The Lymphatic System

Functions of the lymphatic system:

1) to maintain the pressure and volume of the extracellular fluid by returning excess water and dissolved substances from the interstitial fluid to the circulation.

2) lymph nodes and other lymphoid tissues are the site of clonal production of immunocompetent  lymphocytes and macrophages in the specific immune response.
 

Filtration forces water and dissolved substances from the capillaries into the interstitial fluid. Not all of this water is returned to the blood by osmosis, and excess fluid is picked up by lymph capillaries to become lymph. From lymph capillaries fluid flows into lymph veins (lymphatic vessels) which virtually parallel the circulatory veins and are structurally very similar to them, including the presence of semilunar valves.

The lymphatic veins flow into one of two lymph ducts. The right lymph duct drains the right arm, shoulder area, and the right side of the head and neck. The left lymph duct, or thoracic duct, drains everything else, including the legs, GI tract and other abdominal organs, thoracic organs, and the left side of the head and neck and left arm and shoulder.

These ducts then drain into the subclavian veins on each side where they join the internal jugular veins to form the brachiocephalic veins.

Lymph nodes lie along the lymph veins successively filtering lymph. Afferent lymph veins enter each node, efferent veins lead to the next node becoming afferent veins upon reaching it.

Lymphokinetic motion (flow of the lymph) due to:

1) Lymph flows down the pressure gradient.

2) Muscular and respiratory pumps push lymph forward due to function of the semilunar valves.

Other lymphoid tissue: 

        1. Lymph nodes: Lymph nodes are small encapsulated organs located along the pathway of lymphatic vessels. They vary from about 1 mm to 1 to 2 cm in diameter and are widely distributed throughout the body, with large concentrations occurring in the areas of convergence of lymph vessels. They serve as filters through which lymph percolates on its way to the blood. Antigen-activated lymphocytes differentiate and proliferate by cloning in the lymph nodes. 

        2. Diffuse Lymphatic Tissue and Lymphatic nodules: The alimentary canal, respiratory passages, and genitourinary tract are guarded by accumulations of lymphatic tissue that are not enclosed by a capsule (i.e. they are diffuse) and are found in  connective tissue beneath the epithelial mucosa. These cells intercept foreign antigens and then travel to lymph nodes to undergo differentiation and proliferation. Local concentrations of lymphocytes in these systems and other areas are called lymphatic nodules. In general these are single and random but are more concentrated in the GI tract in the ileum, appendix, cecum, and tonsils. These are collectively called the Gut Associated Lymphatic Tissue (GALT). MALT (Mucosa Associated Lymphatic Tissue) includes these plus the diffuse lymph tissue in the respiratory tract. 

        3. The thymus:   The thymus is where immature lymphocytes differentiate into T-lymphocytes. The thymus is fully formed and functional at birth. Characteristic features of thymic structure persist until about puberty, when lymphocyte processing and proliferation are dramatically reduced and eventually eliminated and the thymic tissue is largely replaced by adipose tissue. The lymphocytes released by the thymus are carried to lymph nodes, spleen, and other lymphatic tissue where they form colonies. These colonies form the basis of T-lymphocyte proliferation in the specific immune response. T-lymphocytes survive for long periods and recirculate through lymphatic tissues.

        The transformation of primitive or immature lymphocytes into T-lymphocytes and their proliferation in the lymph nodes is promoted by a thymic hormone called thymosin.  Ocassionally the thymus persists and may become cancerous after puberty and and the continued secretion of thymosin and the production of abnormal T-cells may contribute to some autoimmune disorders.  Conversely, lack of thymosin may also allow inadequate immunologic surveillance and thymosin has been used experimentally to stimulate T-lymphocyte proliferation to fight lymphoma and other cancers. 

        4. The spleen: The spleen filters the blood and reacts immunologically to blood-borne antigens. This is both a morphologic (physical) and physiologic process. In addition to large numbers of lymphocytes the spleen contains specialized vascular spaces, a meshwork of reticular cells and fibers, and a rich supply of macrophages which monitor the blood.  Connective tissue forms a capsule and trabeculae which contain myofibroblasts, which are contractile.  The human spleen holds relatively little blood compared to other mammals, but it has the capacity for contraction to release this blood into the circulation during anoxic stress. White pulp in the spleen contains lymphocytes and is equivalent to other lymph tissue,  while red pulp contains large numbers of red blood cells that it filters and degrades.

    The spleen functions in both immune and hematopoietic systems. Immune functions include: proliferation of lymphocytes, production of antibodies, removal of antigens from the blood. Hematopoietic functions include: formation of blood cells during fetal life, removal and destruction of aged, damaged and abnormal red cells and platelets, retrieval of iron from hemoglobin degradation, storage of red blood cells.

