Mechanisms of Capillary ExchangeCapillaries are the only place for exchange between blood and surrounding tissue.Route across endothelial cells:1. Diffusion:Across cell membrane by Simple diffusion for lipid soluble substances:Particularly important for gases (O2 and CO2) and lipid-soluble substances (e.g., anesthetics); fluid and electrolytes are also exchanged, in part, by diffusion forces (Fick's First Law of diffusion)

Factors that affect diffusion:a. Lipid-Soluble Substances Diffuse Directly Through the Cell Membranes of the Capillary Endotheliumb. Effect of concentration difference on net rate of diffusion through the Capillary Membrane. The “net” rate of diffusion of a substance through any membrane is proportional to the concentration difference of the substance between the two sides of the membraneIf a substance is lipid soluble, it can diffuse directly through the cell membranes of the capillary without having to go through the pores. Such substances include oxygen and carbon dioxide. Because these substances can permeate all areas of the capillary membrane, their rates of transport through the capillary membrane are many times faster than the rates for lipid-insoluble substances, such as sodium ions and glucose that can go only through the pores. c. Capillary density: increase capillary density increase diffusion because increase surface area.2. Water-Soluble, Non–Lipid-Soluble Substances Diffuse Through A. Intercellular “Pores” in the Capillary Membrane (Fenestrated capillaries): Fenestrated capillaries (fenstra: window) have pores in the endothelial cells (60-80 nm in diameter) that are spanned امتدادby a diaphragm of radially شعاعيoriented fibrils and allow small molecules and limited amounts of protein to diffuse.B. Intercellular clefts between the endothelial cells (continuous capillaries): Many substances needed by the tissues are soluble in water but cannot pass through the lipid membranes of the endothelial cells; such substances include water molecules, sodium ions, chloride ions, and glucose. Although only 1/1000 of the surface area of the capillaries is represented by the intercellular clefts between the endothelial cells, the velocity of thermal molecular motion in the clefts is so great that even this small area is sufficient to allow tremendous diffusion of water and water-soluble substances through these cleft-pores. To give one an idea of the rapidity with which these substances diffuse, the rate at which water molecules diffuse through the capillary membrane is about 80 times as great as the rate at which plasma itself flows linearly along the capillary. That is,

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the water of the plasma is exchanged with the water of the interstitial fluid 80 times before the plasma can flow the entire distance through the capillary.

Effect of Molecular Size on Passage through the Pores. The width of the capillary intercellular cleft-pores, 6 to 7 nanometers, is about 20 times the diameter of the water molecule, which is the smallest molecule that normally passes through the capillary pores. The diameters of plasma protein molecules, however, are slightly greater than the width of the pores. Other substances, such as sodium ions, chloride ions, glucose, and urea, have inter-mediate diameters. Therefore, the permeability of the capillary pores for different substances varies according to their molecular diameters.commonly encountered, demonstrating, for instance, that the permeability for glucose molecules is 0.6 times that for water molecules, whereas the permeability for albumin molecules is very slight—only 1/1000 that for water molecules. A word of caution must be issued at this point. The capillaries in various tissues have extreme differences in their permeabilities. For instance, the membranes of the liver capillary sinusoids are so permeable that even plasma proteins pass through these walls, almost as easily as water and other substances. Also, the permeability of the renal glomerular membrane for water and electro-lytes is about 500 times the permeability of the muscle capillaries, but this is not true for the plasma proteins; for these proteins, the capillary permeabilities are very slight, as in other tissues and organs. When we study these different organs later in this text, it should become clear why some tissues require greater degrees of capillary permeability than do other tissues. For example, greater degrees of capillary permeability are required for the liver to transfer tremendous amounts of nutrients between the blood and liver parenchymal cells and for the kidneys to allow filtration of large quantities of fluid for the formation of urine.Effect of Concentration Difference on Net Rate of Diffusion through the Capillary Membrane. The “net” rate of diffusion of a substance through any membrane is proportional to the concentration difference of the substance between the two sides of the membrane. That is, the greater the difference between the concentrations of any given substance on the two sides of the capillary membrane, the greater the net movement of the substance in one direction through the membrane. For instance, the concentration of oxygen in capillary blood is normally greater than in the interstitial fluid. Therefore, large quantities of oxygen normally move from the blood toward the tissues. Conversely, the concentration of carbon dioxide is greater in the tissues than in the blood, which causes excess carbon dioxide to move into the blood and to be carried away from the tissues. The rates of diffusion through the capillary membranes of most nutritionally important substances are so great that only slight concentration differences suffice to cause more than adequate transport between the plasma and interstitial fluid. For instance, the concentration of oxygen in the interstitial fluid immediately outside the capillary is no more than a few percent less than its concentration in the plasma of the blood, yet this slight difference causes enough oxygen to move from the blood into

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the interstitial spaces to provide all the oxygen required for tissue metabolism—often as much as several liters of oxygen per minute during very active states of the body.However, in a state of acute or chronic inflammation, ischemia–reperfusion, atherosclerosis, sepsis, diabetes, thermal injury, angiogenesis or tumor metastasis, mediators such as histamine, serotonin, thrombin, bradykinin, substance P, Platelet-activating factor (PAF), cytokines, growth factors such as vascular endothelial growth factor (VEGF) and reactive oxygen species induce endothelial cell retraction, which increases the intercellular space and subsequently the permeability to solute and plasma proteins. 3. Transcytosis (Vesicular Transport)Vesicular transport is involved in the translocation of macromolecules across capillary endothelium by endocytosis and exocytosis Transcytosis, blood substances move into the cell by endocytosis then across the endothelial cells that compose the capillary structure. Finally, these materials exit by exocytosis, process in which vesicles go out from a cell to the interstitial space. Transcytosis is mainly used by large molecules that are lipid-insoluble, such as the insulin hormone. A minimum amount of substances cross by transcytosis. Once vesicles exit the capillaries, they go to the interstitium. Sometimes vesicles can merge with other vesicles, so their contents are mixed, or can directly go to a specific tissue. This material intermixed increases the functional capability of the vesicle.Sometimes vesicles fuses with each other forming vesicular channels

Present in the endothelial cells are many minute plasmalemmal vesicles, also called caveolae (small caves). These plasmalemmal vesicles form from oligomers of proteins called caveolins that are associated with molecules of cholesterol and sphingolipids.

