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At least 19 recordsLinked to original sources
PubMed1979

Stem cell migration induced by erythropoietin or haemolytic anaemia: the effects of actinomycin and endotoxin contamination of erythropoietin preparations.

The injection of erythropoietin or the induction of anaemia with phenylhydrazine leads to changes in murine pluripotent and granulocyte-macrophage stem cells indicating migration from marrow to spleen. In order to evaluate the interrelationship between erythroid differentiation and stem cell migration we have selectively suppressed erythroid differentiation with actinomycin D. Anaemia or EP injection resulted in stem cell changes consistent with migration; actinomycin blocked these changes in anaemic but not EP injected mice while blocking erythropoiesis in both groups. The erythropoietin contained from 0.01 to 1000 microgram/ml of endotoxin as defined by the limulus test; it decreased marrow erythropoiesis and stimulated marrow granulopoiesis. Adsorption of the erythropoietin preparation with limulus lysate removed endotoxin without decreasing erythropoietin activity. Adsorbed erythropoietin stimulated erythropoiesis and not granulopoiesis, and stem cell changes induced by its administration were largely blocked by actinomycin, suggesting that endotoxin in the non-adsorbed erythropoietin caused the actinomycin resistant stem cell changes. The observation that actinomycin blocks both erythroid differentiation and stem cell migration suggests that these two physiologic events are closely linked. The effects of injected erythropoietin on murine haemopoietic stem cells may, to a significant extent, be secondary to the presence of endotoxin in the erythropoietin preparations.

Anemia, Hemolytic↗
PubMed1979

Erythropoietin levels in the course of a patient with erythropoietin-producing renal cell carcinoma and transplantation of this tumor in nude mice.

Erythropoietin was measured by exhypoxic polycythemic mouse method in the course of a 64-yr-old male with renal cell carcinoma associated with erythrocytosis. Serum erythropoietin fluctuated with progression of the disease. Preoperative elevated erythropoietin (0.11 U/ml, p greater than 0.05) subsided after nephrectomy and again increased with developing lung metastasis (0.1 U/ml, p greater than 0.02). Erythropoietin was markedly increased in the tumorous extracts from primary renal cell carcinoma in the kidney (0.2 U/g, p greater than 0.01) and lung metastasis (0.8 U/g, p greater than 0.01). Renal cell carcinoma from the lung metastasis was transplanted into nude mice, resulting in erythrocytosis in some of these mic. In the erythrocytotic mice, erythropoietin was elevated to levels of 0.25--0.9 U/g (p greater than 0.01) in the tumorous extracts and increased (0.67 U/ml, p greater than 0.02) in the serum. These results indicate that this renal cell carcinoma is an erythropoietin-producing tumor, and this tumor has been successfully transplanted in nude mice for the first time.

Adenocarcinoma↗
PubMed1979

In vitro assay for erythropoietin: erythroid colony formation in methyl cellulose used for the measurement of erythropoietin in plasma.

Erythroid colony formation in methyl cellulose has been used for the measurement of erythropoietin in plasma. Livers from newborn mice less than 24 hr old were found to provide convenient target cells. Newborn mouse liver contains a substantial number of erythroid colony-forming cells (CFU-e) that have a high sensitivity to erythropoietin, the dose--response curve for erythropoietin reaching a plateau at 50 mU/ml. As little as 0.5 m/ml of the hormone is detectable. Removal of cells that adhered to glass prior to culturing doubled the number of colonies formed in the presence of erythropoietin. Addition of untreated plasmas that showed high erythropoietin titers in the exhypoxic polycythemic mice assay gave variable results. Some of the plasmas stimulated colony formation actively and in a linear fashion. However, the majority of the plasmas were toxic to the cultures. Dialyzing the plasmas for 3 days against distilled water effectively removed the toxicity. Results obtained with the method are in good agreement with the values found using the exhypoxic polycythemic mice assay.

Animals↗
PubMed1977

The interaction of erythropoietin with fetal liver cells. II. Inhibition of the erythropoietin effect by interferon.

