胞数及血小板数的关系及其意义。方法采用夹心酶联免疫法测定81例恶性血液病患者及28例健康人血清EPO、TPO,同时检测其红细胞数、血红蛋白、血小板... 详细信息

目的探讨恶性血液病患者血清红细胞生成素(EPO)、血小板生成素(TPO)水平与血红蛋白,红细胞数及血小板数的关系及其意义。方法采用夹心酶联免疫法测定81例恶性血液病患者及28例健康人血清EPO、TPO,同时检测其红细胞数、血红蛋白、血小板数。结果恶性血液病病人血清EPO水平较正常组显著增高,各组病人血清EPO水平均与Hb、RBC呈负相关。急性白血病、慢性白血病、淋巴瘤血清TPO水平高于正常组,多发性骨髓瘤血清TPO水平低于对照组;急性白血病、淋巴瘤TPO水平与PLT呈负相关,慢性白血病、多发性骨髓瘤TPO水平与PLT数不相关。结论恶性血液病血清EPO、TPO水平较正常明显增高,且与Hb,PLT呈负相关。对于某些恶性血液病病人的贫血、血小板减少,使用rhEPO、rhTPO治疗可能有效。

关键词：血液肿瘤/病理生理红细胞生成素/血液血小板生成素/血液

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Normal erythropoietin response in chronic hepatitis C patients with ribavirin-induced anaemia

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ANTIVIRAL THERAPY 2003年第1期8卷 57-63页

作者： Mangoni, ED Marrone, A Saviano, D Del Vecchio, C Utili, R Ruggiero, G Univ Naples 2 Cattedra & Div Med Interna Epatol Naples Italy Studio Diagnost Nucl Naples Italy Univ Sannio Dipartimento Ingn Benevento Italy

Background: Ribavirin administration for chronic hepatitis C is associated with the development of haemolytic anaemia, which affects treatment efficacy and tolerability. In a pilot study, the exogenous administration of erythropoietin has been shown to be beneficial, reducing the rate of ribavirin dose reduction. How ribavirin administration affects normal erythropoietin production has not been determined. Aim: To investigate the endogenous erythropoietin response in hepatitis C patients with ribavirin-induced anaemia. Methods: Serum erythropoietin was measured before and during interferon-ribavirin treatment in 18 HCV-positive subjects. Mathematical analysis and modelling were applied to compare the degree of erythropoietin increase in HCV-positive and in otherwise healthy anaemic patients, and estimate the endogenous excess erythropoietin production in response to ribavirin-induced anaemia. Results: Erythropoietin concentration increased significantly in response to anaemia caused by ribavirin. The physiological erythropoietin response to the ribavirin-induced anaemia was as adequate in HCV-positive subjects as it is in anaemic subjects without liver disease. The recommended exogenous erythropoietin dose appears three-times greater than the endogenous erythropoietin boost. Conclusion: Chronic liver damage by HCV does not affect the physiological erythropoietin response to ribavirin-induced anaemia. While the rationale for erythropoietin treatment of ribavirin-induced anaemia is not straightforward, the currently recommended dosing regimen should be reassessed.

关键词：贫血溶血性/化学诱导抗病毒药/副作用抗病毒药/治疗应用药物疗法联合红细胞生成素/血液丙型肝炎慢性/药物疗法丙型肝炎慢性/代谢干扰素α/治疗应用模型生物学重组蛋白质类利巴韦林/副作用利巴韦林/治疗应用成年人老年人女(雌)性人类男(雄)性中年人

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Efficient and regulated erythropoietin production by naked DNA injection and muscle electroporation

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第11期96卷 6417-6422页

作者： Rizzuto, G Cappelletti, M Maione, D Savino, R Lazzaro, D Costa, P Mathiesen, I Cortese, R Ciliberto, G Laufer, R La Monica, N Fattori, E Ist Ric Biol Mol P Angeletti I-00040 Rome Italy Univ Oslo Dept Physiol N-0317 Oslo Norway

We show that an electric treatment in the form of high-frequency, low-voltage electric pulses can increase more than 100-fold the production and secretion of a recombinant protein from mouse skeletal muscle. Therapeutical erythopoietin (EPO) levels were achieved in mice with a single injection of as little as 1 mu g of plasmid DNA, and the increase in hematocrit after EPO production was stable and long-lasting. Pharmacological regulation through a tetracycline-inducible promoter allowed regulation of serum EPO and hematocrit levels. Tissue damage after stimulation was transient. The method described thus provides a potentially safe and low-cost treatment for serum protein deficiencies.

