Guyton Ch 16 PDF: The Microcirculation and Lymphatic System

CHAPTER 16 UNIT IV The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow The mo...

CHAPTER 16 UNIT IV The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow The most purposeful functions of the microcirculation venules can still contract considerably, despite the weak are the transport of nutrients to the tissues and removal muscle. of cell excreta. The small arterioles control blood flow to This typical arrangement of the capillary bed is not each tissue, and local conditions in the tissues, in turn, found in all parts of the body, although a similar arrange- control the diameters of the arterioles. Thus, each tissue, ment may serve the same purposes. Most importantly, in most cases, controls its own blood flow in relationship the metarterioles and precapillary sphincters are in close to its individual needs as discussed in Chapter 17. contact with the tissues they serve. Therefore, the local The walls of the capillaries are thin and constructed of conditions of the tissues—such as the concentrations of single-layer, highly permeable endothelial cells. Therefore, nutrients, end products of metabolism, and hydrogen water, cell nutrients, and cell excreta can all interchange ions—can cause direct effects on the vessels to control quickly and easily between the tissues and circulating local blood flow in each small tissue area. blood. The peripheral circulation of the entire body has about Structure of the Capillary Wall. Figure 16-2 shows the 10 billion capillaries, with a total surface area estimated to ultramicroscopic structure of typical endothelial cells in be 500 to 700 square meters (about one eighth the surface the capillary wall as found in most organs of the body, area of a football field). It is rare that any single functional especially in muscles and connective tissue. Note that cell of the body is more than 20 to 30 micrometers away the wall is composed of a unicellular layer of endothelial from a capillary. cells and is surrounded by a thin basement membrane on the outside of the capillary. The total thickness of the capillary wall is only about 0.5 micrometer. The internal STRUCTURE OF THE MICROCIRCULATION diameter of the capillary is 4 to 9 micrometers, barely AND CAPILLARY SYSTEM large enough for red blood cells and other blood cells to The microcirculation of each organ is organized to squeeze through.! serve that organ’s specific needs. In general, each nutri- ent artery entering an organ branches six to eight times Pores in the Capillary Membrane. Figure 16-2 shows before the arteries become small enough to be called two small passageways connecting the interior of the cap- arterioles, which generally have internal diameters of illary with the exterior. One of these passageways is an in- only 10 to 15 micrometers. Then, the arterioles branch tercellular cleft, which is the thin-slitted, curving channel two to five times, reaching diameters of 5 to 9 microm- that lies at the top of the figure between adjacent endothe- eters at their ends, where they supply blood to the lial cells. Each cleft is interrupted periodically by short capillaries. ridges of protein attachments that hold the endothelial The arterioles are highly muscular, and their diameters cells together but, between these ridges, fluid can perco- can change by many times. The metarterioles (the termi- late freely through the cleft. The cleft normally has a uni- nal arterioles) do not have a continuous muscular coat, form spacing, with a width of about 6 to 7 nanometers (60 but smooth muscle fibers encircle the vessel at intermit- to 70 angstroms [Å]), which is slightly smaller than the tent points, as shown in Figure 16-1. diameter of an albumin protein molecule. At the point where each true capillary originates from Because the intercellular clefts are located only at the a metarteriole, a smooth muscle fiber usually encircles the edges of the endothelial cells, they usually represent no capillary. This structure is called the precapillary sphinc- more than 1/1000 of the total surface area of the capillary ter. This sphincter can open and close the entrance to the wall. Nevertheless, the rate of thermal motion of water capillary. molecules, as well as most water-soluble ions and small The venules are larger than the arterioles and have solutes, is so rapid that all these substances diffuse with a much weaker muscular coat. Yet, the pressure in the ease between the interior and exterior of the capillaries venules is much less than that in the arterioles, so the through these slit pores, the intercellular clefts. 193 UNIT IV The Circulation Arteriole Venule Intercellular cleft Basement membrane Precapillary sphincters Capillaries Caveolae (Plasmalemmal vesicles) Vesicular Endothelial channel?? cell Smooth Caveolin muscle cells Phospholipid Sphingolipid Cholesterol Metarteriole Arteriovenous bypass Figure 16-2. Structure of the capillary wall. Note especially the in- tercellular cleft at the junction between adjacent endothelial cells. It Figure 16-1. Components of the microcirculation. is believed that most water-soluble substances diffuse through the capillary membrane along the clefts. Small membrane invaginations, called caveolae, are believed to play a role in transporting macromol- Present in the endothelial cells are many minute plas- ecules across the cell membrane. Caveolae contain caveolins, which malemmal vesicles, also called caveolae (small caves). are proteins that interact with cholesterol and polymerize to form These plasmalemmal vesicles form from oligomers of pro- the caveolae. teins called caveolins that are associated with molecules of cholesterol and sphingolipids. Although the precise func- tions of caveolae are still unclear, they are believed to play 4. In the glomerular capillaries of the kidney, numer- a role in endocytosis (the process whereby the cell engulfs ous small oval windows called fenestrae penetrate all material from outside the cell) and transcytosis of mac- the way through the middle of the endothelial cells romolecules across the interior of the endothelial cells. so that tremendous amounts of small molecular and The caveolae at the surface of the cell appear to imbibe ionic substances (but not the large molecules of the small packets of plasma