TRANSPORT IN HUMAN

On average, your body has about 5 liters of blood continually traveling through it by way of the circulatory system. The heart, the lungs, and the blood vessels work together to form the circle part of the circulatory system. The pumping of the heart forces the blood on its journey. The body's circulatory system really has three distinct parts: pulmonary circulation, coronary circulation, and systemic circulation. Or, the lungs (pulmonary), the heart (coronary), and the rest of the system (systemic). Each part must be working independently in order for them to all work together.

BLOOD
The human body contains about 5 litres of blood. Blood consists of: 1. A pale yellow fluid called plasma 2. Red blood cells 3. White blood cells 4. Platelets, which are fragment of cells The blood cells and platelets make up about 45% of blood volume and the plasma about 55%.

PLASMA
Blood plasma is a pale yellow fluid. It's total volume in a normal adult is around 2.5 to 3 litres. Plasma contains clotting agents and on exposure to air it will form a clot. The clear fluid exuded from clotted whole blood and clotted plasma is called serum. The quantities of the constituents of serum are the same as those for plasma minus the small Constituent % amount of clotting agents, such as fibrinogen, Water 90.0 destroyed during the clotting process. Protein 0.8
0.9 Blood plasma comprises around 20 % of the Inorganic ions 1.1 boy's extracellular fluid and is very similar in Organic substances The table show the constituent of plasma composition to interstitial fluid. The main difference being the protein content. Interstial fluid contains much less protein at around 2% by volume. This is because most of the plasma protein molecules are too large to pass through the capillary walls into the interstitial area. The small amount of protein which does leak through is eventually taken up by the lymph and then ultimately returned to the blood.

Plasma proteins form 3 major groups and have these various functions The three groups are : albumin (60% of total plasma protein) fibrinogen (4% of total plasma protein) globulins (36% of total plasma protein) further fractions (alpha, beta and gamma) can be distinguished within the globulin group. The relative proportions of plasma proteins can vary in certain diseases and electrophoretic tracings showing such changes can be a useful diagnostic aid. Most of the plasma proteins are produced by the liver. The gamma globulins are produced by cells of the body's immune system. Albumin is the smallest of the plasma proteins and is just small enough to pass through capillary walls. In normal circumstances this leads to the small amount of leakage into the interstitial fluid already mentioned. In severe kidney disease large amounts of albumin are able to leak out

through the damaged kidney tubules and can be detected in the urine. Because the liver can quickly and easily replace lost albumin the body may lose large amounts of the protein without showing signs of disease. Functions of the plasma proteins include : Intravascular osmotic effect. This is important in maintaining fluid and electrolyte balance and is discussed more fully in those sessions. Contributes to the viscosity of the plasma Transport of insoluble substances around the body by allowing them to bind to protein molecules. Protein reserve for the body Clotting this is discussed further in sessions on wounds and wound healing Inflammatory response again discussed further in the sessions on the immune system.

Protection from infection the gamma globulins function as antibodies and their role is discussed more fully in the sessions on the immune system. Maintenance of the acid-base balance. Again this is explored in more detail in the session on fluid and electrolyte balance. The blood plasma contains inorganic ions which are important in regulating cell function and maintaining homeostasis. For example depletion of potassium may occur following severe diarrhea and vomiting. Potassium affects cell excitability and severe loss will cause muscle weakness and abnormalities of the cardiac impulse. The same problems may result in severe sodium depletion. Lack of sodium in the plasma will result in a reduction in the overall volume of extracellular fluid which in turn leads to a drop in blood pressure causing weakness, dizziness, mental confusion and fainting.

In addition to CONCENTRATION ION SYMBOL (mmol/l) proteins and inorganic Sodium Na+ 135-146 ions the blood plasma Potassium K+ 3.5-5.2 carries a wide range Calcium Ca++ 2.1-2.7 Chloride Cl98-108 of substances in Hydrogen Carbonate HCO323-31 transit to various Phosphate PO4-0.7-1.4 tissues throughout The above table shows the normal range of concentration of inorganic ions in the the body. These include blood plasma. dissolved gases (mainly carbon dioxide). Oxygen is not very soluble in water hence the need for the specialized oxygen transporting red blood cells. Nutrients are carried in the blood plasma. The most abundant being glucose which is the primary source of energy for cell metabolism. Other nutrients in transit in the plasma include amino acids, fatty acids, triglycerides, cholesterol and vitamins. Waste products of metabolism are also transported by the plasma including urea, uric acid and cratinine from the kidneys and bilirubin from the gall bladder.

