\ W/ Intermediate normoblast t
\ Late normoblast
normal erythrocytes are termed macrocytes; smaller-than-normal erythrocytes are referred to as microcytes. Poikilo-cytosis is the presence of irregularly shaped erythrocytes. Burr cells are spiked erythrocytes generated by alterations in the plasma environment. Schistocytes are fragments of red cells damaged during blood flow through abnormal blood vessels or cardiac prostheses.
The hemoglobin content of erythrocytes is also reflected in the staining pattern of cells on dried films. Normal cells appear red-orange throughout, with a very slight central pallor as a result of the cell shape. Hypochromic cells appear pale with only a ring of deeply colored hemoglobin on the periphery. Other pathological variations in red cell appearance include spherocytes—small, densely staining red cells with loss of biconcavity as a result of congenital or acquired cell membrane abnormalities,- and target cells—which have a densely staining central area with a pale surrounding area. Target cells are thin but bulge in the middle, unlike normal erythrocytes. This alteration is a consequence of hemoglobinopathies, mutations in the structure of hemoglobin. Target cells are observed in liver disease and after splenectomy.
Nucleated red cells are normally not seen in peripheral blood because their nuclei are lost before they move from the bone marrow into the blood. However, they appear in many blood and marrow disorders, and their presence can be of diagnostic significance. One type of nucleated red cell, the normoblast (see Fig. 11.4), is seen in several types of anemias, especially when the marrow is actively responding to demand for new erythrocytes. In seriously ill patients, the appearance of normoblasts in peripheral blood is a grave prognostic sign preceding death, often by several hours. Another nucleated erythrocyte, the megaloblast, is seen in peripheral blood in pernicious anemia and folic acid deficiency.
Erythrocyte Destruction. Red cells circulate for about 120 days after they are released from the marrow. Some of the senescent (old) red cells break up (hemolyze) in the bloodstream, but the majority are engulfed by macrophages in the monocyte-macrophage system. The hemoglobin released on destruction of red cells is metabol-ically catabolized and eventually reused in the synthesis of new hemoglobin. Hemoglobin released by red cells that lyse in the circulation either binds to haptoglobin, a protein in plasma, or is broken down to globin and heme. Heme binds a second plasma carrier protein, hemopexin, which, like haptoglobin, is cleared from the circulation by macrophages in the liver. In the macrophage, released hemoglobin is first broken into globin and heme. The globin portion is catabolized by proteases into constituent amino acids that are used in protein synthesis. Heme is broken down into free iron (Fe3 + ) and biliverdin, a green substance that is further reduced to bilirubin (see Chapter 27).
Iron Recycling. Most of the iron needed for new hemoglobin synthesis is obtained from the heme of senescent red cells. Iron released by macrophages is transported in the ferric state in plasma bound to the iron transporting protein, transferrin. Cells that need iron (e.g., for heme synthesis) possess membrane receptors to which transferrin binds. The receptor-bound transferrin is then internalized. The iron is released, reduced intracellularly to the ferrous state, and either incorporated into heme or stored as ferritin, a complex of protein and ferrous hydroxide. Iron is also stored as ferritin by macrophages in the liver. A portion of the ferritin is catabolized to hemosiderin, an insoluble compound consisting of crystalline aggregates of ferritin. The accumulation of large amounts of hemosiderin formed during periods of massive hemolysis can result in damage to vital organs, including the heart, pancreas, and liver.
The recycling of iron is quite efficient, but small amounts are continuously lost. Iron loss increases substantially in women during menstruation. Iron stores must be replenished by dietary uptake. The majority of iron in the diet is derived from heme in meat ("organic iron"), but iron can also be provided by the absorption of inorganic iron by intestinal epithelial cells. In these cells, iron attached to heme is released and reduced to the ferrous form (Fe2+) by intracellular flavoprotein. The reduced iron (both released from heme and absorbed as the inorganic ion) is transported through the cytoplasm bound to a transferrin-like protein. When it is released to the plasma, it is oxidized to the ferric state and bound to transferrin for use in heme synthesis.