or extracellular fluid that contain plasma proteins) can filter through the glomeruli plasma proteins. These vesicles can then move slowly without having to pass through the clefts between through the endothelial cell. Some of these vesicles may the endothelial cells.! coalesce to form vesicular channels all the way through the endothelial cell, as shown in Figure 16-2.! FLOW OF BLOOD IN THE CAPILLARIES—VASOMOTION Special Types of Pores in Capillaries of Certain Or- gans. The pores in capillaries of some organs have special Blood usually does not flow continuously through the characteristics to meet the specific needs of the organs. capillaries. Instead, it flows intermittently, turning on and Some of these characteristics are as follows: off every few seconds or minutes. The cause of this inter- 1. In the brain, the junctions between the capillary en- mittency is the phenomenon called vasomotion, which dothelial cells are mainly tight junctions that allow only means intermittent contraction of the metarterioles and extremely small molecules such as water, oxygen, and precapillary sphincters (and sometimes even the very carbon dioxide to pass into or out of the brain tissues. small arterioles). 2. In the liver, the clefts between the capillary endothe- lial cells are nearly wide open so that almost all dis- Regulation of Vasomotion. The most important factor solved substances of the plasma, including the plasma affecting the degree of opening and closing of the metar- proteins, can pass from the blood into the liver tissues. terioles and precapillary sphincters that has been found 3. The pores of the gastrointestinal capillary mem- thus far is the concentration of oxygen in the tissues. branes are midway in size between those of the When the rate of oxygen usage by the tissue is great— muscles and those of the liver. so that tissue oxygen concentration decreases below 194 Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow Arterial end Blood capillary Venous end stituents in the plasma and interstitial fluids that do not readily pass through the capillary membrane.! Lipid-Soluble Substances Diffuse Directly Through the Cell Membranes of the Capillary Endothelium. If UNIT IV 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 trans- port through the capillary membrane are many times faster than the rates for lipid-insoluble substances, such as sodium ions and glucose, which can go only through Lymphatic capillary the pores.! Water-Soluble, Non–Lipid-Soluble Substances Diffuse Through Intercellular Pores in the Capillary Membrane. Figure 16-3. Diffusion of fluid molecules and dissolved substances Many substances needed by the tissues are soluble in wa- between the capillary and interstitial fluid spaces. ter but cannot pass through the lipid membranes of the endothelial cells; these include water molecules, sodium normal—the intermittent periods of capillary blood flow ions, chloride ions, and glucose. Although only 1/1000 occur more often, and the duration of each period of flow of the surface area of the capillaries is represented by lasts longer, thereby allowing the capillary blood to carry the intercellular clefts between the endothelial cells, the increased quantities of oxygen (as well as other nutrients) velocity of thermal molecular motion in the clefts is so to the tissues. This effect, along with multiple other fac- great that even this small area is sufficient to allow tre- tors that control local tissue blood flow, is discussed in mendous diffusion of water and water-soluble substances Chapter 17.! through these cleft pores. To give an idea of the rapidity with which these substances diffuse, the rate at which wa- Average Function of the Capillary System. Despite the ter molecules diffuse through the capillary membrane is fact that blood flow through each capillary is intermittent, about 80 times greater than the rate at which plasma itself so many capillaries are present in the tissues that their flows linearly along the capillary. That is, the water of the overall function becomes averaged. That is, there is an av- plasma is exchanged with the water of the interstitial fluid erage rate of blood flow through each tissue capillary bed, 80 times before the plasma can flow the entire distance an average capillary pressure within the capillaries, and an through the capillary.! average rate of transfer of substances between the blood of the capillaries and the surrounding interstitial fluid. In the Effect of Molecular Size on Passage Through the remainder of this chapter, we are concerned with these Pores. The width of the capillary intercellular cleft pores, averages, although it should be remembered that the av- 6 to 7 nanometers, is about 20 times the diameter of the erage functions are, in reality, the functions of billions of water molecule, which is the smallest molecule that nor- individual capillaries, each operating intermittently in re- mally passes through the capillary pores. The diameters sponse to local conditions in the tissues.! 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 in- EXCHANGE OF WATER, NUTRIENTS, termediate diameters. Therefore, the permeability of the AND OTHER SUBSTANCES BETWEEN capillary pores for different substances varies according THE BLOOD AND INTERSTITIAL FLUID to their molecular diameters. Table 16-1 lists the relative permeabilities of the capil- Diffusion Through the Capillary Membrane Is the lary pores in skeletal muscle for various substances, dem- Most Important Means of Transferring Substances onstrating, for example, that the permeability for glucose Between Plasma and Interstitial Fluid. Figure 16-3 il- molecules is 0.6 times that for water molecules, whereas lustrates that as the blood flows along the lumen of the the permeability for albumin molecules is very slight— capillary, tremendous numbers of water molecules and only one 1/1000 that for water molecules. dissolved particles diffuse back and forth through the cap- A word of caution must be stated at this point. The illary wall, providing continual mixing between the inter- capillaries in various tissues have extreme differences stitial fluid and plasma. Electrolytes, nutrients, and waste in their permeabilities. For example, the membranes of products of metabolism all diffuse easily through the cap- the liver