White Blood Cells (leukocytes)

White blood cells

• are much less numerous than red (the ratio between the two is around 1:700),
• have nuclei,
• participate in protecting the body from infection,
• consist of lymphocytes and monocytes with relatively clear cytoplasm, and three types of granulocytes, whose cytoplasm is filled with granules.

Lymphocytes: There are several kinds of lymphocytes, each with different functions to perform , 25% of wbc The most common types of lymphocytes are

• B lymphocytes ("B cells"). These are responsible for making antibodies.
• T lymphocytes ("T cells"). There are several subsets of these:
  • inflammatory T cells that recruit macrophages and neutrophils to the site of infection or other tissue damage
  • cytotoxic T lymphocytes (CTLs) that kill virus-infected and, perhaps, tumor cells
  • helper T cells that enhance the production of antibodies by B cells

Although bone marrow is the ultimate source of lymphocytes, the lymphocytes that will become T cells migrate from the bone marrow to the thymus where they mature. Both B cells and T cells also take up residence in lymph nodes, the spleen and other tissues where they

• encounter antigens;
• continue to divide by mitosis;
• mature into fully functional cells.

Monocytes : also originate in marrow, spend up to 20 days in the circulation, then travel to the tissues where they become macrophages. Macrophages are the most important phagocyte outside the circulation. Monocytes are about 9% of normal wbc count

Macrophages are large, phagocytic cells that engulf

• foreign material (antigens) that enter the body
• dead and dying cells of the body.

Neutrophils

The most abundant of the WBCs. about 65% of normal white count  These cells spend 8 to 10 days in the circulation making their way to sites of infection etc  Neutrophils squeeze through the capillary walls and into infected tissue where they kill the invaders (e.g., bacteria) and then engulf the remnants by phagocytosis. They have two types of granules: the most numerous are specific granules which contain bactericidal agents such as lysozyme; the azurophilic granules are lysosomes containing peroxidase and other enzymes

Eosinophils : The number of eosinophils in the blood is normally quite low (0–450/µl). However, their numbers increase sharply in certain diseases, especially infections by parasitic worms. Eosinophils are cytotoxic, releasing the contents of their granules on the invader.

Basophils : rare except during infections where these cells mediate inflammation by secreting histamine and heparan sulfate (related to the anticoagulant heparin). Histamine makes blood vessels permeable and heparin inhibits blood clotting. Basophils are functionally related to mast cells.  . The mediators released by basophils also play an important part in some allergic responses such as hay fever and an anaphylactic response to insect stings.

Thrombocytes (platelets):

Thrombocytes are cellular derivatives from megakaryocytes which contain factors responsible for the intrinsic clotting mechanism. They represent fragmented cells  which contain residual organelles including rough endoplasmic reticulum and Golgi apparati. They are only 2-microns in diameter, are seen in peripheral blood either singly or, often, in clusters, and have a lifespan of 10 days.

Regulation of glomerular filtration :

1. Extrinsic regulation : 

- Neural regulation : sympathetic and parasympathetic nervous system which causes vasoconstriction or vasodilation respectively .
- Humoral regulation : Vasoactive substances may affect the GFR , vasoconstrictive substances like endothelin ,Angiotensin II , Norepinephrine , prostaglandine F2 may constrict the afferent arteriole and thus decrease GFR , while the vasodilative agents like dopamine , NO , ANP , Prostaglandines E2 may dilate the afferent arteriole and thus increase the filtration rate .

2. Intrinsic regulation : 

- Myogenic theory ( as in the intrinsic regulation of cardiac output) .
- Tubuloglomerular feedback: occurs by cells of the juxtaglomerular apparatus that is composed of specific cells of the distal tubules when it passes between afferent and efferent arterioles ( macula densa cells ) , these cells sense changes in flow inside the tubules and inform specific cells in the afferent arteriole (granular cells ) , the later secrete vasoactive substances that affect the diameter of the afferent arteriole.

Production of Hormones

The kidneys produce and interact with several hormones that are involved in the control of systems outside of the urinary system.

Calcitriol. Calcitriol is the active form of vitamin D in the human body. It is produced by the kidneys from precursor molecules produced by UV radiation striking the skin. Calcitriol works together with parathyroid hormone (PTH) to raise the level of calcium ions in the bloodstream. When the level of calcium ions in the blood drops below a threshold level, the parathyroid glands release PTH, which in turn stimulates the kidneys to release calcitriol. Calcitriol promotes the small intestine to absorb calcium from food and deposit it into the bloodstream. It also stimulates the osteoclasts of the skeletal system to break down bone matrix to release calcium ions into the blood.
 
Erythropoietin. Erythropoietin, also known as EPO, is a hormone that is produced by the kidneys to stimulate the production of red blood cells. The kidneys monitor the condition of the blood that passes through their capillaries, including the oxygen-carrying capacity of the blood. When the blood becomes hypoxic, meaning that it is carrying deficient levels of oxygen, cells lining the capillaries begin producing EPO and release it into the bloodstream. EPO travels through the blood to the red bone marrow, where it stimulates hematopoietic cells to increase their rate of red blood cell production. Red blood cells contain hemoglobin, which greatly increases the blood’s oxygen-carrying capacity and effectively ends the hypoxic conditions.
 
