The total mass of RBCs in the circulatory system is regulated within narrow limits, and thus (1) an adequate number of RBCs are always available to provide sufficient transport of oxygen from the lungs to the tissues, yet (2) the cells do not become so numerous that they impede blood flow. This control mechanism is diagrammed in Figure 1 and is described in the following sections.

Fig1. Function of the erythropoietin mechanism to increase  production of red blood cells when tissue oxygenation decreases. 

Tissue Oxygenation Is the Most Essential Regulator of Red Blood Cell Production. Conditions that decrease the quantity of oxygen transported to the tissues ordinarily increase the rate of RBC production. Thus, when a person becomes extremely anemic as a result of hemorrhage or any other condition, the bone marrow begins to produce large quantities of RBCs. Also, destruction of major portions of the bone marrow, especially by x-ray therapy, causes hyperplasia of the remaining bone marrow, in an attempt to supply the demand for RBCs in the body.

At very high altitudes, where the quantity of oxygen in the air is greatly decreased, insufficient oxygen is trans ported to the tissues and RBC production is greatly increased. In this case, it is not the concentration of RBCs in the blood that controls RBC production but the amount of oxygen transported to the tissues in relation to tissue demand for oxygen.

Various diseases of the circulation that decrease tissue blood flow, particularly those that cause failure of oxygen absorption by the blood as it passes through the lungs, can also increase the rate of RBC production. This result is especially apparent in prolonged cardiac failure and in many lung diseases because the tissue hypoxia resulting from these conditions increases RBC production, with a resultant increase in hematocrit and usually total blood volume as well.

Erythropoietin Stimulates Red Blood Cell Production, and Its Formation Increases in Response to Hypoxia. The principal stimulus for RBC production in low oxygen states is a circulating hormone called erythropoietin, a glycoprotein with a molecular weight of about 34,000. In the absence of erythropoietin, hypoxia has little or no effect to stimulate RBC production. However, when the erythropoietin system is functional, hypoxia causes a marked increase in erythropoietin production and the erythropoietin, in turn, enhances RBC production until the hypoxia is relieved.

Erythropoietin Is Formed Mainly in the Kidneys. Normally, about 90 percent of all erythropoietin is formed in the kidneys, and the remainder is formed mainly in the liver. It is not known exactly where in the kidneys the erythropoietin is formed. Some studies suggest that erythropoietin is secreted mainly by fibroblast like interstitial cells surrounding the tubules in the cortex and outer medulla, where much of the kidney’s oxygen consumption occurs. It is likely that other cells, including the renal epithelial cells, also secrete the erythropoietin in response to hypoxia.

Renal tissue hypoxia leads to increased tissue levels of hypoxia-inducible factor–1 (HIF1), which serves as a transcription factor for a large number of hypoxia inducible genes, including the erythropoietin gene. HIF1 binds to a hypoxia response element residing in the erythropoietin gene, inducing transcription of messenger RNA and, ultimately, increased erythropoietin synthesis.

At times, hypoxia in other parts of the body, but not in the kidneys, stimulates kidney erythropoietin secretion, which suggests that there might be some nonrenal sensor that sends an additional signal to the kidneys to produce this hormone. In particular, both norepinephrine and epinephrine and several of the prostaglandins stimulate erythropoietin production.

When both kidneys are removed from a person or when the kidneys are destroyed by renal disease, the person invariably becomes very anemic because the 10 percent of the normal erythropoietin formed in other tissues (mainly in the liver) is sufficient to cause only one third to one half the RBC formation needed by the body.

Erythropoietin Stimulates Production of Proerythroblasts from Hematopoietic Stem Cells. When an animal or a person is placed in an atmosphere of low oxygen, erythropoietin begins to be formed within minutes to hours, and it reaches maximum production within 24 hours. Yet almost no new RBCs appear in the circulating blood until about 5 days later. From this fact, as well as from other studies, it has been determined that the important effect of erythropoietin is to stimulate the production of proerythroblasts from hematopoietic stem cells in the bone marrow. In addition, once the proerythroblasts are formed, the erythropoietin causes these cells to pass more rapidly through the different erythroblastic stages than they normally do, further speeding up the production of new RBCs. The rapid production of cells continues as long as the person remains in a low oxygen state or until enough RBCs have been produced to carry adequate amounts of oxygen to the tissues despite the low level of oxygen; at this time, the rate of erythropoietin production decreases to a level that will maintain the required number of RBCs but not an excess.

In the absence of erythropoietin, few RBCs are formed by the bone marrow. At the other extreme, when large quantities of erythropoietin are formed and if plenty of iron and other required nutrients are available, the rate of RBC production can rise to perhaps 10 or more times normal. Therefore, the erythropoietin mechanism for controlling RBC production is a powerful one.

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مواضيع ذات صلة

Hemoglobin Formation

Stages of Differentiation of Red Blood Cells

Genesis of Blood Cells

Role of the Nervous System in Rapid Control of Arterial Pressure

Special Features of Nervous Control of Arterial Pressure

The Lymphatic System Plays A Key Role in Controlling Interstitial Fluid Protein Concentration, Volume, and Pressure

Formation of Lymph

Rate of Lymph Flow

Exchange of Water, Nutrients, and Other Substances Between the Blood and Interstitial Fluid

Flow of Blood in the Capillaries—Vasomotion

Structure of the Microcirculation and Capillary System

Basic Principles of Circulatory Function