关键词： 5'非翻译区/遗传学巨细胞病毒/遗传学电刺激电穿孔/方法红细胞生成素/生物合成红细胞生成素/血液红细胞生成素/遗传学基因表达调控基因转移技术动力学小鼠近交BALBC 小鼠近交C3H 小鼠近交C57BL 小鼠近交DBA 肌骨骼/细胞学肌骨骼/生理学质粒启动区遗传重组蛋白质类/生物合成敏感性与特异性时间因素动物女(雌)性小鼠

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A pharmacodynamic analysis of erythropoietin-stimulated reticulocyte response in phlebotomized sheep

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期295卷 346-351页

作者： Chapel, SH Veng-Pedersen, P Schmidt, RL Widness, JA Univ Iowa Coll Pharm Iowa City IA 52242 USA Univ Iowa Coll Med Dept Pediat Iowa City IA 52242 USA

The pharmacodynamics (PD) of the reticulocyte response resulting from phlebotomy-induced erythropoietin (EPO) was investigated in adult sheep. The anemia caused by the controlled phlebotomy (Hb, < 4 g/dl, t = 0) resulted in a rapid increase in EPO with peak concentrations from 200 to 1400 mU/ml at 0.5 to 3 days generating a delayed reticulocyte response with peak levels from 9.3 to 14.1% at 2.5 to 5.1 days. The PD EPO-reticulocyte relationship is well described by a simple kinetic model involving 3 relevant physiologic parameters: T-1 = lag-time (0.73 +/- 0.32 days, mean +/- S.D.), T-2 = reticulocyte maturation time (5.61 +/- 1.41 days), and k = EPO efficacy coefficient (0.052 +/- 0.048% g/dl mU/ml/day). Accordingly, 0.52% reticulocytes at 10 g/dl Hb level are generated per day at an EPO concentration of 100 mU/ml. The difference between the T-2 parameter in this study and the maturation time reported for humans may be due to interspecies differences or different technique and experimental conditions. The PD transduction appears largely linear in the observed EPO concentration range, indicating a full utilization of EPO without any significant PD saturation. Also, the EPO concentration versus time profiles resulting from the phlebotomy were similar to exogenous EPO profiles resulting from s.c. therapeutic dosing. This study supports the hypothesis that s.c. EPO dosing is more efficacious than i.v. dosing.

关键词：红细胞生成素/血液红细胞生成素/生理学模型生物学静脉切开术网状细胞/生理学绵羊动物

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ENHANCING THE EFFICACY OF PREOPERATIVE AUTOLOGOUS BLOOD DONATION BY ERYTHROPOIETIN

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TRANSFUSION SCIENCE 1994年第2期15卷 171-177页

作者： SCHLAEPPI, B GUNTER, P NYDEGGER, UE CENT LAB HEMATOL CH-3010 BERNSWITZERLAND

A double-blind, randomized and placebo-controlled study was performed with 62 patients undergoing orthopedic hip surgery. Mean hemoglobin levels at surgery, after four weekly blood-donations were 12.3, 12.7 and 13.9 g/dL for the patients receiving placebo, 100 and 200 IU/kg r-hu EPO respectively, via the subcutaneous route. The groups receiving r-hu EPO were operated on without any homologous blood supply. The endogenous erythropoietin levels remained stable throughout the observation period in the treatment groups, whereas they increased in the placebo group. The study confirms the known efficacy of erythropoietin in preoperative autologous blood-donation, but the ideal dose for each individual patient remains to be defined.