To investigate the effect of interferon on the proliferation of normal erythroid precursor cells, various interferon preparations were added to mouse fetal liver cells cultured in a liquid microculture system. The effect of interferon was studied using cellular tritiated thymidine incorporation both in the presence and in the absence of erythropoietin. Interferon was found to suppress cellular tritiated thymidine incorporation. The suppression was directly related to the antiviral activity and was not found when control preparations were used. The mechanism of suppression seemed to involve a direct effect on the cells which was dependent of erythropoietin. These studies suggest that the viral inhibitory effects of interferon may also be accompanied by effects on normal cellular proliferation.

Animals↗
PubMed1979

Radioimmunoassay of erythropoietin.

A radioimmunoassay for erythropoietin has been developed using 125I labeled pure human erythropoietin and an anti-erythropoietin antiserum produced in a rabbit immunized with human erythropoietin. Two techniques are presented for labeling erythropoietin, both resulting in an immunologically reactive labeled reactant. One method involves the use of lactoperoxidase and the other a reagent known as IODO-GEN. The second International Reference Preparation of human erythropoietin is used as a standard and a double antibody scheme is used for the separation of the free and antibody bound labeled hormone. The radioimmunoassay is sensitive to an absolute amount of erythropoietin equivalent to 0.4 milliunits. Bioassays for erythropoietin require approximately 100 times this amount. The use of pure erythropoietin as the labeled reactant has removed certain discrepancies seen in previous attempts to develop radioimmunoassays for this hormone, e.g., sera from patients without kidneys do not give the high values previously seen. Sera from anemic individuals not only give rise to high radioimmunoassay values but also show a parallel relationship with the erythropoietin standard when halving dilutions are analyzed. Desialated erythropoietin is also reactive with the same parallelism. Bleeding of a normal individual increases the serum erythropoietin level and transfusion decreases it. Erythropoietin from a variety of laboratory animals is also reactive in the radioimmunoassay, with very high values being observed in hypoxic animals.

Anemia↗
PubMed1979

Contamination of erythropoietin by endotoxin: in vivo and in vitro effects on murine erythropoiesis.

Endotoxin was detected in all erythropoietin preparations tested and was removed from four lots, without loss of erythropoietic activity, by adsorption with limulus amebocyte lysate. Comparison of adsorbed (endotoxin-depleted) and nonadsorbed (endotoxin-containing) erythropoietin preparations demonstrated significant inhibition of CFU-e and BFU-e in vitro by nonadsorbed erythropoietin at concentrations higher than 0.25 U/ml and 2.0 U/ml, respectively. CFU-e and BFU-e were inhibited significantly by readdition in vitro of 10(-5)-10(-3) mug of endotoxin per unit of limulus-adsorbed erythropoietin. Administration of saline or 6 U of nonadsorbed or adsorbed erythropoietin twice a day for 4 days of CF1 mice resulted in reticulocyte counts of 2.1%, 9.9%, and 15.9%, respectively. Nonadsorbed erythropoietin resulted in a 29% decrease in erythropoiesis, a 42% decrease in CFU-e, and a 16% increase in granulopoiesis in the marrow, whereas adsorbed erythropoietin caused a 28% increase in erythropoiesis, no significant change in CFU-e and a 19% decrease in granulopoiesis in the marrow. Both preparations resulted in marked increases in splenic erythropoiesis and granulopoiesis. The effects of adsorbed erythropoietin are similar to those produced following stimulation of hematopoiesis by endogenous erythropoietin. Hemopoietic changes induced by nonadsorbed erythropoietin in vivo and in vitro are affected substantially by contamination of the erythropoietin preparations with endotoxin.

Adsorption↗
PubMed1976

Specific precipitating antibody to human urinary erythropoietin.

In the present experiments, human urinary erythropoietin was purified from the urine of a patient suffering from pure red cell aplasia, using ethanol precipitation, gel filtration on the Sephadex G-100 column and electrofocusing. The anti-human urinary erythropoietin was prepared by injecting the isolated erythropoietin with Freund's complete adjuvant into rabbits intracutaneously. The specificity of the anti-human urinary erythropoietin was ascertained by a double diffusion technique and immunoelectrophoresis, observing a single precipitation line at the alpha2-globulin region against human serum or human urinary erythropoietin (Standard B). This precipitating anti-human urinary erythropoietin inhibited completely the effects of erythropoietin (Standard B) on the heme synthesis of bone marrow cells in vitro. The precipitating antigen with the specific anti-human urinary erythropoietin, that is, erythropoietic stimulating factor of the fraction 2, had the ability to enhance heme synthesis in bone marrow cells in vitro. The specific anti-human urinary erythropoietin makes it possible to determine the serum erythropoietin levels in various diseases by means of quantitative immunoelectrophoresis.

