CELLS DERIVED FROM THE MYELOID LINEAGE

As shown in Figure 9.1, cells derived from common myeloid progenitors include erythrocytes, mast cells, and cells developed from myeloblasts— basophils, neutrophils, and eosinophils—as well as macrophages, which develop from monocytes. In addition, megakaryocytes give rise to thrombocytes or platelets. Another way of looking at circulating blood cells is to categorize them as erythrocytes, platelets and leukocytes. Erythrocytes are by far the most abundant circulating blood cells. Each microliter of blood contains 4-6 million erythrocytes, several hundred thousand platelets, and 4,000-6,000 leukocytes. Of the total number of leukocytes, 40%-75% are neutrophils and l%-6% are eosinophils and basophils, while mononuclear cells, which include monocytes and lymphocytes, account for 30%-50% of the total leukocytes.

The dopaminergic system in erythrocytes and platelets

Human erythrocytes have a structure of a biconcave disk with a diameter of 7 jum. They lack a nucleus and most organelles, and their average life in the circulation is 120 days. The cytoplasm of erythrocytes is rich in hemoglobin, an iron-containing, 68-kDa biomolecule that binds oxygen via its heme subunit and gives rise to the red color of the cells and blood. The cell membrane of erythrocyte is composed of a mesh of fibrous proteins that confer the cells with great flexibility and the ability to deform while traversing the narrow capillary network of the circulatory system. The erythrocyte membrane contains ion pumps that maintain high levels of intracellular potassium and low levels of calcium. The main function of erythrocytes is to carry oxygen from the lungs to the tissues and carbon dioxide, as a waste product, away from the tissues and back to the lungs.

The dopaminergic system interacts with erythrocytes at several levels. One interaction is through the stimulation of erythropoiesis in bone marrow cells [4]. Another is via the ability of erythrocytes to degrade DA, based on their high expression of catechol-O-methyltransferase (COMT), the major peripheral DA metabolizing enzyme [24]. This property of erythrocytes is of particular relevance to patients with Parkinson's disease (PD) who are treated with L-Dopa in combination with inhibitors of Dopa decarboxylase and COMT in order to maximize L-Dopa's uptake by the brain. Erythrocytes also have high expression levels of phenol sulfotransferase [25], the enzyme that catalyzes sulfo-conjugation of DA and is responsible for the generation of dopamine sulfate (DA-S), the major circulating form of DA in humans. Although mature human erythrocytes express over 200 genes that are associated with signal transduction, there is no documentation that they express any of the DARs. Yet, erythrocytes are fully capable of uptake and accumulation of DA via a saturable transporter, possibly via the choline transporter whose relationship to DAT is unclear [26].

A well-studied function of DA in erythrocytes is inhibition of apoptosis, which is normally triggered by oxidative stress, hypertonic shock, removal of extracellular Cl~, or energy depletion. To distinguish between apoptosis of nucleated cells and that in erythrocytes, the term "eryptosis" was coined [27]. In this study, treatment of erythrocytes with ionomycin, a Ca2+ ionophore, led to cell shrinkage, cell membrane blebbing and breakdown of membrane phosphatidylserine asymmetry, all typical features of apoptosis in nucleated cells. Several catecholamines, including DA, inhibited the activated entry of Ca2+ into erythrocytes by removal of Cl-, thus preventing the increase of cytosolic Ca2+ activity that causes cell shrinkage. The authors concluded that the effect of catecholamines on apoptosis is due to a direct or an indirect inactivation of the calcium-permeable, nonse- lective cation conductance.

The above results uncovered a novel mechanism by which catecholamines can modify the half-life of erythrocytes as well as their adhesion to the vascular wall. The antagonistic action of DA may also operate during several stress situations that increase erythrocyte apoptosis, all of which occur by the activation of a Ca2+-permeable nonselective cation conductance. The effects of DA on eryptosis do not appear to involve a DAR and, thus, may be receptor independent.

Platelets are small in size, 2-3 pm in the greatest diameter, and have no cell nucleus. They are derived from megakaryocytes of the bone marrow and enter the circulation as fragments of cytoplasm [28]. Activated platelets have cell membrane projections covering their surface. The average life span of circulating platelets is 8-9 days and is controlled by an internal apoptotic regulating pathway that involves BcI-xl- Old platelets are destroyed by phagocytosis in the spleen and liver. A major function of platelets is in hemostasis, or the process of stopping bleeding at the site of interrupted endothelium. Platelets accumulate at the site of vascular injury and plug the hole after undergoing several sequential events: adhesion, activation, and aggregation. Formation of the platelet plug (primary hemostasis) is accompanied by activation of the coagulation cascade, resulting in fibrin deposition and linking (secondary hemostasis).

Human platelets express D2R, D3R, and D5R [29], as well as DAT [30]. Depending upon the dose used, variable effects of DA have been reported on platelet aggregation [31]. In the micromolar range, DA induces platelet aggregation and inhibits epinephrine (Epi)-induced aggregation. An enhancing effect of DA on ADP-induced platelet aggregation is also seen in the nanomolar range. At veiy high concentrations (outside the physiological range), DA inhibits ADP-induced platelet aggregation. More detail on DA and wound healing is presented in Chapter 11.

 
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