关键词：血液成分除去法/方法失血手术/预防和控制输血自体/方法红细胞生成素/血液红细胞生成素/治疗应用髋假体手术前护理外科手术老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans

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BLOOD 2000年第9期95卷 2983-2989页

作者： Stohlawetz, PJ Dzirlo, L Hergovich, N Lackner, E Mensik, C Eichler, HG Kabrna, E Geissler, K Jilma, B Univ Hosp Vienna Sch Med Dept Clin Pharmacol TARGET A-1090 Vienna Austria Univ Vienna Sch Med Dept Internal Med 1 Div Hematol Vienna Austria Univ Vienna Sch Med Div Transfus Med Blood Grp Serol & Transfus Med Vienna Austria

A recent study in dogs suggested that erythropoietin (EPO) not only promotes the synthesis of increased numbers of reticulated platelets but that these newly produced platelets are hyperreactive compared with controls, Because of the increasing use of EPO in the perioperative setting, we characterized the effects of EPO on platelet reactivity in healthy human volunteers. In a randomized, controlled trial, we studied the effects of EPO on platelet reactivity, thrombopoiesis, and endothelial activation in circumstances similar to those of autologous blood donation. Thirty healthy male volunteers received placebo or EPO (100 or 500 U/kg of body weight given intravenously) three times a week for 2 weeks and underwent phlebotomy on days 8 and 15, Thrombin receptor-activating peptide induced expression of P-selectin, and CD63 increased 2- to 3-fold during EPO treatment. The enhanced platelet reactivity was also reflected by a 50% increase in soluble P-selectin in plasma. Plasma E-selectin levels increased in a dose-dependent fashion by more than 100% during EPO treatment, indicating substantial activation of endothelial cells. A 10% to 20% increase in platelet counts was observed in both EPO groups on day 5, In the placebo group, platelets increased only several days after the first phlebotomy, The increase in platelet counts was not reflected by changes in the amounts of reticulated platelets or circulating progenitor cells. In summary, we found that EPO markedly enhances endothelial activation and platelet reactivity, which may adversely affect patients at cardiovascular risk. However, the increased platelet reactivity could be exploited in patients with platelet dysfunction. (Blood, 2000;95:2983-2989) (C) 2000 by The American Society of Hematology.

关键词：抗原 CD/分析血小板/药物作用血小板/生理学细胞黏附分子/血液双盲法 E选择素/血液内皮血管/药物作用内皮血管/生理学红细胞生成素/投药和剂量红细胞生成素/血液红细胞生成素/药理学血细胞生成/药物作用血细胞生成/生理学血红蛋白类/代谢输注静脉内寡肽类/药理学 P选择素/血液安慰剂血小板计数/药物作用血小板膜糖蛋白类/分析受体凝血酶/生理学网状细胞计数/药物作用时间因素成年人动物狗人类男(雄)性

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N^G-monomethyl-L-arginine inhibits erythropoietin gene expression by stimulating GATA-2

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BLOOD 2000年第5期96卷 1716-1722页

作者： Tarumoto, T Imagawa, S Ohmine, K Nagai, T Higuchi, M Imai, N Suzuki, N Yamamoto, M Ozawa, K Univ Tsukuba Inst Clin Med Div Hematol Tsukuba Ibaraki 3058575 Japan Jichi Med Sch Dept Hematol Minami Kawachi Tochigi 32904 Japan Univ Tsukuba Ctr Tsukuba Adv Res Alliance Tsukuba Ibaraki 305 Japan Univ Tsukuba Inst Basic Med Sci Tsukuba Ibaraki 305 Japan Chugai Pharmaceut Co Ltd Tokyo Japan

N-G-monomethyl-L-arginine (L-NMMA) has been reported to be elevated in uremic patients. Based on the hypothesis that the pathogenesis of the anemia of renal disease might be due to the perturbation of transcription factors of the erythropoietin (Epo) gene by L-NMMA, the present study was designed to investigate the effect of L-NMMA on Epo gene expression through the GATA transcription factor. L-NMMA caused decreased levels of Nc, cyclic guanosine monophosphate (cGMP), and Epo protein in Hep3B cells. L-NAME (analogue of L-NMMA) also inhibited Epo production in anemic mice. Transfection of the Epo promoter-luciferase gene into Hep3B cells revealed that L-NMMA inhibited the Epo promoter activity. However, L-NMMA did not inhibit the Epo promoter activity when mutated Epo promoter (GATA to TATA) was transfected, and L-NMMA did not affect the enhancer activity. Electrophoretic mobility shift assays demonstrated the stimulation of GATA binding activity by L-NMMA. However, L-NMMA had no effect on the binding activity of hepatic nuclear factor-4, COUP-TF1, hypoxia-inducing factor-1,or NF-kappa B, Furthermore, cGMP inhibited the L-NMMA-induced GATA binding activity. L-NMMA also increased GATA-2 messenger RNA expression. These results demonstrate that L-NMMA suppresses Epo gene expression by upregulation of the GATA transcription factor and support the hypothesis that L-NMMA is one of the candidate substances that underlie the pathogenesis of renal anemia. (C) 2000 by The American Society of Hematology.