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Although the precise functions of caveolae are still unclear, they are believed to play a role in endocytosis (the process by which the cell engulfs material from outside the cell) and transcytosis of macromolecules across the interior of the endothelial cells. The caveolae at the surface of the cell appear to imbibe شربsmall packets of plasma or extracellular fluid that contain plasma proteins. These vesicles can then move slowly through the endothelial cell. Some of these vesicles may coalesce to form vesicular channels all the way through the endothelial cellInterstitium & interstitial fluid About one sixth of the total volume of the body consists of spaces between cells, which collectively are called the interstitium. The fluid in these spaces is called the interstitial fluid.

The structure of the interstitium contains two major types of solid structures: (1) collagen fiber bundles The collagen fiber bundles extend long distances in the interstitium. The collagen fiber are extremely strong and therefore provide most of the tensional strength of the tissues.(2) Proteoglycan filaments. The proteoglycan filaments, however, are extremely thin coiled or twisted molecules composed of about 98 percent hyaluronic acid and 2 percent protein. These molecules are so thin that they cannot be seen with a light microscope and are difficult to demonstrate even with the electron micro-scope. Nevertheless, they form a mat of very fine reticular filaments aptly described as a “brush pile.”“Gel” in the Interstitium. The fluid in the interstitium is derived by filtration and diffusion from the capillaries. It contains almost the same constituents as plasma except for much lower concentrations of proteins because proteins do not easily pass outward through the pores of the capillaries. The interstitial fluid is entrapped mainly in the minute spaces among the proteoglycan filaments. This combination of proteoglycan filaments and fluid entrapped within them has the characteristics of a gel and therefore is called tissue gel. Because of the large number of proteoglycan filaments, it is difficult for fluid to flow easily through the tissue gel. Instead, fluid mainly diffuses through the gel; that is, it moves molecule by molecule from one place to another by kinetic, thermal motion rather than by large numbers of molecules moving together. Diffusion through the gel occurs about 95 to 99 percent as rapidly as it does through free fluid. For the short distances between the capillaries and the tissue cells, this diffusion allows rapid transport through the interstitium not only of water molecules but also of electrolytes, small molecular weight nutrients, cellular excreta, oxygen, carbon dioxide, and so forth.

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“Free” Fluid in the Interstitium. Although almost all the fluid in the interstitium normally is entrapped within the tissue gel, occasionally small rivulets of “free” fluid and small free fluid vesicles are also present, which means fluid that is free of the proteoglycan molecules and therefore can flow freely. When a dye is injected into the circulating blood, it often can be seen to flow through the interstitium in the small rivulets, usually coursing along the surfaces of collagen fibers or surfaces of cells. The amount of “free” fluid present in normal tissues is slight—usually less than 1 percent. Conversely, when the tissues develop edema, these small pockets and rivulets of free fluid expand tremendously until one half or more of the edema fluid becomes freely flowing fluid independent of the proteoglycan filaments.Bulk flow (Convection):It includes: A. Reabsorption (to blood)B. Filtration (from blood)The major mechanism of exchange are:The difference between diffusion and filtration1. Diffusion: is the movement of substance because differences in concentration (from higher concentration to lower concentration) on two sides. It is the principle mechanism of micro-vascular exchange such as CO2, O2, and glucose.2. Filtration: is the process by which fluid is forced through a membrane or other barrier because of differences in pressure (from higher pressure to lower pressure) on two sides Starling forces maintains the balance between filtration and re-absorption of H2O depends both on the difference in hydrostatic and oncotic pressure between the blood and the tissue and on the permeability of the vessel.Qw = K ¿ [(Pc – Pi) –σ (πc – πi)] where Qw : bulk flow of water , K: permeability-surface area coefficient, Pc: capillary pressure, Pi: interstitial fluid pressure, σ: reflection coefficient, πc:

capillary(or plasma) colloid osmotic pressure, πi: interstitial fluid colloid osmotic pressure. The permeability-surface area coefficient or it is sometime called capillary filtration coefficient (K): Is represented by the product of: surface area (or the length of the vessel) permeability (or the number or size of the pores through which water can exit the blood vessel). The filtration coefficient can also be expressed for separate parts of the body in terms of rate of filtration per minute per mm Hg per 100 grams of tissue. On this basis, the capillary filtration coefficient of the average tissue is about 0.01 ml/min/mm Hg/100 g of tissue. However because of extreme differences in permeability of the capillary systems in different tissues, this coefficient varies more than 100-fold among the different tissues. It is very small in brain and muscle, moderately large in subcutaneous tissue, large in the intestine, and extremely large in the liver and glomerulus of the kidney where the pores are either numerous or wide open. By the same token, the permeation of proteins through the capillary membranes varies greatly as well. The concentration expressed as g of protein/dl of the interstitial fluid; in brain is close to zero, muscle is about, 1.5 g/dl; in subcutaneous tissue, 2 g/dl; in intestine 4 g/dl; and in liver, 6 g/dl. Reflection coefficient (σ): is the inverse of the permeability of the vessel wall to protein. A molecule in the blood that reflects from the capillary wall and does not cross the capillary wall into the interstitium has zero permeability. A molecule in the blood that cross the capillary wall into the interstitium and does not reflects from the capillary wall has maximum coefficient of 1. Continuous capillaries have a high σ (>0.9), whereas discontinuous and fenestrated capillaries are very "leaky" to proteins have a relatively low σ. When the value for σ is very low, plasma and tissue oncotic pressures may have a negligible influence on the net driving force.Capillary plasma colloid osmotic pressure (πc):