Renin. Renin is not a hormone itself, but an enzyme that the kidneys produce to start the renin-angiotensin system (RAS). The RAS increases blood volume and blood pressure in response to low blood pressure, blood loss, or dehydration. Renin is released into the blood where it catalyzes angiotensinogen from the liver into angiotensin I. Angiotensin I is further catalyzed by another enzyme into Angiotensin II.

Angiotensin II stimulates several processes, including stimulating the adrenal cortex to produce the hormone aldosterone. Aldosterone then changes the function of the kidneys to increase the reabsorption of water and sodium ions into the blood, increasing blood volume and raising blood pressure. Negative feedback from increased blood pressure finally turns off the RAS to maintain healthy blood pressure levels.

The Nerve Impulse

When a nerve is stimulated the resting potential changes. Examples of such stimuli are pressure, electricity, chemicals, etc. Different neurons are sensitive to different stimuli(although most can register pain). The stimulus causes sodium ion channels to open. The rapid change in polarity that moves along the nerve fiber is called the "action potential." In order for an action potential to occur, it must reach threshold. If threshold does not occur, then no action potential can occur. This moving change in polarity has several stages:

Depolarization

The upswing is caused when positively charged sodium ions (Na+) suddenly rush through open sodium gates into a nerve cell. The membrane potential of the stimulated cell undergoes a localized change from -55 millivolts to 0 in a limited area. As additional sodium rushes in, the membrane potential actually reverses its polarity so that the outside of the membrane is negative relative to the inside. During this change of polarity the membrane actually develops a positive value for a moment(+30 millivolts). The change in voltage stimulates the opening of additional sodium channels (called a voltage-gated ion channel). This is an example of a positive feedback loop.

Repolarization

The downswing is caused by the closing of sodium ion channels and the opening of potassium ion channels. Release of positively charged potassium ions (K+) from the nerve cell when potassium gates open. Again, these are opened in response to the positive voltage--they are voltage gated. This expulsion acts to restore the localized negative membrane potential of the cell (about -65 or -70 mV is typical for nerves).

Hyperpolarization

When the potassium ions are below resting potential (-90 mV). Since the cell is hyper polarized, it goes to a refractory phrase.

Refractory phase

The refractory period is a short period of time after the depolarization stage. Shortly after the sodium gates open, they close and go into an inactive conformation. The sodium gates cannot be opened again until the membrane is repolarized to its normal resting potential. The sodium-potassium pump returns sodium ions to the outside and potassium ions to the inside. During the refractory phase this particular area of the nerve cell membrane cannot be depolarized. This refractory area explains why action potentials can only move forward from the point of stimulation.

Factors that affect sensitivity and speed

Sensitivity

Increased permeability of the sodium channel occurs when there is a deficit of calcium ions. When there is a deficit of calcium ions (Ca+2) in the interstitial fluid, the sodium channels are activated (opened) by very little increase of the membrane potential above the normal resting level. The nerve fiber can therefore fire off action potentials spontaneously, resulting in tetany. This could be caused by the lack of hormone from parathyroid glands. It could also be caused by hyperventilation, which leads to a higher pH, which causes calcium to bind and become unavailable.

Speed of Conduction

This area of depolarization/repolarization/recovery moves along a nerve fiber like a very fast wave. In myelinated fibers, conduction is hundreds of times faster because the action potential only occurs at the nodes of Ranvier (pictured below in 'types of neurons') by jumping from node to node. This is called "saltatory" conduction. Damage to the myelin sheath by the disease can cause severe impairment of nerve cell function. Some poisons and drugs interfere with nerve impulses by blocking sodium channels in nerves. See discussion on drug at the end of this outline.

1. Automatic control (sensory) of respiration is in - brainstem (midbrain) 

2. Behavioral/voluntary control is in - the cortex

3. Alveolar ventilation -the amount of atmospheric air that actually reaches the alveolar per breath and that can participate in the exchange of gasses between alveoli and blood

4. Only way to increase gas exchange in alveolar capillaries - perfusion-limited gas exchange 

5. Pulmonary ventiliation not effected by - concentration of bicarbonate ions

6. Central chemoreceptors - medulla -  CO2, O2 and H+ concentrations

7. Peripheral chemoreceptors - carotid and aortic bodies- PO2, PCO2 and pH 

8. Major stimulus for respiratory centers - arterial PCO2 

9. Rhythmic breathing depends on 
1. continuous (tonic) inspiratory drive from DRG (dorsal respiratory group)
2. intermittent (phasic) expiratory input from cerebrum, thalamus, cranial nerves and ascending spinal cord sensory tracts

10. Primary site for gas exchange - type I epithelial cells for alveoli