capillary sinusoids are so permeable that even illary membrane. The proteins are the only dissolved con- plasma proteins pass through these walls, almost as easily 195 UNIT IV The Circulation Table 16-1 Relative Permeability of Skeletal Muscle Capillary Pores to Different-Sized Molecules Substance Molecular Weight Permeability Free fluid vesicles Water 18 1.00 NaCl 58.5 0.96 Urea 60 0.8 Rivulets Glucose 180 0.6 of free fluid Sucrose 342 0.4 Inulin 5000 0.2 Myoglobin 17,600 0.03 Hemoglobin 68,000 0.01 Albumin 69,000 0.001 Data from Pappenheimer JR: Passage of molecules through capillary walls. Physiol Rev 33:387, 1953. Collagen fiber Proteoglycan Capillary bundles filaments Figure 16-4. Structure of the interstitium. Proteoglycan filaments as water and other substances. Also, the permeability of are everywhere in the spaces between the collagen fiber bundles. Free fluid vesicles and small amounts of free fluid in the form of rivu- the renal glomerular membrane for water and electrolytes lets occasionally also occur. is about 500 times the permeability of the muscle capillar- ies, but this is not true for the plasma proteins. For these proteins, the capillary permeabilities are very slight, as INTERSTITIUM AND INTERSTITIAL FLUID in other tissues and organs. When we study these differ- ent organs later in this text, it should become clear why About one sixth of the total volume of the body consists some tissues require greater degrees of capillary perme- of spaces between cells, which collectively are called the ability than other tissues. For example, greater degrees of interstitium. The fluid in these spaces is called the inter- capillary permeability are required for the liver to transfer stitial fluid. tremendous amounts of nutrients between the blood and The structure of the interstitium is shown in Figure 16-4. liver parenchymal cells and for the kidneys to allow filtra- It contains two major types of solid structures: (1) collagen tion of large quantities of fluid for the formation of urine.! fiber bundles; and (2) proteoglycan filaments. The collagen fiber bundles extend long distances in the interstitium. Diffusion Through the Capillary Membrane Is Propor- They are extremely strong and provide most of the ten- tional to the Concentration Difference Between the sional strength of the tissues. The proteoglycan filaments, Two Sides of the Membrane. The greater the difference however, are extremely thin, coiled or twisted molecules between the concentrations of any given substance on the composed of about 98% hyaluronic acid and 2% protein. two sides of the capillary membrane, the greater the net These molecules are so thin that they cannot be seen with a movement of the substance in one direction through the light microscope and are difficult to demonstrate, even with membrane. For example, the concentration of oxygen in the electron microscope. Nevertheless, they form a mat of capillary blood is normally greater than in the interstitial very fine reticular filaments aptly described as a brush pile. fluid. Therefore, large quantities of oxygen normally move from the blood toward the tissues. Conversely, the con- Gel in the Interstitium. The fluid in the interstitium is centration of carbon dioxide is greater in the tissues than derived by filtration and diffusion from the capillaries. in the blood, which causes excess carbon dioxide to move It contains almost the same constituents as plasma ex- into the blood and to be carried away from the tissues. cept for much lower concentrations of proteins because The rates of diffusion through the capillary membranes proteins do not easily pass outward through the pores of of most nutritionally important substances are so great the capillaries. The interstitial fluid is entrapped mainly that only slight concentration differences cause more in the minute spaces among the proteoglycan filaments. than adequate transport between the plasma and inter- This combination of proteoglycan filaments and fluid en- stitial fluid. For example, the concentration of oxygen in trapped within them has the characteristics of a gel; it is the interstitial fluid immediately outside the capillary is therefore called tissue gel. no more than a few percent less than its concentration in Because of the large number of proteoglycan filaments, the plasma of the blood, yet this slight difference causes it is difficult for fluid to flow easily through the tissue gel. enough oxygen to move from the blood into the intersti- Instead, fluid mainly diffuses through the gel; that is, it tial spaces to provide all the oxygen required for tissue moves molecule by molecule from one place to another metabolism—often as much as several liters of oxygen per by kinetic thermal motion rather than by large numbers minute during very active states of the body.! of molecules moving together. 196 Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow Diffusion through the gel occurs about 95% to 99% Capillary Plasma colloid as rapidly as it does through free fluid. For the short dis- pressure osmotic pressure tances between the capillaries and tissue cells, this diffu- (Pc) (!p) sion allows for rapid transport through the interstitium, not only of water molecules but also of substances such UNIT IV as electrolytes, low-molecular-weight nutrients, cellular excreta, oxygen, and carbon dioxide.! Interstitial Interstitial fluid fluid pressure colloid osmotic pressure Free Fluid in the Interstitium. Although almost all the (Pif) (!if) fluid in the interstitium normally is entrapped within the Figure 16-5. Fluid pressure and colloid osmotic pressure forces op- tissue gel, occasionally small rivulets of free fluid and small erate at the capillary membrane and tend to move fluid outward or free fluid vesicles are also present, which means fluid that is inward through the membrane pores. 