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The term “colloid” osmotic pressure is derived from the fact that a protein solution resembles a colloidal solution despite the fact that it is actually a true molecular solution.Colloids is a term used to collectively refer to the large molecular weight (nominally MW > 30,000) particles present in a solution. In normal plasma, the plasma proteins are the major colloids present. As the colloids are solutes they contribute to the total osmotic pressure of the solution. This component due to the colloids is typically quite a small percent of the total osmotic pressure. It is referred to as colloid osmotic pressure (or sometimes as the oncotic pressure). In plasma, the oncotic pressure is only about 0.5% of the total osmotic pressure. This may be a small percent but because colloids cannot cross the capillary membrane easily, oncotic pressure is extremely important in trans-capillary fluid dynamics. Only the molecules or ions that fail to pass through the pores of a semipermeable membrane exert osmotic pressure. Because the proteins are the only dissolved constituents in the plasma and interstitial fluids that do not readily pass through the capillary pores, it is the proteins of the plasma and interstitial fluids that are responsible for the osmotic pressures on the two sides of the capillary membrane. To distinguish this osmotic pressure from that which occurs at the cell membrane, it is called either colloid osmotic pressure or oncotic pressure. Osmotic pressure is the pressure developed by solutes dissolved in water working across a selectively permeable membrane. It is generated by all the dissolved solutes (salts, nutrients, proteins) all dissolved solutes. Oncotic pressure or (is) Colloid Osmotic Pressure - the part of the osmotic pressure created by the larger colloidal solute components. it tends to cause osmosis of fluid inward through the capillary membrane. The normal value is about 28 mmHg (19mmHg + 9mmHg); A. 19 mmHg is caused by molecular effect of dissolved protein The plasma protein is a mixture of protein with different molecular weight and number. Effect of the Different Plasma Proteins on Colloid Osmotic PressureThe plasma proteins are a mixture that contains albumin, globulins, and fibrinogen, with an average molecular weight of 69,000, 140,000, and 400,000, respectively. Thus, 1 gram of globulin contains only half as many molecules as 1 gram of albumin, and 1 gram of fibrinogen contains only one sixth as many molecules as 1 gram of albumin. Osmotic pressure is determined by the number of molecules dissolved in a fluid rather than by the mass of these molecules. Therefore, when corrected for number of molecules rather than mass, the following chart gives both the relative mass concentrations (g/dl) of the different types of proteins in normal plasma and their respective contributions to the total plasma colloid osmotic pressure (πp). Thus, about 80 percent of the total colloid osmotic pressure of the plasma results from the albumin, 20 percent from the globulins, and almost none from fibrinogen. Therefore, from the point of view of capillary and tissue fluid dynamics, it is mainly albumin that is important. B. 9 mmHg by the cation held in the plasma by the protein This is because negative charge of protein exerts attraction on Na and other positive charge ion this is called "Donnan effect".

The Gibbs-Donnan effect

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Left panel, Two solutions are separated by a membrane that is permeable to Na+, Cl-, and H2O, but not permeable to protein (P-). The osmolality of solution A is identical to that of solution B. Right panel, Cl- diffuses from solution B to A down its concentration gradient. This causes solution A to become electrically negative with respect to solution B. This membrane voltage then drives the diffusion of Na+ from solution B to A. The accumulation of additional Na+ and Cl- in solution A increases its osmolality and causes water to flow from B to A.Tissue (interstitial) Oncotic Pressure (Interstitial fluid colloid osmotic pressure) (πi):The oncotic pressure of the interstitial fluid depends on the interstitial protein concentration and the reflection coefficient of the capillary wall. The more permeable the capillary barrier is to proteins, the higher the interstitial oncotic pressure. This pressure is also determined by the amount of fluid filtration into the interstitium. For example, increased capillary filtration decreases interstitial protein concentration and reduces the oncotic pressure. A reduction in the interstitial oncotic pressure increases the net oncotic pressure across the capillary endothelium (πC - πi), which opposes filtration and promotes reabsorption thereby serving as a mechanism to limit capillary filtration. In a "typical" tissue, tissue oncotic pressure is about 5 mmHg (i.e., much lower than capillary plasma oncotic pressure).Only small amount of plasma protein do leak through the pores into the interstitial fluid. Protein concentration in interstitium is 3gm/dL (about 40% of plasma) and the average colloid osmotic pressure for this concentration of protein is about 8mmHg. There is no Gibbs-Donnan effect

Capillary hydrostatic pressure (Pc): it tends to force fluid outward through the capillary membrane. It varies from tissue to tissue; it is high in kidney (45mmHg) and low in intestine (10mHg). In skeletal muscle, capillary pressure is nearly 40 mmHg at arterial end and 12 mmHg at venous end. This pressure drives fluid out of the capillary (i.e., filtration), and is highest at the arteriolar end of the capillary and lowest at the venular end. Depending upon the organ, the pressure may drop along the length of the capillary by 15-30 mmHg (axial or longitudinal pressure gradient). The axial gradient favors filtration at the arteriolar end (where PC is greatest) and reabsorption at the venular end of the capillary (where PC is the lowest). The average capillary hydrostatic pressure is determined by arterial and venous pressures (PA and PV), and by the ratio of post-to-precapillary resistances (RV/RA). An increase in either arterial or venous pressure will increase capillary pressure; however, a given change in PA is only about one-fifth as effective in changing PC as the same absolute change in PV. Because venous resistance is relatively low, changes in PV are readily transmitted back to the capillary, and conversely, because arterial resistance is relatively high, changes in PA are poorly transmitted downstream to the capillary. Therefore, PC is much more influenced by changes in PV than by changes in PA. Furthermore, PC is increased by precapillary vasodilation (particularly by arteriolar dilation), whereas precapillary vasoconstriction decreases PC. Venous constriction increases PC, whereas venous dilation decreases PC.The effects of arterial and venous pressures and resistances on PC are summarized in the following relationship:

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The above expression is derived from a simple model comprised of a series-coupled pre- and post-capillary resistance. In many tissues, the post-to-precapillary resistance ratio is about 0.2, which means that precapillary resistance (mostly arteriolar) is about 5-times greater than post-capillary (venular) resistance. When this ratio is 0.2, a given change in arterial pressure is only about one-fifth as effective in changing capillary pressure as a comparable change in venous pressure. If this ratio increases, as occurs with arteriolar vasodilation, then arterial pressure has a greater influence on capillary pressure, which rises. Conversely, arteriolar constriction decreases this ratio and decreases capillary pressure.Tissue (Interstitial) Pressure (Pi)This hydrostatic pressure is determined by the interstitial fluid volume and the compliance of the tissue interstitium, which is defined as the change in volume divided by the change in pressure. The more fluid that filters into the interstitium, the greater the volume of the interstitial space (Vi) and the hydrostatic pressure within that space (Pi). In some organs, the interstitial compliance is low, which means that small increases in interstitial volume lead to large increases in pressure. Examples of this include the brain and kidney, which are encased by rigid bone (brain) or by a capsule (kidney). In contrast, soft tissues such as skin, muscle and lung have a high compliance and therefore the interstitial space can undergo a large expansion with a relatively small increase in pressure. As interstitial volume increases, interstitial pressure increases, which can limit the amount of filtration into the interstitium because this pressure opposes the capillary hydrostatic pressure. In other words, as the hydrostatic pressure gradient (PC - Pi) decreases owing to the rise in interstitial pressure, fluid filtration will be attenuated. However, large increases in tissue interstitial pressure can lead to tissue damage and cellular death. Normally, Pi is near zero. In some tissues it is slightly sub-atmospheric, whereas in others it is slightly positive.Interstitial fluid hydrostatic pressure (Pi) tends to force fluid inward through the capillary membrane when it is positive but outward when it is negative. The normal interstitial fluid pressure is usually several mmHg negative with respect to the pressure of the surrounds each tissue; for example, in the kidney the capsular pressure surround the kidney average about +13mmHg, whereas the interstitial fluid pressure is +6mmHg. The pressure exerted on the skin is atmospheric pressure, which is considered to be zero pressure, while the interstitial fluid pressure is sub-atmospheric.

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In most natural cavities of the body where there is free fluid in dynamic equilibrium with the surrounding interstitial fluids, the pressures that have been measured have been negative. Some of these cavities and pressure measurements are as follows: • Intra-pleural space: −8 mm Hg • Joint synovial spaces: −4 to −6 mm Hg • Epidural space: −4 to −6 mm Hg All of the above forces are seen at the arterial and venous side, but it tends to push fluid toward interstitium at the arterial side and toward the capillary at the venous side. The best example is the skin:

Arterial Venous Forces tending to move fluid outward

Capillary pressure 30 10Negative interstitial free fluid pressure 3 3Interstitial fluid colloid osmotic pressure 8 8

Total outward forces 41 21Forces tending to move fluid inward

Plasma colloid osmotic pressure 28 28

Total inward forces 28 28Summation of forces outward and inward 13 7

Thus, the summation of forces at the arterial end of the capillary shows a net filtration pressure of 13 mmHg, tending to move in the outward direction through the capillary pores. Thus, the summation of forces at the venous end of the capillary shows a net filtration pressure of 7 mmHg, is the (net re-absorption pressure) tending to move in the inward direction through the capillary pores.The re-absorption pressure is considerably less than the filtration pressure at the capillary arterial ends, but remember that the venous capillary are more numerous and more permeable than the arterial capillaries, so that less pressure is required to cause the inward movement of fluid. The re-absorption pressure causes about nine tenth of the fluid that has filtered out of the arterial of the capillaries to re-absorbed at the venous end. The remainder flows into the lymph vessels.Lymphatic system:Functions of the lymphatic system include following:1. Tissue drainage: Every day, around 24 liters (about 0.3% of cardiac output) of fluid filtered from plasma, carrying dissolved substances and some plasma protein, escape from the arterial end of the capillaries into the tissues. Most of this fluid is returned direct the blood stream via the capillary at its venous end, but 2 to 4 liters of fluid are drained away by the lymphatic vessels. Fluid removed from the interstitium in order to maintain a gel state; without this, the tissues would rapidly become waterlogged, and the cardiovascular system would begin to fail as the blood volume falls.Lymph transports the plasma proteins that seep out of the capillary beds back to the bloodstream.2. Absorption in the small intestine: The lymphatic system is one of the major routes for absorption of nutrients from the gastrointestinal tract, especially for absorption of virtually all fat and fat-soluble materials e.g. the fat-soluble vitamins in food, are absorbed into the central lacteals (lymphatic vessels) of the villi. Indeed, after a fatty meal, thoracic duct lymph sometimes contains as much as 1 to 2 percent fat. The transport of absorbed long-chain fatty acids and cholesterol from the intestine via lymphatic3. Immunity: The lymphatic organs are concerned with the production and maturation of lymphocytes, the white blood cells responsible for immunity. Bone marrow is therefore considered to be lymphatic tissue, since lymphocytes are produced there.

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Lymph carries away larger particles, e.g. bacteria and cell debris from damaged tissues, which can then be filtered out and destroyed by the lymph nodes. Lymph contains

Lymph:Lymph is a clear watery fluid, similar in composition to plasma, with less composition of plasma proteins. Lymph is identical in composition to interstitial fluid.

Lymphocytes: They circulate in the lymphatic system allowing them to patrol the different regions of the body.

In the Lacteals of the small intestine, fats absorbed into the lymphatics give the lymph (now called chyle), a milky appearance.

The thoracic duct is the conduit for lymph and dietary fat to reach venous blood stream Lymph consist of fat 1-3% composed of Triglyceride (70% long chain), protein (3%),

electrolytes content is the same as plasma except of lower calcium concentration and lymphocytes (T lymphocytes)

Lymph daily production is dependent on the diet and daily dietary intake. Lymphatic vessels can be dividing into two types: initial lymphatic collecting lymphatic. Terminal Lymphatic Capillaries(Initial lymphatic) and Their Permeability:

It is lack valves and smooth muscles in their walls. They are found in regions such as the intestine or skeletal muscle. Tissue fluid appears to enter them through loss junction between the endothelial

cells that form their walls. The fluid in them apparently is massaged by: Muscle contraction of the

organsContraction of arterioles and venules.Movement of parts of body.