Hormones, such as cortisol and thyroxine are also transported around the body in plasma attached to plasma proteins. Other substances can be transported in the plasma the most obvious examples being drugs and alcohol.

RED BLOOD CELLS

Erythrocytes in a peripheral blood smear derive their reddish color from the protein haemoglobin, and usually appear round or oval with a pale-staining centre region. They are biconcave in shape, as seen arrowed in this scanning electron microscopic image. This shape increases the cell's surface area and facilitates diffusion of O2(oxygen gas) and CO2(carbon dioxide gas) into or out of the cell. Likewise, the lack of nuclei and organelles contribute to increased haemoglobin content and gas-carrying capacity. Cell shape is maintained by a cytoskeleton composed of several proteins (spectrin, actin, etc.), but normal erythrocytes must be very flexible. They become deformed when flowing through capillaries and narrow slits in the spleen (see section on the lymphatic system).

They become deformed when flowing through capillaries and narrow slits in the spleen (see section on the lymphatic system). As mentioned before red blood cells (RBC's) or erythrocytes are highly specialized for the transport of oxygen. The nucleus is lost in the process of red blood cell formation in the bone marrow. This process is known as haemopoeisis. During this process all of the internal cell organelles are also degraded thus allowing the RBC to carry more haemoglobin. As you can see by the above photomicrograph red blood cells in life are highly deformable and are able to squeeze through minute gaps. All red blood cells have a limited life span of around 100 to 120 days and must therefore be continuously replaced. Mature red blood cells are unable to synthesize new enzymes to replace those lost during normal cell metabolic processes due to their lack of inner organelles. It is probable that as the RBC's age they become less deformable due to diminishing efficiency of ion pumping mechanisms and as a result they are no longer able to pass through the filtering system of the spleen and are thus removed by being literally eaten up by white blood cells in a process known as phagocytosis.

Aged RBC's are removed by the spleen, liver and the bone marrow. Although it appears that the spleen is most active their relative importance to each other under normal circumstances is uncertain. Certainly we know that individuals who have lost their spleen are able to function normally with few limitations. RBC's have a specialized cytoskeleton in order to maintain their shape. This composes of an actin/spectrin network held together by another protein call ankyrin. A condition known as Hereditary Spherocytosis is caused by an abnormal arrangement of the internal This slide shows a blood sample from a person with hereditary spherocytosis cytoskeleton of RBC's. In this condition the ankyrin binding of spectrin is absent. As a result the cell membrane is not adequately braced and is too easily deformed. Individuals who suffer the condition have spherical RBC's which are abnormally fragile and do not resist osmotic pressure.

Haemoglobin (Hb) is a red colored protein pigment found within RBC's. It is formed during haemopoesis mature red cells are unable to produce further supplies of haemoglobin. It consists of two basic parts: the iron containing pigment haem the protein globin The main function of haemoglobin is oxygen uptake in the lungs, carriage in the RBC's and release in other tissues. The process is dependent on the partial pressure of oxygen at these sites. Haemoglobin also carries CO2 as carbaminohaemoglobin. Haemoglobin is also a powerful buffering agent in the maintenance of blood pH levels. The picture above show the haemoglobin molecule All of these functions are discussed in greater detail in the appropriate sections on respiration and fluid and electrolyte balance.

The most common blood disorder is anaemia in which an inadequate haemoglobin supply causes weakness, pallor and sometimes, breathlessness. It may be the result of impaired RBC functioning or increased RBC destruction. The most common cause is iron deficiency. Iron is essential for the formation of haemoglobin and a deficiency in the diet means that cells formed in the bone marrow are pale-staining (hypochromic) and smaller than normal (microcytic). Excessive red cell destruction usually occurs if the red cells produced are structurally abnormal in some way and are therefore liable to damage in their passage around the body. Any such cells are removed prematurely and in excess by the spleen resulting in haemolytic anaemia this is often due to a genetic abnormality such as Hereditary Spherocytosis or Sickle Cell Anaemia.