关键词：缺氧碱基序列结合部位/遗传学环GMP/代谢 DNA/遗传学 DNA/代谢 DNA结合蛋白质类/药物作用 DNA结合蛋白质类/代谢酶抑制剂/药理学红细胞生成素/血液红细胞生成素/遗传学红细胞生成素/代谢 GATA2转录因子基因表达调控/药物作用萤光素酶类/药物作用萤光素酶类/遗传学萤光素酶类/代谢分子序列数据突变 NG-硝基精氨酸甲酯/药理学一氧化氮/代谢启动区(遗传学)/遗传学蛋白质结合重组融合蛋白质类/药物作用重组融合蛋白质类/遗传学重组融合蛋白质类/代谢转录因子/药物作用转录因子/代谢肿瘤细胞培养的/细胞学肿瘤细胞培养的/药物作用肿瘤细胞培养的/代谢 ωN-甲基精氨酸/药理学动物人类小鼠

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Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin

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ANNALS OF THE RHEUMATIC DISEASES 2000年第3期59卷 217-222页

作者： Voulgarelis, M Kokori, SIG Ioannidis, JPA Tzioufas, AG Kyriaki, D Moutsopoulos, HM Natl Univ Athens Sch Med Dept Pathophysiol Athens 11527 Greece Univ Ioannina Sch Med Dept Hyg & Epidemiol Clin & Mol Epidemiol Unit GR-45110 Ioannina Greece Laikon Gen Hosp Dept Nucl Med Athens Greece

Objective-To study the prevalence of different causes of anaemia in patients with systemic lupus erythematosus (SLE) and their associations with immunological and clinical parameters and to evaluate the contribution of erythropoietin (Epo) and anti-erythropoietin (anti-Epo) autoantibodies to the development of SLE anaemia. Methods-132 SLE patients with anaemia (defined as haemoglobin of 12 g/dl or less for women and 13.5 g/dl or less for men) from among a total of 345 consecutive SLE patients were prospectively enrolled into the study. Standard haematological and immunological tests were performed and serum Epo and anti-Epo antibodies were assayed. Results-The identified causes were anaemia of chronic disease (ACD) n=49 (37.1%), iron deficiency anaemia (IDA) n=47 (35.6%), autoimmune haemolytic anaemia (AHA) n=19 (14.4%) and other causes n=17 (12.9%). There was significant heterogeneity in the severity of anaemia between the four groups (p<0.01) with AHA cases being on average more severe. The proportion of patients with anticardiolipin antibodies, low complement levels and anti-dsDNA differed significantly among the four groups;these markers were particularly common in patients with AHA, and uncommon in patients with IDA. Twenty one of 100 tested patients had anti-Epo antibodies. Such antibodies were seen practically only in patients with ACD (odds ratio 3.1, p=0.041) and in patients with high lupus activity (ECLAM) scores (odds ratio 1.27 per point, p=0.055). Epo response was inadequate in 42.4% and 41.2% of patients with ACD and AHA, respectively. Conclusions-Anaemia in SLE usually takes the form of ACD and IDA, however autoimmune haemolysis is not uncommon. SLE patients with different causes of anaemia differ in regard to several immunological parameters. Epo response is blunted in anaemic SLE patients, particularly those with ACD and AHA.

关键词：贫血/血液贫血/病因学贫血/免疫学贫血溶血性自身免疫性/病因学贫血溶血性自身免疫性/免疫学贫血缺铁性/病因学贫血缺铁性/免疫学自身抗体/血液红细胞生成素/血液红细胞生成素/免疫学随访研究红斑狼疮系统性/血液红斑狼疮系统性/并发症红斑狼疮系统性/免疫学前瞻性研究成年人女(雌)性人类男(雄)性中年人

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Origin and fate of erythropoietin in human milk

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PEDIATRIC RESEARCH 2000年第5期48卷 660-667页

作者： Juul, SE Zhao, YR Dame, JB Du, Y Hutson, AD Christensen, RD Univ Florida Coll Med Dept Pediat Gainesville FL 32610 USA Univ Florida Coll Med Gen Clin Res Ctr Gainesville FL 32610 USA