The fluid that returns to the circulation by way of the lymphatics is extremely important because substances of high molecular weight, such as proteins, cannot be absorbed from the tissues in any other way, although they can enter the lymphatic capillaries almost unimpeded. The reason for this mechanism is a special structure of the lymphatic capillaries, the endothelial cells of the lymphatic capillary attached by anchoring filaments to the surrounding connective tissue.

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At the junctions of adjacent endothelial cells, the edge of one endothelial cell overlaps the edge of the adjacent cell in such a way that the overlapping edge is free to flap inward, thus forming a minute valve that opens to the interior of the lymphatic capillary. Interstitial fluid, along with its suspended particles, can push the valve open and flow directly into the lymphatic capillary. However, this fluid has difficulty leaving the capillary once it has entered because any backflow closes the flap valve. Thus, the lymphatics have valves at the very tips of the terminal lymphatic capillaries, as well as valves along their larger vessels up to the point where they empty into the blood circulation.

Formation of lymphLymph is derived from interstitial fluid that flows into the lymphatics. Therefore, lymph as it first enters the terminal lymphatics has almost the same composition as the interstitial fluid. The protein concentration in the interstitial fluid of most tissues averages about 2 g/dl, and the protein con-centration of lymph flowing from these tissues is near this value. Lymph formed in the liver has a protein concentration as high as 6 g/dl, and lymph formed in the intestines has a protein concentration as high as 3 to 4 g/dl. Because about two thirds of all lymph normally is derived from the liver and intestines, the thoracic duct lymph, which is a mixture of lymph from all areas of the body, usually has a protein concentration of 3 to 5 g/dl. The lymphatic system represents the only mechanism for returning albumin and other interstitial macro-molecules to the circulation system. This system recovers approximately 200gm of protein daily (which is equal to 25 to 50% of the total circulating plasma protein) that has been lost from the micro-circulation. The macro-molecules enter the lymphatic, presumably at the junctions between the endothelial cells, and the proteins are returned to the bloodstream via the lymphatic.

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The lymphatic system is also one of the major routes for absorption of nutrients from the gastrointestinal tract, especially for absorption of virtually all fats in food. Indeed, after a fatty meal, thoracic duct lymph sometimes contains as much as 1 to 2 percent fat. Finally, even large particles, such as bacteria, can push their way between the endothelial cells of the lymphatic capillaries and in this way enter the lymph. As the lymph passes through the lymph nodes, these particles are almost entirely removed and destroyed. Rate of lymph flowAbout 100 milliliters per hour of lymph flows through the thoracic duct of a resting human, and approximately another 20 milliliters flows into the circulation each hour through other channels, making a total estimated lymph flow of about 120 ml/hr or 2 to 3 liters per day. Effect of Interstitial Fluid Pressure on Lymph Flow. Note that normal lymph flow is very little at interstitial fluid pressures more negative than the normal value of −6 mm Hg. Then, as the pressure rises to 0 mm Hg (atmospheric pressure), flow increases more than 20-fold. Therefore, any factor that increases interstitial fluid pressure also increases lymph flow if the lymph vessels are functioning normally. Such factors include the following: • Elevated capillary hydrostatic pressure • Decreased plasma colloid osmotic pressure • Increased interstitial fluid colloid osmotic pressure • Increased permeability of the capillaries All of these factors causes a balance of fluid exchange at the blood capillary membrane to favor fluid movement into the interstitium, thus increasing interstitial fluid volume, interstitial fluid pressure, and lymph flow all at the same time. When the interstitial fluid pressure becomes 1 or 2 mm Hg greater than atmospheric pressure (>0 mm Hg), lymph flow fails to rise any further at still higher pressures. This results from the fact that the increasing tissue pressure not only increases entry of fluid into the lymphatic capillaries but also compresses the outside surfaces of the larger lymphatics, thus impeding lymph flow. At the higher pressures, these two factors balance each other almost exactly, so lymph flow reaches a maximum flow rate. This maximum flow rate is illustrated by the upper level plateau

Lymphatic Pump Increases Lymph Flow. Valves exist in all lymph channels.

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When a collecting lymphatic or larger lymph vessel becomes stretched with fluid, the smooth muscle in the wall of the vessel automatically contracts. Furthermore, each segment of the lymph vessel between successive valves functions as a separate automatic pump. That is, even slight filling of a segment causes it to contract, and the fluid is pumped through the next valve into the next lymphatic segment. This fluid fills subsequent segment and a few seconds later it, too, contracts, the process continuing all along the lymph vessel until the fluid is finally emptied into the blood circulation. In a very large lymph vessel such as the thoracic duct, this lymphatic pump can generate pressures as great as 50 to 100 mm Hg. Pumping causes by external intermittent compression of lymphaticsIn addition to the pumping caused by intrinsic intermittent contraction of the lymph vessel walls, any external factor that intermittently compresses the lymph vessel also can cause pumping. In order of their importance, such factors are as follows: • Contraction of surrounding skeletal muscles • Movement of the parts of the body • Pulsations of arteries adjacent to the lymphatics • Compression of the tissues by objects outside the body The lymphatic pump becomes very active during exercise, often increasing lymph flow 10- to 30-fold. Conversely, during periods of rest, lymph flow is sluggish (almost zero).Lymphatic Capillary Pump. The terminal lymphatic capillary is also capable of pumping lymph, in addition to the pumping by the larger lymph vessels. The walls of the lymphatic capillaries are tightly adherent to the surrounding tissue cells by means of their anchoring filaments. Therefore, each time excess fluid enters the tissue and causes the tissue to swell, the anchoring filaments pull on the wall of the lymphatic capillary and fluid flows into the terminal lymphatic capillary through the junctions between the endothelial cells. Then, when the tissue is compressed, the pressure inside the capillary increases and causes the overlapping edges of the endothelial cells to close like valves. Therefore, the pressure pushes the lymph forward into the collecting lymphatic instead of backward through the cell junctions. The lymphatic capillary endothelial cells also contain a few contractile actomyosin filaments. In some animal tissues (e.g., the bat’s wing), these filaments have been observed to cause rhythmical contraction of the lymphatic capillaries in the same rhythmic way that many of the small blood vessels and larger lymphatic vessels contract. Therefore, it is probable that at least part of lymph pumping results from lymph capillary endothelial cell contraction in addition to contraction of the larger muscular lymphatics. The lymphatic system plays a key role in controlling interstitial fluid protein concentration, volume, and pressure:It is already clear that the lymphatic system functions as an “overflow mechanism” to return excess proteins and excess fluid volume from the tissue spaces to the circulation. Therefore, the lymphatic system also plays a central role in controlling (1) the concentration of proteins in the interstitial fluids,