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 3. The capillary plasma colloid osmotic pressure small rivulets, usually coursing along the surfaces of col- (Πp), which tends to cause osmosis of fluid inward lagen fibers or surfaces of cells. through the capillary membrane The amount of free fluid present in most normal tis- 4. The interstitial fluid colloid osmotic pressure (Πif ), sues is slight, usually less than 1%. Conversely, when the which tends to cause osmosis of fluid outward tissues develop edema, these small pockets and rivulets of through the capillary membrane free fluid expand tremendously until one half or more of If the sum of these forces—the net filtration pressure— the edema fluid becomes free-flowing fluid, independent is positive, there will be a net fluid filtration across the of the proteoglycan filaments.! capillaries. If the sum of the Starling forces is negative, there will be a net fluid absorption from the interstitial spaces into the capillaries. The net filtration pressure FLUID FILTRATION ACROSS (NFP) is calculated as follows: CAPILLARIES NFP = Pc − Pif − ∏ p + ∏ if The hydrostatic pressure in the capillaries tends to force fluid and its dissolved substances through the capillary pores into As discussed later, the NFP is slightly positive under the interstitial spaces. Conversely, osmotic pressure caused normal conditions, resulting in a net filtration of fluid by the plasma proteins (called colloid osmotic pressure) across the capillaries into the interstitial space in most tends to cause fluid movement by osmosis from the inter- organs. The rate of fluid filtration in a tissue is also deter- stitial spaces into the blood. This osmotic pressure exerted mined by the number and size of the pores in each capil- by the plasma proteins normally prevents significant loss of lary, as well as the number of capillaries in which blood is fluid volume from the blood into the interstitial spaces. flowing. These factors are usually expressed together as Also important is the lymphatic system, which returns the capillary filtration coefficient (Kf). The Kf is therefore to the circulation the small amounts of excess protein and a measure of the capacity of the capillary membranes to fluid that leak from the blood into the interstitial spaces. filter water for a given NFP and is usually expressed as ml/ In the remainder of this chapter, we discuss the mecha- min per mm Hg NFP. nisms that control capillary filtration and lymph flow The rate of capillary fluid filtration is therefore deter- function together to regulate the respective volumes of mined as follows: the plasma and interstitial fluid. Filtration = K f × NFP Hydrostatic and Colloid Osmotic Forces Determine In the following sections, we discuss each of the forces Fluid Movement Through the Capillary Membrane. that determine the rate of capillary fluid filtration.! Figure 16-5 shows the four primary forces that deter- mine whether fluid will move out of the blood into the CAPILLARY HYDROSTATIC PRESSURE interstitial fluid or in the opposite direction. These forces, called Starling forces, were named after the physiologist Various methods have been used to estimate the capil- Ernest Starling who first demonstrated their importance: lary hydrostatic pressure: (1) direct micropipette cannu- 1. The capillary hydrostatic pressure (Pc), which tends to lation of the capillaries, which gives an average capillary force fluid outward through the capillary membrane pressure of about 25 mm Hg in some tissues, such as 2. The interstitial fluid hydrostatic pressure (Pif ), the skeletal muscle and gut, and (2) indirect functional which tends to force fluid inward through the cap- measurement of the capillary pressure, which gives a illary membrane when Pif is positive but outward capillary pressure averaging about 17 mm Hg in these when Pif is negative tissues. 197 UNIT IV The Circulation Micropipette Method for Measuring Capillary Pressure. Interstitial Fluid Pressures in Tightly Encased Tissues. To measure pressure in a capillary by cannulation, a micro- Some tissues of the body are surrounded by tight en- scopic glass pipette is thrust directly into the capillary, and casements, such as the cranial vault around the brain, the pressure is measured by an appropriate micromanome- the strong fibrous capsule around the kidney, the fibrous ter system. Using this method, capillary pressures have been sheaths around the muscles, and the sclera around the measured in exposed tissues of animals and in large capillary eye. In most of these tissues, regardless of the method loops of the eponychium at the base of the fingernail in hu- used for measurement, the interstitial fluid pressures are mans. These measurements have given pressures of 30 to 40 mm Hg in the arterial ends of the capillaries, 10 to 15 mm positive. However, these interstitial fluid pressures al- Hg in the venous ends, and about 25 mm Hg in the middle. most invariably are still less than the pressures exerted In some capillaries, such as the glomerular capillaries on the outsides of the tissues by their encasements. For of the kidneys, the pressures measured by the micropipette example, the cerebrospinal fluid pressure surrounding the method are much higher, averaging about 60 mm Hg. The brain of an animal lying on its side averages about +10 peritubular capillaries of the kidneys, in contrast, have a mm Hg, whereas the brain interstitial fluid pressure aver- hydrostatic pressure that averages only about 13 mm Hg. ages about +4 to +6 mm Hg. In the kidneys, the capsular Thus, the capillary hydrostatic pressures in different tissues pressure surrounding the kidney averages about +13 mm are highly variable, depending on the particular tissue and Hg, whereas the reported renal interstitial fluid pressures the physiological condition.! have averaged about +6 mm Hg. Thus, if one remembers that the pressure exerted on the skin is atmospheric pres- INTERSTITIAL FLUID HYDROSTATIC sure, which is considered to be zero pressure, one might PRESSURE formulate a general rule that the normal interstitial fluid There are several methods for measuring interstitial fluid pressure is usually several millimeters of mercury negative hydrostatic pressure, each of which gives slightly different with respect to the pressure that surrounds each tissue. values, depending on the method used and the tissue in In most natural cavities of the body, where there is free which the pressure is measured. In loose subcutaneous fluid in dynamic equilibrium with the surrounding inter- tissue, interstitial fluid pressure measured by the differ- stitial fluids, the pressures that have been measured have ent methods is usually a few millimeters of mercury less been negative. Some of these cavities and