Erythropoietic system

Studies with normal erythropoietic systems are hampered by the difficulties of obtaining sufficient erythroid cells of specific developmental stages. However, cell strains are available of both human and murine origin which allow the study of the final stages of erythroid development in vitro. 

Most patients with Al intoxication develop an erythropoietin-resistant microcytic anemia in the absence of iron deficiency, and this may be a useful early indication of Al toxicity [41,93,254,255]. The chemical similarity between Fe3+ and Al3+ suggest that both elements will have similar metabolic effects, suggesting that iron and Al compete during erythropoiesis, resulting from a reversible block in heme synthesis due either to a defect in porphyrin synthesis or to impaired iron utilization. It was also suggested that the main mechanisms for Al toxicity in the erythropoietic system are the interference of Al in the uptake and utilization of iron and an interaction of Al with cellular membrane components, affecting not only their structures but also their functions [256]. 

It has been known for some time that copper deficiency leads to anemia and failure of the erythropoietic system to matiure (50,51). Although the exact mechanism involved is still not well defined, recent evidence suggests that copper may be essential for iron absorption and mobilization for hemoglobin synthesis. A ferrous-to-ferric cycle with respect to the role of copper in iron metabolism has been proposed by several workers. Role of ceruloplasmin in the spontaneous oxidation of... 

A mathematical model of the control system for erythropoiesis is presented. It is postulated that the rate of erythropoiesis is controlled by a hormone, erythropoietin, which is released from the kidney in response to reduced renal oxygen supply. Equations are developed relating erythropoietin release to arterial oxyhemoglobin concentration, and hemoglobin production to plasma erythropoietin concentration, with appropriate time delays. Effects of plasma volume changes during hypoxia are included. The model simulates the dynamic response of the erythropoietic system to a step decrease in the pOt of inspired air. Contributions of the parameters and relationships to the predicted response are analyzed. The model response compares favorably with experimental data obtained from mice subjected to different degrees of hypoxia. 

The balance of this paper will be devoted to a model that has been used to facilitate the understanding of a complex biological control system. The erythropoietic system is relatively simple. However, when the interactions of associated physiological systems are considered, the control of erythropoiesis becomes highly interactive and complex. 

The model was designed to simulate the response of the erythropoietic system to a step decrease in the p02 of inspired air. However, the response to other types of stimuli such as acute hemorrhage could also be evaluated. 

In efforts to overcome these and other complexities drug evaluations are being made In simpler syst s, although the extrapolation of the results of such work to cover protection of Intact mammals is not exact.1 A good correlation between the radioprotective potency of amlnothlol drugs and their ability to protect the erythropoietic system of mice (as measured by Fe uptake) has been obtained no correlation was observed when the serotonin type of radioprotector was used. The method can be used for... 

A rare type of porphyria in which the basic abnormality is confined to the erythropoietic system. Among the clinical features which can occur are photosensitivity with blistering, hirsutism and red teeth and bones. It is transmitted genetically by a recessive type of inheritance. 

A group of disorders in which there is disturbance of porphyrin biosynthesis resulting in increased blood and tissue levels of porphyrins or their precursors. Most types of porph3rria are hereditary while one (symptomatic cutaneous hepatic porphyria) is acquired. The porphyrias can be classified into several groups depending upon whether the basic abnormality is in the liver or the erythropoietic system or both ... 

The possibility that HbF and HbA can coexist in individual erythrocytes of adult and neonatal human blood has also been demonstrated by spectrophotometric and cytochemical methods (Matioli et al., 1962 Zipursky et al., 1962 Shepard et al., 1962). The switch from HbF and HbA thus consists evidently of a change in the direction of work of what is essentially the same single erythropoietic system, and not a complete replacement of one erythropoietic system by another new one, which might be expected from data showing changes in the localization of erythropoiesis in dif-ferentphases of embryonic development (Maximov and Bloom, 1957). 