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(2) the volume of interstitial fluid, and (3) the interstitial fluid pressure. Let us explain how these factors interact. First, remember that small amounts of proteins leak continuously out of the blood capillaries into the interstitium. Only minute amounts, if any, of the leaked proteins return to the circulation by way of the venous ends of the blood capillaries. Therefore, these proteins tend to accumulate in the interstitial fluid, which in turn increases the colloid osmotic pressure of the interstitial fluids. Second, the increasing colloid osmotic pressure in the interstitial fluid shifts the balance of forces at the blood capillary membranes in favor of fluid filtration into the interstitium. Therefore, in effect, fluid is trans-located osmotically outward through the capillary wall by the proteins and into the interstitium, thus increasing both interstitial fluid volume and interstitial fluid pressure. Third, the increasing interstitial fluid pressure greatly increases the rate of lymph flow, which carries away the excess interstitial fluid volume and excess protein that has accumulated in the spaces. Thus, once the interstitial fluid protein concentration reaches a certain level and causes comparable increases in interstitial fluid volume and pressure, the return of protein and fluid by way of the lymphatic system becomes great enough to balance the rate of leakage of these into the interstitium from the blood capillaries. Therefore, the quantitative values of all these factors reach a steady state, and they will remain balanced at these steady state levels until something changes the rate of leakage of proteins and fluid from the blood capillaries. Significance of negative interstitial fluid pressure as a means for holding the body tissues together Traditionally, it has been assumed that the different tissues of the body are held together entirely by connective tissue fibers. However, connective tissue fibers are very weak or even absent at many places in the body, particularly at points where tissues slide over one another (e.g., skin sliding over the back of the hand or over the face). Yet, even at these places, the tissues are held together by the negative interstitial fluid pressure, which is actually a partial vacuum. When the tissues lose their negative pressure, fluid accumulates in the spaces and the condition known as edema occurs. EdemaEdema refers to the presence of excess fluid in the body tissues.Intracellular EdemaTwo conditions are especially prone to cause intracellular swelling: (1) Lack of adequate nutrition to the cells and Depression of the metabolic systems of the tissues:For example, when blood flow to a tissue is decreased, the delivery of oxygen and nutrients is reduced. If the blood flow becomes too low to maintain normal tissue metabolism, the cell membrane ionic pumps become depressed. When this occurs, sodium ions that normally leak into the interior of the cell can no longer be pumped out of the cells, and the excess sodium ions inside the cells cause osmosis of water into the cells. Sometimes this can increase intracellular volume of a tissue area (even of an entire ischemic leg, for example) to two to three times normal. When this occurs, it is usually a prelude to death of the tissue.Importance of the Na+-K+ Pump for Controlling Cell Volume. One of the most important functions of the Na+-K+ pump is to control the volume of each cell. Without function of this pump, most cells of the body would swell until they burst. The mechanism for controlling the volume is as follows: Inside the cell are large numbers of proteins and other organic molecules that cannot escape from the cell. Most of these are negatively charged and therefore attract large numbers of potassium, sodium, and other positive ions as well. All these molecules and ions then cause osmosis of water to the interior of the cell. Unless this is checked, the cell will swell indefinitely until it bursts. The normal mechanism for preventing this is the Na+-K+ pump.

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Note again that this device pumps three Na+ ions to the outside of the cell for every two K+ ions pumped to the interior. Also, the membrane is far less permeable to sodium ions than to potassium ions, so that once the sodium ions are on the outside, they have a strong tendency to stay there. Thus, this represents a net loss of ions out of the cell, which initiates osmosis of water out of the cell as well. If a cell begins to swell for any reason, this automatically activates the Na+-K+ pump, moving still more ions to the exterior and carrying water with them. Therefore, the Na+-K+ pump performs a continual surveillance role in maintaining normal cell volume.(2)Intracellular edema can occur in inflamed tissues:Inflammation usually has a direct effect on the cell membranes to increase their permeability, allowing sodium and other ions to diffuse into the interior of the cell, with subsequent osmosis of water into the cells.(3)Hyponatrimia meaning there is less sodium or more water in extracellular fluid. When there is this condition, the water moves from compartment of low concentration of solute to the compartment with high concentration of solute that is inside the cell causing swelling of the cell. Example brain edemas.

Extracellular EdemaExtracellular fluid edema occurs when there is excess fluid accumulation in the extracellular spaces. There are two general causes of extracellular edema: (1) Abnormal leakage of fluid from the plasma to the interstitial spaces across the capillaries, andThe most common clinical cause of interstitial fluid accumulation is excessive capillary fluid filtration. (2) Failure of the lymphatic to return fluid from the interstitium back into the blood. Lymphatic Blockage Causes EdemaWhen lymphatic blockage occurs, edema can become especially severe because plasma proteins that leak into the interstitium have no other way to be removed. The rise in protein concentration raises the colloid osmotic pressure of the interstitial fluid, which draws even more fluid out of the capillaries.(1) Blockage of lymph flow can be especially severe with infections of the lymph nodes, such as occurs with infection by filaria nematodes. (2)Blockage of the lymph vessels can occur in certain types of cancer or after surgery in which lymph vessels are removed or obstructed. For example, large numbers of lymph vessels are removed during radical mastectomy