pressure mea- than atmospheric pressure; that is, the values are called surements are as follows: negative interstitial fluid pressure. In other tissues that are surrounded by capsules, such as the kidneys, the intersti- tial pressure is generally positive (i.e., greater than atmo- ! spheric pressure). The methods most widely used have been: (1) measurement of the pressure with a micropi- Summary: Interstitial Fluid Pressure in Loose Subcu- pette inserted into the tissues; (2) measurement of the taneous Tissue Usually Subatmospheric. Although the pressure from implanted perforated capsules; and (3) aforementioned different methods give slightly different measurement of the pressure from a cotton wick inserted values for interstitial fluid pressure, most physiologists into the tissue. These different methods provide differ- believe that the interstitial fluid pressure in loose subcu- ent values for interstitial hydrostatic pressure, even in the taneous tissue is, in normal conditions, slightly less subat- same tissues. mospheric, averaging about −3 mm Hg.! Measurement of Interstitial Fluid Pressure Using Pumping by the Lymphatic System—Basic Cause Micropipettes. The same type of micropipette used for meas- of the Negative Interstitial Fluid Pressure. The lym- uring capillary pressure can also be used in some tissues for phatic system is discussed later in the chapter, but first we measuring interstitial fluid pressure. The tip of the micropi- need to understand the basic role that this system plays pette is about 1 micrometer in diameter, but even this is 20 or in determining interstitial fluid pressure. The lymphatic more times larger than the sizes of the spaces between the pro- system is a kind of scavenger system that removes excess teoglycan filaments of the interstitium. Therefore, the pressure fluid, excess protein molecules, debris, and other matter that is measured is probably the pressure in a free fluid pocket. Pressures measured using the micropipette method from the tissue spaces. Normally, when fluid enters the range from −2 to +2 mm Hg in loose tissues, such as skin terminal lymphatic capillaries, the lymph vessel walls au- but, in most cases, they average slightly less than atmos- tomatically contract for a few seconds and pump the fluid pheric pressure.! into the blood circulation. This overall process creates the Measurement of Interstitial Free Fluid Pressure in slight negative pressure that has been measured for fluid Implanted Perforated Hollow Capsules. Interstitial free in the interstitial spaces.! fluid pressure measured when using 2-centimeter diam- eter capsules in normal loose subcutaneous tissue averages about −6 mm Hg but, with smaller capsules, the values are PLASMA COLLOID OSMOTIC PRESSURE not greatly different from the −2 mm Hg measured by the Plasma Proteins Cause Colloid Osmotic Pressure. As micropipette.! discussed in Chapter 4, only the molecules or ions that fail 198 Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow to pass through the pores of a semipermeable membrane total quantity of protein in the plasma but, because this exert osmotic pressure. Because the proteins are the only volume is four times the volume of plasma, the average dissolved constituents in the plasma and interstitial fluids protein concentration of the interstitial fluid of most tis- that do not readily pass through the capillary pores, it is sues is usually only 40% of that in plasma, or about 3 g/ the proteins of the plasma and interstitial fluids that are dl. Quantitatively, the average interstitial fluid colloid UNIT IV responsible for the osmotic pressures on the two sides of osmotic pressure for this concentration of proteins is the capillary membrane. To distinguish this osmotic pres- about 8 mm Hg.! sure from that which occurs at the cell membrane, it is called colloid osmotic pressure or oncotic pressure. The FLUID VOLUME EXCHANGE THROUGH term colloid osmotic pressure is derived from the fact that THE CAPILLARY MEMBRANE a protein solution resembles a colloidal solution, despite the fact that it is actually a true molecular solution.! The different factors affecting fluid movement through the capillary membrane have been discussed, so we can Normal Values for Plasma Colloid Osmotic Pressure. put all these factors together to see how the capillary sys- The colloid osmotic pressure of normal human plasma av- tem maintains normal fluid volume distribution between erages about 28 mm Hg; 19 mm of this pressure is caused the plasma and interstitial fluid. by molecular effects of the dissolved protein, and 9 mm is The average capillary pressure at the arterial ends caused by the Donnan effect—that is, extra osmotic pres- of the capillaries is 15 to 25 mm Hg greater than at sure caused by sodium, potassium, and the other cations the venous ends. Because of this difference, fluid filters bound to the plasma proteins.! out of the capillaries at their arterial ends but, at their venous ends, fluid is reabsorbed back into the capillaries Effect of the Different Plasma Proteins on Colloid Osmotic (see Figure 16-3). Thus, a small amount of fluid actually Pressure. The plasma proteins are a mixture that contains al- “flows” through the tissues from the arterial ends of the bumin, globulins, and fibrinogen, with an average molecular capillaries to the venous ends. The dynamics of this flow weight of 69,000, 140,000, and 400,000, respectively. Thus, 1 are as follows. 