Erythropoietin (Epo) is a normal constituent of human milk, but the origin and fate of this cytokine in milk are not known. Regarding its origin, we hypothesized that cells of the mammary gland secrete Epo into milk actively and, therefore, that concentrations in milk do not correlate with concentrations in serum. Regarding its fate, we hypothesized that Epo concentrations in milk change with time postpartum and that Epo in milk is protected from digestion in the neonatal gastrointestinal tract. To address these issues, we measured Epo concentrations in 103 milk samples (ELISA), 55 of which were paired with serum. Mammary duct epithelial cells were evaluated as a source of Epo by breast tissue immunohistochemistry and by cell culture. Circulating and milk Epo were compared by Western analysis to detect size differences, possibly reflecting differences in processing. Epo stability in simulated conditions of digestion was evaluated. We observed that milk Epo concentrations increase as a function of duration of breast-feeding and have a negative correlation with serum Epo or milk protein concentration. Mammary duct epithelial cells from breast biopsies of lactating women had marked immunoreactivity to Epo, but such activity was minimal to absent in nonlactating breast tissue. Further evidence that mammary duct epithelia produce Epo was obtained by observing Epo mRNA and protein expression in cultured human mammary epithelial cells. The molecular size of Epo in milk and serum is identical. Recombinant Epo added to human milk or commercial infant formulas was relatively stable in conditions that simulate gastric and small intestinal conditions of newborn infants;however, recombinant Epo added to D5W was not protected from digestion. We conclude that Epo concentrations in milk increase as a function of the duration of breast feeding, that Epo is actively secreted into human milk by mammary duct epithelia, and that the Epo within milk is largely protected from digestion.

关键词：碱基序列乳房/代谢细胞培养的 DNA引物/遗传学消化红细胞生成素/血液红细胞生成素/遗传学红细胞生成素/代谢免疫组织化学乳人/代谢产后期/代谢 RNA 信使/遗传学 RNA 信使/代谢时间因素成年人女(雌)性人类中年人

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Maternal smoking and fetal erythropoietin levels

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OBSTETRICS AND GYNECOLOGY 2000年第4期95卷 561-564页

作者： Gruslin, A Perkins, SL Manchanda, R Fleming, N Clinch, JJ Univ Ottawa Dept Obstet & Gynecol Ottawa Hosp Div Maternal Fetal Med Ottawa ON K1H 8L6 Canada Univ Ottawa Dept Pathol & Lab Med Ottawa Hosp Ottawa ON K1H 8L6 Canada Ottawa Hosp Res Inst Clin Epidemiol Unit Ottawa ON Canada

Objective: To determine the influence of maternal smoking on fetal erythropoietin concentrations in health term pregnancies and test the correlation between cotinine, a biomarker of maternal smoking, and erythropoietin levels in fetuses. Methods: We invited women with healthy term pregnancies to participate in the study, excluding those with conditions previously known to be associated with elevated fetal erythropoietin levels. We recorded demographic data, smoking status, and labor outcome prospectively for each patient. Umbilical venous samples were collected, and serum was stored at -70C to be analyzed later for erythropoietin and cotinine. Umbilical arterial samples were tested for pH and base excess determination. We compared fetal erythropoietin and cotinine between smokers and nonsmokers and examined correlations between erythropoietin and cotinine. Kruskal-Wallis test, t test, median test, and Spearman rank correlation test were used when appropriate. Statistical significance was P < .05. Results: We recruited 35 nonsmokers and 26 smokers and analyzed their samples. The two groups were comparable in demographics and birth outcomes, except for birth weights, which were lower in smokers. Fetal erythropoietin concentrations increased significantly with increasing maternal cigarette consumption, ranging from none to more than 15 cigarettes per day (P = .03). There was positive correlation between fetal erythropoietin and cotinine concentrations (r = .41;P = .04), suggesting a dose-response relationship. Conclusion: Fetuses of smokers had increased erythropoietin concentrations that correlate positively with fetal cotinine levels;which suggests an increased risk of subacute hypoxia related to degree of maternal cigarette consumption. (C) 2000 by The American College of Obstetricians and Gynecologists.

关键词：可替宁/血液红细胞生成素/血液胎血/化学母亲行为吸烟成年人女(雌)性人类妊娠

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