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Safety Factors That Normally Prevent EdemaThe reason the abnormality must be severe is that three major safety factors prevent excessive fluid accumulation in the interstitial spaces: (1) Low compliance of the interstitium when interstitial fluid pressure is in the negative pressure range, (2) The ability of lymph flow to increase 10-to 50-fold, and (3) “Wash-down” of interstitial fluid protein concentration, which reduces interstitial fluid colloid osmotic pressure as capillary filtration increases. Importance of interstitial gel in preventing fluid accumulation in the interstitium In normal tissues with negative interstitial fluid pressure, virtually all the fluid in the interstitium is in gel form. That is, the fluid is bound in a proteoglycan meshwork so that there are virtually no “free” fluid spaces larger than a few hundredths of a micrometer in diameter. The importance of the gel is that it prevents fluid from flowing easily through the tissues because of impediment from the “brush pile” of trillions of proteoglycan filaments. Also, when the interstitial fluid pressure falls to very negative values, the gel does not contract greatly because the meshwork of proteoglycan filaments offers an elastic resistance to compression. In the negative fluid pressure range, the interstitial fluid volume does not change greatly, regardless of whether the degree of suction is only a few millimeters of mercury negative pressure or 10 to 20 mm Hg negative pressure. In other words, the compliance of the tissues is very low in the negative pressure range.

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By contrast, when interstitial fluid pressure rises to the positive pressure range, there is a tremendous accumulation of free fluid in the tissues. In this pressure range, the tissues are compliant, allowing large amounts of fluid to accumulate with relatively small additional increases in interstitial fluid hydrostatic pressure. Most of the extra fluid that accumulates is “free fluid” because it pushes the brush pile of proteoglycan filaments apart. Therefore, the fluid can flow freely through the tissue spaces because it is not in gel form. When this free flow of fluid occurs, the edema is said to be pitting edema (such as heart renal, and liver failure) because one can press the thumb against the tissue area and push the fluid out of the area. When the thumb is removed, a pit is left in the skin for a few seconds until the fluid flows back from the surrounding tissues.

This type of edema is distinguished from non-pitting edema, which occurs when the tissue cells swell instead of the interstitium or when the fluid in the interstitium becomes clotted with fibrino-gen so that it cannot move freely within the tissue spaces. Such as Mxyoedema, elphantisis, and angioneurotic

Importance of the proteoglycan filaments as a “Spacer” مفساح او المجال for theيفسحcells and in preventing rapid flow of fluid in the tissues. The proteoglycan filaments, along with much larger collagen fibrils in the interstitial spaces, act as a “spacer” between the cells.Nutrients and ions do not diffuse readily through cell membranes; therefore, without adequate spacing between the cells, these nutrients, electrolytes, and cell waste products could not be rapidly exchanged between the blood capillaries and cells located at a distance from one another. The proteoglycan filaments also prevent fluid from flowing too easily through the tissue spaces. If it were not for the proteoglycan filaments, the simple act of a person standing up would cause large amounts of interstitial fluid to flow from the upper body to the lower body. When too much fluid accumulates in the interstitium, as occurs in edema, this extra fluid creates large channels that allow the fluid to flow readily through the interstitium. Therefore, when severe edema occurs in the legs, the edema fluid often can be decreased by simply elevating the legs. Even though fluid does not flow easily through the tissues in the presence of the compacted proteoglycan filaments, different substances within the fluid can diffuse through the tissues at least 95 percent as easily as they normally diffuse. Therefore, the usual diffusion of nutrients to the cells and the removal of waste products from the cells are not compromised by the proteoglycan fila-ments of the interstitium.(1) Safety Factor Caused by Low Compliance of the Interstitium in the Negative Pressure Range (Low compliance of the interstitium when interstitial fluid pressure is in the negative pressure range)

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In most loose subcutaneous tissues of the body is slightly less than atmospheric pressure, averaging about –3 mm Hg. This slight suction in the tissues helps hold the tissues together. In the negative pressure range (less than 0 mmHg), the compliance of the tissues is low.Low compliance (small change in volume large increase in interstitial fluid hydrostaticPressure (or interstitial free fluid pressure) opposes further capillary filtrationIn the positive pressure range (above 0 mmHg), the compliance of the tissues is high.High compliance (large change in volume small increase in interstitial fluid hydrostaticPressure (or interstitial free fluid pressure) no further opposes capillary filtrationedema

Because the normal interstitial fluid hydrostatic pressure is –3 mm Hg, the interstitial fluid hydrostatic pressure must increase by about 3 mm Hg before large amounts of fluid will begin to accumulate in the tissues. Therefore, the safety factor against edema is a change of interstitial fluid pressure of about 3 mm Hg. (2) Increased Lymph Flow as a Safety Factor against EdemaThe lymphatics act as a safety factor against edema because lymph flow can increase 10- to 50-fold when fluid begins to accumulate in the tissues. This allows the lymphatics to carry away large amounts of fluid and proteins in response to increased capillary filtration, preventing the interstitial pressure from rising into the positive pressure range. The safety factor caused by increased lymph flow has been calculated to be about 7 mm Hg.(3) “Wash down” of the Interstitial Fluid Protein as a Safety Factor against Edema

As increased amounts of fluid are filtered into the interstitium,

The interstitial fluid pressure increases,

Causing increased lymph flow.