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. It should be Analysis of the Forces Causing Filtration at the recalled from the discussion of osmotic pressure in Chapter Arterial End of the Capillary. The approximate average 4 that osmotic pressure is determined by the number of mol- forces operative at the arterial end of the capillary that ecules dissolved in a fluid rather than by the mass of these mol- cause movement through the capillary membrane are ecules. The following chart gives both the relative mass con- shown as follows: centrations (g/dl) of the different types of proteins in normal mm Hg plasma and their respective contributions to the total plasma Forces Tending to Move Fluid Outward colloid osmotic pressure (Πp). These values include the Don- nan effect of ions bound to the plasma proteins: Capillary hydrostatic pressure (arterial end of 30 capillary) g/dl Πp (mm Hg) Negative interstitial fluid hydrostatic pressure 3 Albumin 4.5 21.8 Interstitial fluid colloid osmotic pressure 8 Globulins 2.5 6.0 TOTAL OUTWARD FORCE 41 Fibrinogen 0.3 0.2 Total 7.3 28.0 Forces Tending to Move Fluid Inward Thus, about 80% of the total colloid osmotic pressure of Plasma colloid osmotic pressure 28 the plasma results from the albumin, 20% from the globu- TOTAL INWARD FORCE 28 lins, and almost none from fibrinogen. Therefore, from the point of view of capillary and tissue fluid dynamics, it is Summation of Forces mainly albumin that is important.! Outward 41 Inward 28 INTERSTITIAL FLUID COLLOID OSMOTIC NET OUTWARD FORCE (AT ARTERIAL END) 13 PRESSURE Although the size of the usual capillary pore is smaller Thus, the summation of forces at the arterial end of than the molecular sizes of the plasma proteins, this is not the capillary shows a net filtration pressure of 13 mm Hg, true of all the pores. Therefore, small amounts of plasma tending to move fluid outward through the capillary pores. proteins do leak into the interstitial spaces through pores This 13 mm Hg filtration pressure causes, on average, and by transcytosis in small vesicles. about 1/200 of the plasma in the flowing blood to filter out The total quantity of protein in the entire 12 liters of of the arterial ends of the capillaries into the interstitial interstitial fluid of the body is slightly greater than the spaces each time the blood passes through the capillaries.! 199 UNIT IV The Circulation Analysis of Reabsorption at the Venous End of the mm Hg Capillary. The low blood pressure at the venous end of Interstitial fluid colloid osmotic pressure 8.0 the capillary changes the balance of forces in favor of ab- TOTAL OUTWARD FORCE 28.3 sorption as follows: mm Hg Mean Forces Tending to Move Fluid Inward Forces Tending to Move Fluid Inward Plasma colloid osmotic pressure 28.0 Plasma colloid osmotic pressure 28 TOTAL INWARD FORCE 28.0 TOTAL INWARD FORCE 28 Summation of Mean Forces Forces Tending to Move Fluid Outward Outward 28.3 Capillary hydrostatic pressure (venous end of 10 Inward 28.0 capillary) NET OUTWARD FORCE 0.3 Negative interstitial fluid hydrostatic pressure 3 Interstitial fluid colloid osmotic pressure 8 Thus, for the total capillary circulation, we find a near- TOTAL OUTWARD FORCE 21 equilibrium between the total outward forces, 28.3 mm Hg, and the total inward force, 28.0 mm Hg. This slight imbal- Summation of Forces ance of forces, 0.3 mm Hg, causes slightly more filtration Inward 28 of fluid into the interstitial spaces than reabsorption. This Outward 21 slight excess of filtration is called net filtration, and it is the NET INWARD FORCE 7 fluid that must be returned to the circulation through the lymphatics. The normal rate of net filtration in the entire Thus, there is a net reabsorption pressure of 7 mm Hg body, not including the kidneys, is only about 2 ml/min.! at the venous ends of the capillaries. This reabsorption pressure is considerably less than the filtration pressure at CAPILLARY FILTRATION COEFFICIENT the capillary arterial ends, but remember that the venous capillaries are more numerous and more permeable than In the previous example, an average net imbalance of the arterial capillaries. Thus less reabsorption pressure is forces at the capillary membranes of 0.3 mm Hg causes required to cause inward movement of fluid. net fluid filtration in the entire body of 2 ml/min. Express- The reabsorption pressure causes about nine tenths ing the net fluid filtration rate for each mm Hg imbalance, of the fluid that has filtered out of the arterial ends of one finds a net filtration rate of 6.67 ml/min of fluid per the capillaries to be reabsorbed at the venous ends. The mm Hg for the entire body. This value is called the whole remaining one tenth flows into the lymph vessels and body capillary filtration coefficient. returns to the circulating blood.! The filtration coefficient can also be expressed for sepa- rate parts of the body in terms of the rate of filtration per minute per mm Hg per 100 grams of tissue. On this basis, STARLING EQUILIBRIUM FOR CAPILLARY the capillary filtration coefficient of the average tissue is EXCHANGE about 0.01 ml/min per mm Hg per 100 g of tissue. How- Ernest Starling pointed out more than a century ago that ever, because of extreme differences in permeabilities and under normal conditions, a state of near-equilibrium surface areas of the capillary systems in different tissues, exists in most capillaries. That is, the amount of fluid this coefficient varies more than 100-fold among the dif- filtering outward from the arterial ends of capillaries ferent tissues. It is very small in brain and muscle, mod- almost exactly equals the fluid returned to the circulation erately large in subcutaneous tissue, large in the intestine, by absorption. The slight disequilibrium that does occur and extremely large in the liver and glomerulus of the kid- accounts for the fluid that is eventually returned to the ney, where the capillary surface is large, and the pores are circulation by way of the lymphatics. numerous or wide open. By the same token, the permeation The following chart shows the principles of the Starling of proteins through the capillary membranes also varies equilibrium. For this chart, the pressures in the arterial greatly. The concentration of protein in the interstitial fluid and venous capillaries are averaged to calculate mean the of muscles is about 1.5 g/dl; in subcutaneous tissue, it is 2 functional capillary pressure for the entire length of the g/dl; in the intestine, it is 4 g/dl; and, in the liver, it is 6 g/dl. capillary. This mean functional capillary pressure is calcu- lated to be 17.3 mm Hg. Effect of Abnormal Imbalance of Forces at the Capil- mm Hg lary Membrane. If the mean capillary pressure rises signif- Mean Forces Tending to Move Fluid Outward icantly above the average value of 17 mm Hg, the net force tending to cause filtration of fluid into the tissue spaces rises. Mean capillary pressure 17.3 Thus, a 20-mm Hg rise in mean capillary pressure causes an Negative interstitial fluid hydrostatic pressure 3.0 increase in net filtration pressure from 0.3 to 20.3%mm%Hg, 200 Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow Masses of lymphocytes and