Animals↗
PubMed1975

Renal biogenesis of erythropoietin.

The widespread and ever expanding use of dialysis in the maintenance of patients with chronic renal disease has added an urgency to the study of the biogenesis of erythropoietin. It seems almost certain that erythropoietin could ameliorate, if not eliminate, the anemia of uremia, but unfortunately, erythropoietin is still not available in therapeutic quantities. Initially, erythropietin was though to be produced by the kidneys" but then the attention became directed at the liver. It was proposed that erythropoietin was produced there as an inactive precursor and that the kidney only acted as an oxygen sensor and as a producer of an erythropoietin-activating enzyme. Recent studies summarized here show that an isolated perfused kidney in the absence of any extrarenal substrate or precursor can synthesize erythropoietin. Consequently, it appears almost certain that the kidney is the endocrine organ of origin of erythropoietin. Further studies suggest that erythropoietin formation involves a phase of oxygen sensing and programming and a phase of synthesis. These phases probably occur in the same cell, and the renal cortex appears to be the most likely location for such cells. The current inability to extract erythropoietin from kidney homogenates is discussed but, unfortunately, not adequately explained.

Animals↗
PubMed1976

Species specificity of guinea pig erythropoietin.

Various stimuli (hypoxic hypoxia, bleeding, carbon monoxide hypoxia and cobalt administration), well known to increase erythropoietin plasma level in many species including man, failed to increase the erythropoietin activity in plasma of guinea pigs when measured in the polycythaemic mice assay. Nevertheless, the plasma of these guinea pigs stimulated the erythropoiesis in polycythaemic guinea pigs which, however, failed to respond to rat erythropoietin. From this it was concluded that not only the erythropoietin, but also the erythropoietin responsive cells in the bone marrow of guinea pigs are species specific. Bilateral nephrectomy in guinea pigs exposed to hypoxia prevented the increase in the erythropoietin plasma level, thus suggesting that, similarly as in other species, also in guinea pigs the kidney is the main organ of erythropoietin elaboration. The species specificity of guinea pig erythropoietin - erythropoiesis system is an interesting exception among mammals, since the erythropoietin of a large number of species belonging to this class was demonstrated to lack species specificity.

Animals↗
PubMedDate not supplied

Erythropoietin production in renal tumors.

A review of the pertinent literature on the relation of erythropoietin production to the presence of renal neoplasm suggests that erythropoietin may be produced either directly by the tumor or indirectly by its physical effect on the adjoining normal renal tissue. The most commonly found tumors which are associated with elevated levels of serum and urinary erythropoietin are the hypernephromas. However, the presence of erythropoietin and an associated erythrocytosis even here occurs only relatively infrequently. Some studies have demonstrated the presence of erythropoietin activity in tumor tissue itself but erythropoietin has not been isolated from renal tumor tissue. In some patients with Wilms' tumor, erythropoietin blood levels may also be increased; however, erythrocytosis in these patients is not a characteristic feature. Other renal tumors rarely produce erythrocytosis and presumably no erythropoietin. Possible explanations for the production of erythropoietin by renal tumors are discussed.

Adenocarcinoma↗
PubMed1979

Erythropoietin levels in uremic nephric and anephric patients.

Erythropoietin titers were measured in anemic nephric and anephric patients undergoing chronic hemodialysis by utilizing a plasma concentration technique. In eight out of 11 anephric patients studied, decreased but detectable levels of erythropoietin were found, suggesting that extrarenal erythropoietin plays a role in the regulation of red cell production in anephric patients. In 14 nephric uremic patients, erythropoietin production was found to be more variable, with one group of eight patients having erythropoietin levels in the range for normal nonanemic individuals (3.9 to 15 mU/ml), and a second group of six patients with erythropoietin higher than normal (greater than 15 mU/ml). Both groups were found to be equally anemic, indicating that in the second group the bone marrow is less responsive to erythropoietin. The severity of secondary hyperparathyroidism was found to be higher in this second group, suggesting a role of PTH in the bone marrow unresponsiveness. A good correlation between biological and immunological erythropoietin activities was found in the plasma from normal subjects and uremic nephric and anephric patients.