The protein concentration of the interstitium decreases

Interstitial fluid colloid osmotic pressure decrease

Decrease net filtration pressure18

Decrease edemaThe safety factor from this effect has been calculated to be about 7 mm Hg.Factors That Can Increase Capillary FiltrationTo understand the causes of excessive capillary filtration, it is useful to review the determinants of capillary filtration Qw = K ¿ [(Pc – Pi) –σ (πc – πi)]From this equation, one can see that any one of the following changes can increase the capillary filtration rate:Σ Increased capillary filtration coefficient.Σ Increased capillary hydrostatic pressure.Σ Decreased plasma colloid osmotic pressure.Causes of increase interstitial fluid and edema:

1. Increase filtration pressure :a) Arterial dilation.b) Venular constriction.c) Increase venous pressure: heart failureincompetent valves venous obstruction increase total ECF volume effect of gravity

2. Decrease osmotic pressure gradient across the capillary: a) Decrease plasma protein level.b) Accumulation of osmotically active substances in interstitium (as albumin and Na)

3. Increase capillary permeability : by any substance cause vasodilatation like: substance P, histamine,

4. Inadequate lymphatic flow : like in elephantiasisCAPILLARY EXCHANGE OF FLUID IN THE LUNGS AND PULMONARY INTERSTITIAL FLUID DYNAMICS The dynamics of fluid exchange across the lung capillary membranes are qualitatively the same as for peripheral tissues. However, quantitatively, there are important differences, as follows: 1. The pulmonary capillary pressure is low, about 7 mm Hg, in comparison with a considerably higher functional capillary pressure in the peripheral tissues of about 17 mm Hg. 2. The interstitial fluid pressure in the lung is slightly more negative than that in peripheral subcutaneous tissue. (This pressure has been measured in two ways: by a micropipette inserted into the pulmonary interstitium, giving a value of about −5 mm Hg, and by measuring the absorption pressure of fluid from the alveoli, giving a value of about −8 mm Hg.) 3. The colloid osmotic pressure of the pulmonary interstitial fluid is about 14 mm Hg, in comparison with less than half this value in the peripheral tissues. 4. The alveolar walls are extremely thin, and the alveolar epithelium covering the alveolar surfaces is so weak that it can be ruptured by any positive pressure in the interstitial spaces greater than alveolar air pressure (>0 mm Hg), which allows dumping of fluid from the interstitial spaces into the alveoli. Now let us see how these quantitative differences affect pulmonary fluid dynamics.

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Interrelations between Interstitial Fluid Pressure and Other Pressures in the Lung. The balance of forces at the blood capillary membrane, as follows:

Thus, the normal outward forces are slightly greater than the inward forces, providing a mean filtration pressure at the pulmonary capillary membrane that can be calculated as follows:

This filtration pressure causes a slight continual flow of fluid from the pulmonary capillaries into the interstitial spaces and, except for a small amount that evaporates in the alveoli, this fluid is pumped back to the circulation through the pulmonary lymphatic system.Negative Pulmonary Interstitial Pressure and the Mechanism for Keeping the Alveoli “Dry.” What keeps the alveoli from filling with fluid under normal conditions? If one remembers that the pulmonary capillaries and the pulmonary lymphatic system normally maintain a slight negative pressure in the interstitial spaces, it is clear that whenever extra fluid appears in the alveoli, it will simply be sucked mechanically into the lung interstitium through the small openings between the alveolar epithelial cells. The excess fluid is then carried away through the pulmonary lymphatic. This is estimated as equal to the pulmonary lymph flow rate. The flow is usually small (eg 10 to 20 ml/min) which is only about 2% of the pulmonary blood flow.Thus, under normal conditions, the alveoli are kept “dry,” except for a small amount of fluid that seeps from the epithelium onto the lining surfaces of the alveoli to keep them moist.

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Safety Factors Preventing Pulmonary OedemaFor pulmonary edema to occur, excess fluid must first accumulate in the interstitium (interstitial edema), then must move into the alveoli (alveolar flooding). The lung is relatively resistant to the onset of pulmonary oedema and this is usually ascribed to several safety factors:(1) Decrease in interstitial oncotic pressure (oncotic buffering mechanism): When filtration increases, the albumin loss in the filtrate decreases. This combined with the increased lymph flow washes the albumin out of the interstitium and interstitial oncotic pressure decreases. This protection does not work if the capillary membrane is damaged eg by septic mediators.(2)High interstitial compliance: A large volume of fluid can accumulate in the gel of the interstitium without much pressure rise. Finally, the interstial tissues become full of fluid, the pressure rises and alveolar flooding occurs. This has been called the bathtub effect: the analogy is that the tub can take a lot of fluid but there comes a point when it is full and suddenly overflows.(3)Low pulmonary capillary hydrostatic pressureExperiments in animals have shown that the pulmonary capillary pressure normally must rise to a value at least equal to the colloid osmotic pressure of the plasma inside the capillaries before significant pulmonary edema will occur

Remember that every time the left atrial pressure rises to high values, the pulmonary capillary pressure rises to a level 1 to 2 mm Hg greater than the left atrial pressure. In these experiments, as soon as the left atrial pressure rose above 23 mm Hg (causing the pulmonary capillary pressure to rise above 25 mm Hg), fluid began to accumulate in the lungs. This fluid accumulation increased even more rapidly with further increases in capillary pressure. The plasma colloid osmotic pressure during these experiments was equal to this 25 mm Hg critical pressure level. Therefore, in the human being, whose normal plasma colloid osmotic pressure is 28 mm Hg, one can predict that the pulmonary capillary pressure must rise from the normal level of 7 mm Hg to more than 28 mm Hg to cause pulmonary edema, giving an acute safety factor against pulmonary edema of 21 mm Hg. (4) Increased lymph flowSafety Factor in Chronic Conditions (rapidity of increase in pulmonary capillary pressure):When the pulmonary capillary pressure remains elevated chronically (for at least 2 weeks), the lungs become even more resistant to pulmonary edema because the lymph vessels expand greatly, increasing their capability of carrying fluid away from the interstitial spaces perhaps as much as 10-fold. Therefore, in patients with chronic mitral stenosis, pulmonary capillary pressures of 40 to 45 mm Hg have been measured without the development of lethal pulmonary edema. Rapidity of Death in Persons with Acute Pulmonary Edema (degree of increase in pulmonary capillary pressure):

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When the pulmonary capillary pressure rises even slightly above the safety factor level, lethal pulmonary edema can occur within hours, or even within 20 to 30 minutes if the capillary pressure rises 25 to 30 mm Hg above the safety factor level. Thus, in acute left-sided heart failure, in which the pulmonary capillary pressure occasionally does rise to 50 mm Hg, death may ensue in less than 30 minutes as a result of acute pulmonary edema.

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