Erythropoiesis control

Maintenance of red cell volume is critical to having an adequate oxygen supply to the tissues [10]. Healthy individuals finely balance erythropoiesis and erythrocyte loss and maintain constant hematocrit. The glycoprotein hormone erythropoietin is the principal controller of the homeostatic mechanism that links tissue oxygen delivery to red cell production. While hypothesized as early as 1863, unequivocal evidence of erythropoietin was first published in 1953. A few years later, scientists showed that animals subjected to bilateral nephrectomy were unable to mount an erythropoietin response to hypoxia. Indeed, the kidneys produce about 90% of circulating erythropoietin. 

As well reviewed elsewhere [2], the control exerted by 5a-reduced steroids on erythropoiesis is best explained by transcriptional control of the erythropoietin gene. Certainly, such androgens are actively concentrated in the nuclear chromatin of bone marrow, both in vivo and in vitro. By contrast, the situation is entirely different with respect to 5/3-reduced steroids. In the embryonic and fetal organs of many animals, aetiocholanolone or 5/3-DHT regulate the appearance of a 5 cap-recognition protein, without which the translation of the mRNAs for haemoglobin E (embry-... 

Eckardt, K.U. (1994). Erythropoietin Oxygen-dependent control of erythropoiesis and its failure in renal disease. Nephron 67 7-23. 

Q4 When the supply of iron is greatly diminished, haemoglobin synthesis is restricted. Erythropoiesis continues and is controlled by erythropoietin from the kidney. Release of this hormone is increased in anaemia, in response to a reduced concentration of circulating haemoglobin. The bone marrow will then be stimulated to produce more red cells, but of smaller size and with smaller haemoglobin content a blood film may show red cells of unequal sizes this is known as anisocytosis. 

Production of RBCs is controlled by erythropoietin from the kidney. Erythropoiesis occurs mainly in red bone marrow of the long bones, sternum and pelvis of the adult. Newly formed red cells enter the circulation as reticulocytes, recognizable because of the inclusion of ribosomes and mitochondria in their cytoplasm. 

Singh FI, Reed J, Noble S,Cangiano JL,Van WyckDB. Effect of intravenous iron sucrose in peritoneal dialysis patients who receive erythropoiesis-stimulating agents for anemia A randomized, controlled trial. Clin J Am Soc Nephrol 2006 1 475-482. 

Biosynthesis of sterols and of dolichol are independently controlled in developing rat brain [214], in maturing mouse spermatocytes [215] and in mouse spleen cells during phenylhydrazine-induced erythropoiesis [216]. 

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. 

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... 

Figure 1. Block diagram of a model for the control of erythropoiesis (HbO), oxyhemoglobin concentration Vi, viscosity factor (HbO), effective oxyhemoglobin concentration R, rate of erythropoietin release (E), plasma erythropoietin concentration E0, normal plasma erythropoietin concentration V , distribution volume for erythropoietin P, rate of hemoglobin production MT, erythrocyte maturation time L, rate of hemoglobin loss TH, total circulating hemoglobin (Hb), blood hemoglobin concentration Vb, blood volume Vp, plasma volume Vp0, normal plasma volume Vpf, steady-state hypoxic plasma volume MCV, mean corpuscular volume MCH, mean corpuscular hemoglobin k, constant...

In summary, a mathematical model has been used to investigate the role of parameters and relationships in producing a response similar to available experimental data. As a result of this work, several questions have been raised concerning the behavior of various components of the system. Thus the model has successfully served as a tool to allow confirming some ideas, questioning of others, and stimulating thought on the various relationships and interaction of the components and subsystems involved in the control of erythropoiesis. 

In response to hypoxia, or low oxygen levels, cells try to restore homeostasis through regulation of cellular metabolism, erythropoiesis, angiogenesis, and balancing decisions between survival and cell death [1]. As part of adaptation to their local microenvironment, most solid tumors have bypassed the normal cellular controls that regulate these processes [2]. The hypoxia-inducible factor (HIF)-la transcription factor is a master regulator of the hypoxic response in... 

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