macrophages Cervical nodes UNIT IV Subclavian vein R. lymphatic duct Axillary nodes Thoracic duct Cisterna chyli Abdominal nodes Inguinal nodes Lymphatic vessel Peripheral lymphatics Blood capillary Tissue cell Lymphatic capillary Interstitial fluid Figure 16-6. The lymphatic system. which results in 68 times as much net filtration of fluid into LYMPH CHANNELS OF THE BODY the interstitial spaces as normally occurs. To prevent accu- mulation of excess fluid in these spaces would require 68 Almost all tissues of the body have special lymph chan- times the normal flow of fluid into the lymphatic system, an nels that drain excess fluid directly from the interstitial amount that is 2 to 5 times too much for the lymphatics to spaces. The exceptions include the superficial portions carry away. As a result, fluid will begin to accumulate in the of the skin, central nervous system, endomysium of mus- interstitial spaces and edema will result. cles, and bones. However, even these tissues have minute Conversely, if the capillary pressure falls very low, net interstitial channels called prelymphatics through which reabsorption of fluid into the capillaries will occur instead interstitial fluid can flow; this fluid eventually empties of net filtration, and the blood volume will increase at the into lymphatic vessels or, in the case of the brain, into expense of the interstitial fluid volume. These effects of the cerebrospinal fluid and then directly back into the imbalance at the capillary membrane in relationship to blood. the development of the different types of edema are dis- Essentially all the lymph vessels from the lower part of cussed in Chapter 25.! the body eventually empty into the thoracic duct, which in turn empties into the blood venous system at the juncture of the left internal jugular vein and left subclavian vein, as LYMPHATIC SYSTEM shown in Figure 16-6. The lymphatic system represents an accessory route Lymph from the left side of the head, left arm, and parts through which fluid can flow from the interstitial spaces of the chest region also enters the thoracic duct before it into the blood. Most importantly, the lymphatics can carry empties into the veins. proteins and large particulate matter away from the tissue Lymph from the right side of the neck and head, right spaces, neither of which can be removed by absorption arm, and parts of the right thorax enters the right lymph directly into the blood capillaries. This return of proteins duct (much smaller than the thoracic duct), which emp- to the blood from the interstitial spaces is an essential func- ties into the blood venous system at the juncture of the tion, without which we would die within about 24 hours. right subclavian vein and internal jugular vein. 201 UNIT IV The Circulation 20 Relative lymph flow Endothelial cells Valves 10 2 times/ 7 times/ mm Hg mm Hg 1 Anchoring filaments −6 −4 −2 0 2 4 Figure 16-7. Special structure of the lymphatic capillaries that per- Pif (mm Hg) mits passage of substances of high molecular weight into the lymph. Figure 16-8. Relationship between interstitial fluid pressure and lymph flow in the leg of a dog. Note that lymph flow reaches a Terminal Lymphatic Capillaries and Their Perme- maximum when the interstitial pressure (Pif) rises slightly above ability. Most of the fluid filtering from the arterial ends atmospheric pressure (0 mm Hg). (Courtesy Dr. Harry Gibson and of blood capillaries flows among the cells and finally is Dr. Aubrey Taylor.) reabsorbed back into the venous ends of the blood capil- laries but, on average, about one tenth of the fluid instead The protein concentration in the interstitial fluid of enters the lymphatic capillaries and returns to the blood most tissues averages about 2 g/dl, and the protein con- through the lymphatic system rather than through the centration of lymph flowing from these tissues is near this venous capillaries. The total quantity of all this lymph is value. Lymph formed in the liver has a protein concentra- normally only 2 to 3 L/day. tion as high as 6 g/dl, and lymph formed in the intestines The fluid that returns to the circulation by way of the has a protein concentration as high as 3 to 4 g/dl. Because lymphatics is extremely important because substances about two thirds of all lymph normally is derived from the of high molecular weight, such as proteins, cannot be liver and intestines, the thoracic duct lymph, which is a absorbed from the tissues in any other way, although mixture of lymph from all areas of the body, usually has a they can enter the lymphatic capillaries almost unim- protein concentration of 3 to 5 g/dl. peded. The reason for this mechanism is a special The lymphatic system is also one of the major routes structure of the lymphatic capillaries, demonstrated in for absorption of nutrients from the gastrointestinal tract, Figure 16-7. This figure shows the endothelial cells of especially for absorption of virtually all fats in food, as the lymphatic capillary attached by anchoring filaments discussed in Chapter 66. After a fatty meal, thoracic duct to the surrounding connective tissue. At the junctions lymph sometimes contains as much as 1% to 2% fat. of adjacent endothelial cells, the edge of one endothe- Finally, even large particles, such as bacteria, can push lial cell overlaps the edge of the adjacent cell in such their way between the endothelial cells of the lymphatic a way that the overlapping edge is free to flap inward, capillaries and in this way enter the lymph. As the lymph thus forming a minute valve that opens to the interior of passes through the lymph nodes, these particles are the lymphatic capillary. Interstitial fluid, along with its almost entirely removed and destroyed, as discussed in suspended particles, can push the valve open and flow Chapter 34.! directly into the lymphatic capillary. However, this fluid has difficulty leaving the capillary once it has entered RATE OF LYMPH FLOW because any backflow closes the flap valve. Thus, the lymphatics have valves at the very tips of the terminal About 100 ml/hr of lymph flows through the thoracic lymphatic capillaries, as well as valves along their larger duct of a resting human, and approximately another 20 ml vessels, up to the point where they empty into the blood flows into the circulation each