Animals↗
PubMed1975

Plasma erythropoietin activity before and after renal homotransplantation in humans.

Plasma erythropoietin levels were determined by Keighley's method to study the changes in erythropoiesis before and after human renal homotransplantation. Results. Erythropoietin titres in pre-transplant patients were low, while they returned to normal after successful renal transplantation. In acute rejection they were significantly high. After its reversal normal levels of erythropoietin were obtained in accordance with a normalization of the graft functions. Reticulocyte counts paralleled with erythropoietin values. Conclusion. High levels of plasma erythropoietin contribute to the diagnosis of acute rejection. Normalization of the plasma erythropoietin levels after the acute rejection could be regarded as an indication for good function of the graft. The grafted kidneys seem to function in producing erythropoietin.

Adult↗
PubMed1975

Erythropoietin effects on iron metabolism in rat bone marrow cells.

This paper describes a study of the incorporation of 59-Fe from 59-Fe-labelled rat transferrin into rat bone marrow cells in culture. 59-Fe was found in both stroma and cytoplasm of marrow cells, and the cytoplasmic 59-Fe separated by polyacrylamide gel electrophoresis, into ferritin, haemoglobin and a low molecular weight fraction. The incorporation of 59-Fe into all three cytoplasmic fractions, but not into the stroma, increased progressively with time. Erythropoietin stimulated the increase of 59-Fe in ferritin within 1 h, the earliest time examined, and more than 3 h later in the stroma and haemoglobin. A proportion of the 59-Fe incorporated into the stroma and low molecular weight iron fractions during a 1 h incubation with 59-Fe-labelled transferrin was mobilised into ferritin and haemoglobin during a subsequent 4-h "cold-chase". Erythropoietin, when present during the "cold-chase", did not influence these 59-Fe fluxes. The erythropoietin stimulation of 59-Fe incorporation into ferritin, one of the earliest erythropoietin effects to be recorded, was therefore considered to be due to an increase of 59-Fe uptake by the hormone-responsive cells rather than a direct effect on ferritin synthesis. 20-h cultures containing erythropoietin when incubated with 59-Fe-labelled transferrin for 4 h, showed dose-related erythropoietin stimulation of 59-Fe incorporation into haemoglobin only. In the presence of 10 mM isonicotinic acid hydrazide, 59-Fe incorporation into haemoglobin was inhibited, as in reticulocytes (Ponka, P. and Neuwrit, J. (1969) Blood 33, 690-707), while that into the stroma, ferritin and low molecular weight iron fractions, was stimulated; there were no reproducible effects of erythropoietin.

Animals↗
PubMed1979

Effect of erythropoietin on anemia of peritoneally dialyzed anephric rats.

The effect of erythropoietin on anemia was studied in anephric rats undergoing peritoneal dialysis. Both the number of bone marrow red cell precursors and plasma iron turnover were markedly depressed in untreated peritoneally dialyzed anephric animals when compared to peritoneally dialyzed sham-operated control rats. Anephric rats receiving 2 U of erythropoietin per day for 12 days had greater than threefold more bone marrow red cell precursors and a twofold larger plasma iron turnover than did the saline injected anephric rats. There was no significant difference in either bone marrow red cell precursors or plasma iron turnover in the erythropoietin-treated anephric rats when compared to the nonuremic controls. Although the rats receiving erythropoietin for 12 days had a significantly higher hematocrit (29.5%) than the saline injected uremic rats did (19.0%), the hematocrit was significantly lower than that found in nonuremic control animals, either receiving erythropoietin (48.1%) or not receiving erythropoietin (41.6%). Our data suggests that erythropoietin is potentially a useful agent for the treatment of anemia of chronic renal failure.

Anemia↗