Disease relevance of EPO

• The sheep erythropoietin gene: molecular cloning and effect of hemorrhage on plasma erythropoietin and renal/liver messenger RNA in adult sheep [1].
• In a separate additional series of experiments, umbilical arterial and venous EPO concentrations were determined in nine normoxic fetuses and in nine fetuses subjected to 12 hours of hypoxia induced by lowering maternal-inspired oxygen content [2].
• Similarly, in the fetal hypoxemia experiments, the placenta demonstrated progressive increases--albeit an order of magnitude greater than the kidneys--in EPO production rate [2].
• CONCLUSIONS: The chronically catheterized fetal sheep is a viable model for studying immunologically induced fetal anemia as hematocrit can be titrated and the fall in RCM and hematocrit are associated with fetal hypoxia and elevated EPO as occurs in the anemic human fetus [3].
• As an extension of these findings, we speculate that the hypoproliferative neonatal anemia that invariably occurs in the early weeks after birth is in part the result of loss of EPO production by the placenta [2].

Psychiatry related information on EPO

• Acute hypoxemia was produced in chronically catheterized sheep fetuses to determine the response time necessary to increase plasma immunoreactive erythropoietin (Ep) concentration [4].

High impact information on EPO

• In this study, human CFU-E have been isolated in sufficient purity to characterize the morphology of these rare cells and in sufficient numbers to measure specific binding of Ep [5].
• Purification of human erythroid colony-forming units and demonstration of specific binding of erythropoietin [5].
• Reticulocytes, plasma iron turnover, and erythrocyte mass changes increased as the amount of Ep-rich plasma was increased [6].
• Ep-rich plasma stimulated erythropoiesis similarly in uremic and normal sheep, regardless of the degree of uremia [6].
• The anemia of chronic renal failure in sheep. Response to erythropoietin-rich plasma in vivo [6].

Chemical compound and disease context of EPO

• Renal lymph did contain measurable levels of Ep following renal artery constriction, unilateral hydronephrosis or phenylhydrazine-induced hemolytic anemia [7].
• Controversy exists regarding the placental permeability of erythropoietin (Ep), a glycoprotein hormone that regulates red blood cell production in the fetus, newborn, and adult after tissue hypoxia [8].
• In the nitrite infused group, however, a significant and progressive increase in mean plasma Ep level over baseline levels was observed during the 4th and 5th h of hypoxemia (p less than 0.01) [4].
• Continuous exposure of mice to 8% O2 for 11 da resulted in a polycythemia of sufficient magnitude and duration to provide appropriate erythropoietic conditions for the erythropoietin assay [9].

Biological context of EPO

• The deduced amino acid sequence of sheep Epo shows 82%, 78% and 80% homology with mature Epos of human, mouse and monkey, respectively [1].
• In 10 studies of human marrow with normal erythropoiesis, human EPO in doses up to 1 unit/ml produced a significant increase in colonies when compared to sheep EPO [10].
• To determine whether EPO pharmacokinetics are perturbed by ablation of the kidneys or liver or by anesthesia, EPO pharmacokinetic parameters were determined in adult sheep [11].
• The logarithm of EPO concentration was correlated with hematocrit (r = -0.74, P < .0001) but not with arterial blood oxygen tension [12].
• Even though EPO receptors have not been found in late gestation ovine and human placental tissue, this does not eliminate the possibility that EPO could traverse the placenta earlier in gestation during organogenesis [13].

Anatomical context of EPO

• 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) [14].
• The present study indicates that the bone marrow significantly contributes to the elimination of EPO in vivo [15].
• Fetal blood was sampled daily for complete blood cell counts, blood gases, iron, erythropoietin (EPO), and electrolyte concentrations [3].
• Under hypoxic conditions (Po(2)=15.6+/-0.4 mm Hg, n=9), umbilical vein EPO concentration (range 151-1245 mU/mL) was higher than arterial concentration (range 140-951 mU/mL) in eight of nine paired samples by 13.6%+/-3.3% (P<.01) [2].
• Thus, brief asphyxia induces EPO and EPO-R in fetal astrocytes, but only after repeated asphyxial insult in neurons [16].

Associations of EPO with chemical compounds

• The O2 CT decreased from 12.3 +/- 1.6 to 4.1 +/- 0.6 ml/dl, and plasma Epo increased from 15 +/- 4 to 1675 +/- 287 mU/ml [1].
• Knowledge regarding the in vivo metabolic fate of the glycoprotein erythropoietin (EPO) is incomplete [11].
• After busulfan-induced bone marrow ablation, EPO PK demonstrated progressive decreases in plasma clearance (CL), elimination half-life [t1/2(beta)], and volume of distribution at steady state (Vss) with concomitant increases in mean residence time (MRT) [15].
• Contrary to speculation by others, results of the present study make it highly unlikely that removal of the terminal sialic acid moieties of EPO contributes significantly to the metabolism of EPO [11].
• Furthermore, there appears to be a threshold degree of anemia required to elicit responses as the fetal EPO, PO(2), and lactate appeared unresponsive until hematocrit fell below 25% [3].

Other interactions of EPO

• Thus the localization of the binucleate cells was the same as that for the EPO mRNA and the EPO protein, whereas the EPO receptor had a more generalized distribution [17].
• After 2 x UCO, higher levels of EPO and EPO-R occurred in the periventricular and cortical WM, corpus callosum, hippocampal CA1, and in neurons of all cortical layers [16].
• There was no change in plasma erythropoietin concentrations or plasma renin activity [18].

Analytical, diagnostic and therapeutic context of EPO

• The expression of the ovine Epo gene in tissues from normal and hemorrhaged sheep was analysed by a competitive RT/PCR method [1].
• The controlled drop in Hb resulted in a rapid increase in plasma EPO to 836 +/- 52 mU/ml (mean +/- coefficient of variation percentage) that was followed by a paradoxical rapid drop 2 to 4 days after the phlebotomy while the animals were still very anemic (Hb = 4.3 +/- 15 g/dl) [19].
• Plasma EPO concentration was determined by radioimmunoassay [12].
• Bilateral nephrectomy did not diminish the Ep response to DT and L-T4 [20].
• Erythropoietin: isolation by affinity chromatography with lectin-agarose derivatives [21].

References