Platelets are irregularly shaped, disk-like fragments of the membrane of their precursor cell, the megakaryocyte. Megakaryocytes shed platelets in the bone marrow sinusoids. From there the platelets are released to the blood, where they function in hemostasis. Several factors stimulate megakaryocytes to release platelets, including the hormone thrombopoietin, which is generated and released into the bloodstream when the number of circulating platelets drops. Platelets have no defined nucleus. They are one fourth to one third the size of erythrocytes. Platelets possess physiologically important proteins, stored in intra-cellular granules, which are secreted when the platelets are activated during coagulation. The role of platelets in blood clotting is discussed below.
Each of the three general types of leukocytes—myeloid, lymphoid, and monocytic—follows a separate line of development from primitive cells (see Fig. 11.2). Mature cells of the myeloid series are termed granulocytes, based on their appearance after staining with polychromatic dyes, such as Wright's stain. While monocytes and lymphocytes may also possess cytoplasmic granules, they are not clearly visualized with commonly used stains. Therefore, monocytes and lymphocytes are often referred to as agranular leukocytes.
The nuclei of most mature granulocytes are divided into two to five oval lobes connected by thin strands of chromatin. This nuclear separation imparts a multinuclear appearance to granulocytes, which are, therefore, also known as polymorphonuclear leukocytes. Three distinct types of granulocytes have been identified based on staining reactions of their cytoplasm with polychromatic dyes: neu-trophils, eosinophils, and basophils.
Neutrophils. Neutrophils are usually the most prevalent leukocyte in peripheral blood. These dynamic cells respond instantly to microbial invasion by detecting foreign proteins or changes in host defense network proteins. Neu-trophils provide an efficient defense against pathogens that have gotten past physical barriers such as the skin. Defects in neutrophil function quickly lead to massive infection— and, quite often, death.
Neutrophils are amoeba-like phagocytic cells. Invading bacteria induce neutrophil chemotaxis—migration to the site of infection. Chemotaxis is initiated by the release of chemotactic factors from the bacteria or by chemotactic factor generation in the blood plasma or tissues. Chemo-tactic factors are generated when bacteria or their products bind to circulating antibodies, by tissue cells when infected with bacteria, and by lymphocytes and platelets after interaction with bacteria.
After neutrophils migrate to the site of infection, they engulf the invading pathogen by the process of phagocytosis. Phagocytosis is facilitated when the bacteria are coated with the host defense proteins known as opsonins.
A burst of metabolic events occurs in the neutrophil after phagocytosis (Fig. 11.6). In the phagocytic vacuole or phagosome, the bacterium is exposed to enzymes that were originally positioned on the cell surface. Thus, phagocytosis involves invagination and then vacuolization of the segment of membrane to which a pathogen is bound. Membrane-bound enzymes, activated when the phagocytic vacuole closes, work in conjunction with enzymes secreted from intracellular granules into the phago-cytic vacuole to destroy the invading pathogen efficiently. One important membrane-bound enzyme, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, produces superoxide anion (O2_). Superoxide is an unstable free radical that kills bacteria directly. Superoxide also participates in secondary free radical reactions to generate other potent antimicrobial agents, such as hydrogen peroxide. Superoxide generation in the phagocytic vacuole proceeds at the expense of reducing agents oxidized in the cytoplasm. The reducing agent, NADPH, is generated from glucose by the activity of the hexose monophosphate shunt. Aerobic cells generate reduced nicotinamide adenine dinucleotide (NADH) and ATP when glucose is oxidized to carbon dioxide. The hexose monophosphate shunt operates in neutrophils and other cells when large
Steps in phagocytosis and intracellular
"killing by neutrophils. i, Cell-surface receptors, including those for exposed opsonins, sense invading pathogens. 2, The neutrophil plasma membrane invaginates to surround the organisms. 3, A membrane-bounded vesicle formed from the invagination of the cell membrane, called a phagosome, traps the bacteria inside the neutrophil. 4, Potent metabolic processes are activated to kill the ingested microbes, including activation of the respiratory burst, resulting in the generation of potent oxidants within the phagosome, and the secretion of bacteria-killing enzymes into the phagosome from neutrophil granules.
amounts of NADPH are needed to maintain intracellular reducing activity.
Oxygen reduction by the NADPH oxidase that generates superoxide in neutrophils is driven by an increased availability of NADPH after phagocytosis:
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