The literature contains a number of examples of developmental systems that are most reasonably interpreted on the basis of the initial production of a stable, inactive, mRNA that becomes activated so as to synthesize its specific protein at the time of differentiation. Perhaps this is best illustrated in the erythropoietic system since hemoglobin is a readily visible index of differentiation. Thus, it has been shown by several workers (cf. Marks et al., 1963 Borsook, 1964) that RNA synthesis stops upon transformation of erythfoblast to normoblast but the hemoglobin is not produced until much later, and presumably the mRNA for this purpose must be activated at the time. 

Scale-up of cell cultures makes use of suspension cultures (erythropoietic cells or microcarriers) or, less often use of capillary beds (hollow fibre systems or glass bead columns), but these suffer from the same disadvantages seen with smaller scale cultures ( 3.4.4). In particular, nutrients are depleted as the medium flows through long columns or beds and high rates of flow coupled with recirculation are often employed. Nevertheless, Organon have used a hollow fibre dialysis system for production of monoclonal antibodies (Schonherr et al., 1985). Invitron s hollow fibre system has been used to produce cell conditioned media and the Cell-Pharm System (Jencons Ltd. Appendix 3) will produce up to 20 g cell secreted product per month. 

Iron deficiency is the most common cause of resistance to erythropoietic therapy. Evaluation and treatment of iron deficiency should occur prior to initiation of erythropoietic therapy as previously discussed (see Figs. 44—1 and 44—2). Inflammation (localized or systemic infection, active inflammatory disease, or surgical trauma) is associated with defective iron utilization known as reticuloendothelial block. Reticuloendothelial block is characterized by a reduction in iron delivery from body stores to the bone marrow, and is generally refractory to iron therapy. Failure to respond to erythropoietic therapy requires evaluation of other factors causing resistance, such as infection, inflammation, chronic blood loss, aluminum toxicity, hemoglobinopathies, malnutrition, and hyperparathyroidism. Erythropoietic therapy may be continued in the infected or postoperative patient, although increased doses are often required to maintain or slow the rate of decline in Hgb/Hct. Deficiencies in folate and vitamin Bi2 should also be considered as potential causes of resistance to erythropoietic therapy, as both are essential for optimal erythropoiesis. Patients on hemodialysis or peritoneal dialysis should be routinely... 

The basic erythropoietic control system consists of the following. The kidney produces and releases a hormone—erythropoietin—in amounts that depend on the state of tissue oxygenation. This hormone is carried in the blood stream to the bone marrow where it stimulates the production of red blood cells. The increased concentration of red blood cells allows the delivery of more oxygen per unit time to the erythropoietin-producing tissue and thus reduces the stimulus for increased production of the hormone. 

While this concept for the control of erythropoiesis is generally accepted, there are at present insufficient data to determine quantitative relationships among the variables involved. In addition, some auxiliary systems must be included to describe fully the erythropoietic response to stress such as hypoxia. The performance of the respiratory system and the relationships expressed by the oxyhemoglobin dissociation curve affect the oxygenation state of the blood. Blood volume, and in particular plasma volume, affect hemoglobin concentration which limits the amount... 

The constants Ke and K7 were selected to produce a viscosity factor of 1.0 for a particular hematocrit (Hctk) and a preselected Vi when the hematocrit is 1.0. The viscosity factor has no effect when the hematocrit is less than Hctk (normally 0.5) and maximum effect when the hematocrit equals 1. The viscosity effect was incorporated into the erythropoietic feedback system by multiplying Vi by the oxyhemoglobin concentration to produce an effective oxyhemoglobin concentration. This effective oxyhemoglobin concentration was then used to determine the rate of erythropoietin release as described earlier. 

Lead hematotoxicity is not only a toxic endpoint of Pb exposure in humans and animals but also provides biomarkers of Pb exposures via early toxic effects on the heme and erythropoietic pyrimidine biosynthesis pathways. Although heme biosynthesis is largely considered here in terms of heme production for utilization in hemoglobin, it is a critical cofactor for diverse metabolic processes, including in the cytochromes and for the 1-hydroxylase enzyme system responsible for generating the hormonal form... 

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