hour through other chan- circulation.! nels, making a total estimated lymph flow of about 120 ml/hr or 2 to 3 L/day. FORMATION OF LYMPH Effect of Interstitial Fluid Pressure on Lymph Flow. Lymph is derived from interstitial fluid that flows into the Figure 16-8 shows the effect of different levels of intersti- lymphatics. Therefore, lymph as it first enters the termi- tial fluid hydrostatic pressure on lymph flow, as measured nal lymphatics has almost the same composition as the in animals. Note that normal lymph flow is very little at interstitial fluid. interstitial fluid pressures more negative than the normal 202 Chapter 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow Pores Valves UNIT IV Lymphatic capillaries Collecting lymphatic Figure 16-9. Structure of lymphatic capillaries and a collecting lymphat- ic, with the lymphatic valves also shown. value of −6 mm Hg. Then, as the pressure rises to 0 mm duct, this lymphatic pump can generate pressure as high Hg (atmospheric pressure), flow increases more than 20- as 50 to 100 mm Hg.! fold. Therefore, any factor that increases interstitial fluid pressure also increases lymph flow if the lymph vessels are Pumping Caused by External Intermittent Compres- functioning normally. Such factors include the following: sion of the Lymphatics. In addition to the pumping caused by intrinsic intermittent contraction of the lymph vessel walls, any external factor that intermittently com- presses the lymph vessel can also cause pumping. In order of their importance, such factors are as follows: All these factors favor net fluid movement into the inter- stitium, thus increasing interstitial fluid volume, intersti- tial fluid pressure, and lymph flow all at the same time. However, note in Figure 16-8 that when the inter- stitial fluid hydrostatic pressure becomes 1 or 2 mm Hg The lymphatic pump becomes very active during exer- greater than atmospheric pressure (>0 mm Hg), lymph cise, often increasing lymph flow 10- to 30-fold. Con- flow fails to rise any further at still higher pressures. versely, during periods of rest, lymph flow is sluggish This results from the fact that the increasing tissue pres- (almost zero).! sure not only increases entry of fluid into the lymphatic capillaries, but also compresses the outside surfaces of Lymphatic Capillary Pump. The terminal lymphatic cap- the larger lymphatics, thus impeding lymph flow. At the illary is also capable of pumping lymph, in addition to the higher pressures, these two factors balance each other, pumping by the larger lymph vessels. As explained earlier so lymph flow reaches a maximum flow rate. This maxi- in the chapter, the anchoring filaments on the walls of the mum flow rate is illustrated by the upper level plateau in lymphatic capillaries tightly adhere to the surrounding Figure 16-8.! tissue cells. Therefore, each time excess fluid enters the tissue and causes the tissue to swell, the anchoring fila- Lymphatic Pump Increases Lymph Flow. Valves exist in ments pull on the wall of the lymphatic capillary, and fluid all lymph channels. Figure 16-9 shows typical valves for flows into the terminal lymphatic capillary through the collecting lymphatics into which the lymphatic capillaries junctions between the endothelial cells. Then, when the empty. tissue is compressed, the pressure inside the capillary in- Videos of exposed lymph vessels in animals and in creases and causes the overlapping edges of the endotheli- humans have shown that when a collecting lymphatic al cells to close like valves. Therefore, the pressure pushes or larger lymph vessel becomes stretched with fluid, the the lymph forward into the collecting lymphatic instead smooth muscle in the wall of the vessel automatically of backward through the cell junctions. contracts. Furthermore, each segment of the lymph ves- The lymphatic capillary endothelial cells also contain a sel between successive valves functions as a separate few contractile actomyosin filaments. In some animal tis- automatic pump. That is, even slight filling of a segment sues (e.g., a bat wing), these filaments have been observed causes it to contract, and the fluid is pumped through the to cause rhythmical contraction of the lymphatic capillar- next valve into the next lymphatic segment. This fluid fills ies in the same rhythmic way that many of the small blood the subsequent segment and a few seconds later it also vessels and larger lymphatic vessels contract. Therefore, contracts, with the process continuing all along the lymph it is probable that at least part of lymph pumping results vessel until the fluid is finally emptied into the blood cir- from lymph capillary endothelial cell contraction in addi- culation. In a very large lymph vessel, such as the thoracic tion to contraction of the larger muscular lymphatics.! 203 UNIT IV The Circulation Summary of Factors That Determine Lymph Flow. Significance of Negative Interstitial From the previous discussion, one can see that the two Fluid Pressure for Holding Body Tissues primary factors that determine lymph flow are (1) the in- Together terstitial fluid pressure and (2) the activity of the lymphat- Traditionally, it has been assumed that the different tis- ic pump. Therefore, one can state that, roughly, the rate sues of the body are held together entirely by connective of lymph flow is determined by the product of interstitial tissue fibers. However, connective tissue fibers are very fluid pressure times the activity of the lymphatic pump.! weak or even absent at many places in the body, particu- Lymphatic System Plays a Key Role in larly at points where tissues slide over one another (e.g., Controlling Interstitial Fluid Protein skin sliding over the back of the hand or over the face). Yet, Concentration, Volume, and Pressure even at these places, the tissues are held together by the negative interstitial fluid pressure, which is actually a par- It is already clear that the lymphatic system functions as tial vacuum. When the tissues lose their negative pressure, an overflow mechanism to return excess proteins and fluid accumulates in the spaces, and the condition known excess fluid volume from the tissue spaces to the circu- as edema occurs. This condition is discussed in Chapter 25. lation. 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