WHITE BLOOD CELLS

There are five main types of White Blood Cell White blood cells use the blood as a means of transport from their origination in the bone marrow to their major sites of activity. The majority of the functions of the white blood cells occur when they leave the blood circulation to enter other body tissues. There are 5 types of white blood cell: neutrophils 40 - 75 % eosinophils 5 % basophils 0.5 % lymphocytes 20 - 50 % monocytes 1 - 5 % The figures show the relative proportions of the different types of white blood cell. The reason for the range of figures shown is that the requirement for different types of white blood cell will vary from time to time.

Neutrophils, eosinophils and basophils are collectively known as granulocytes due to prominent granules in their cytoplasm. Lymphocytes and monocytes are classed as white blood cells because they are a constituent of blood and ultimately originate from the bone marrow. However they are mainly found in structures such as the lymph nodes and the spleen.

NEUTROPHILS
Neutrophils are the most common granulocyte. They have segmented nuclei, typically with 2 to 5 lobes connected together by thin strands of chromatin which can be difficult to see; the cell may thus appear to have multiple nuclei. The nuclear chromatin is condensed into coarse clumps.

Small numbers of immature neutrophils or band form neutrophils may be seen in a blood smear. These are incompletely segmented and often have a 'C-shaped' nucleus. The cytoplasm of neutrophils contains 3 types of granule: Primary granules are non-specific and contain lysosomal enzymes, defensins, and some lysozyme. The granules are similar to lysosomes. They stain aviolet color when prepared with Wright's stain which is commonly used in studying the blood. The enzymes produce hydrogen peroxide which is a powerful anti-bacterial agent. Secondary granules are specific to neutrophils and stain light pink ('neutral stain'). They contain collagenase, to help the cell move through connective tissue, and lactoferrin, which is toxic to bacteria and fungi. Tertiary granules have only recently been recognised. It is thought that they produce proteins which help the neutrophils to stick to other cells and hence aid the process of phagocytosis.

Once in the area of infection neutrophils respond to chemicals (called chemotaxins which are released by bacteria and dead tissue cells) and move towards the area of highest concentration. Here they begin the process of phagocytosis in which they engulf the offending cells and destroy them with their powerful enzymes. Because this process consumes so much energy the neutrophils glycogen reserves are soon depleted and they die soon after phagocytosis. When the cells die their contents are released and the remnants of their enzymes cause liquefaction of closely adjacent tissue. This results in an accumulation of dead neutrophils, tissue fluid and abnormal materials known as pus.

EOSINOPHILS
Eosinophils have a bi-lobed nucleus. They increase greatly in many types of parasitic infection and defense against the larvae of parasitic worms and unicellular organisms seems to be one of their primary functions. The granules of eosinophils contain a substance called MBP (major basic protein) which is toxic to many parasitic larvae.

Eosinophils also have surface receptors for the antibody immunoglobulin E (IgE). These receptors are not found in neutrophils and again this is thought to reflect their role in parasitic infection. They also increase in number in some allergic states. For example their numbers increase in the nasal and bronchial mucosal linings in hay fever and asthma and in some adverse drug reactions. It is thought that they may neutralise the effect of histamine. Eosinophils also have a marked diurnal variation with their numbers being highest in the morning and lowest in the afternoon although why this is the case is at present unclear.

BASOPHILS
Basophils are the least common of the white blood cells. They are characterised by their large cytoplasmic granules which obscure the nucleus in stained preparations as shown in the right.

They have many similarities with mast cells and actually become mast cells on leaving the blood and entering surrounding tissues. Both basophils and mast cells have highly specific receptors for IgE produced in response to various allergens. Response to specific allergens is rapid and results in expulsion of the cells granular contents which contain histamines and other vasodilating agents. This results in the reaction known as immediate hypersensitivity. This can result in hay fever, some forms of asthma, urticaria (nettle rash) and most seriously anaphylactic shock.

MONOCYTES
Monocytes are the largest cell type seen in blood smears. Their nuclei are not multilobular like granulocytes, but may be deeply indented or U-shaped, with reticular-appearing chromatin.

The cytoplasm of monocytes contains numerous lysosomal granules which give it a uniform grayish-blue "ground-glass" appearance. They form part of a cell network known as the monocyte-macrophage system. This comprises bone marrow precursor cells (monoblasts and promonocytes), circulating monocytes and both free and fixed tissue macrophages. Monocytes eventually leave the bloodstream to become tissue macrophages which remove dead cell debris as well as attacking organisms such as Tubercule Bacilli (which causes TB) and some fungi. Neither of these can be dealt with effectively by the neutrophils. Unlike neutrophils monocytes are able to reolace their lysosomal contents and are thought to have a much longer active life. Cells which derive from monocytes include the: Kupffer cells of the liver sinus lining cells of the spleen and lymph nodes pulmonary alveolar macrophages free macrophages in the synovial, pleural and peritoneal fluid dendritic antigen presenting cells

LYMPHOCYTES
These are the most numerous white blood cell in young children and the second most numerous in older children and adults. Their numbers increase in response to viral infections. Lymphocytes are distinguished by having a deeply staining nucleus which may be eccentric in location, and a relatively small amount of cytoplasm. The small ring of cytoplasm contains numerous ribosomes and stains blue. Small numbers of lysosomal granules may also be seen in the cytoplasm of some lymphocytes.

In this image, a lymphocyte and a dumbbell-shaped Red Blood Cell (RBC) can be seen in the lumen of a small blood vessel. Note the pseudopodia and the small amount of cytoplasm of the lymphocyte. The two major types of lymphocyte found in the blood are B-lymphocytes and T-lymphocytes. Both have different but linked roles in the generation of specific immune response. The small mature lymphocytes circulating in the blood are constantly sampling their environment for foreign materials. Their role is discussed more fully in the sessions on the immune system. Increased numbers of white blood cells appear in the peripheral blood in a variety of disorders. The most important and most life threatening disorders are the leukaemias. Here there is a malignant proliferation of white cell precursors in the bone marrow.

This produces vast numbers of white blood cells and their precursors which then spill over into the blood stream. The various types of leukaemia are classified according to the cell line involved (granulocytic, monocytic, lymphocytic etc.) and also according to their degree of malignancy. In chronic leukaemias the proproliferating cells are more differentiated (i.e. they have more closely reached maturity) whereas in acute leukaemias the proliferating cells are the virtually undifferentiated precursor cells such as lymphoblasts in acute lymphoblastic leukaemia.

This image show a blood sample from a patient suffering from acute monocytic leukaemia.

The image on the right shows a slide of a blood smear from a patient suffering from acute lymphoblastic leukaemia. Note the prolifretaion of lymphoblastic cells as compared to other more normal blood slides in these pages.

The image on the right shows a blood smear from apatient suffering from chronic lymphocytic leukaemia. Note the lymphocytes (x) and smudge cells (y).

The slide on the right shows a blood sample taken from a patient suffering chronic myelogenous leukaemia. Note the proliferation of various types of white blood cell.

PLATELETS
Blood platelets, or thrombocytes, are not true cells, but rather cytoplasmic fragments of a large cell in the bone marrow, the megakaryocyte. The central portion of a platelet stains purple with Wright's stain and is referred to as the granulomere. The peripheral portion stains clear and is The image above shows a number of platelets stained purple associated with some RBC's. called the hyalomere. Platelet contents include glycogen granules, the open canalicular system (OCS), which is composed of canaliculi formed from invaginations of the platelet plasma membrane, mitochondria, occasional Golgi elements and ribosomes. Platelets have several types of membrane-bound granules which contain a number of constituents including fibrinogen and several growth factors (e.g., PDGF).

Platelet activation occurs when injury to the vessel wall exposes subendothelial components, especially collagen. Platelets adhere to the damaged area and become cohesive to other platelets. This aggregation leads to the formation of a platelet plug, which prevents further blood loss and allows the repair process to begin. The micrograph shown below shows activated platelets adhering to some damaged cells. Severe reduction in the number of circulating platelets results in a condition known as thrombocytopenia. It is a condition which causes spontaneous bleeding as a reaction to minor trauma. This is due to failure of the platelets to seal over microscopic breaches in blood vessel walls. In the skin this is manifest by a reddish-purple blotchy rash. This can be either small blotches called purpura or larger

Cytotoxic drugs used in treatment of cancers may cause this condition. It is also seen associated with acute leukaemias.