Lymphatics return excess interstitial fluid to the blood
Lymphatics arise in the interstitium as small, thin-walled channels of endothelial cells that then join together to form increasingly larger vessels (Fig. 20-11). The initial lymphatics (previously called terminal lymphatics) are similar to capillaries but with many interendothelial junctions that behave like one-way microvalves, also called primary lymph valves. Anchoring filaments tether the initial lymphatics to surrounding connective tissue. The walls of the larger collecting lymphatics are similar to those of small veins, consisting of endothelium and sparse smooth muscle. The large lymphatic vessels, like the veins, have secondary lymph valves that restrict retrograde movement of lymph. Lymph nodes are located along the path of the collecting lymphatics. The large lymphatics ultimately drain into the left and right subclavian veins.
FIGURE 20-11 Flow of lymph into initial and collecting lymphatics.
At the level of the initial lymphatics, interendothelial junctions have few tight junctions or adhesion molecules connecting neighboring endothelial cells. As a result, flaps of endothelial cells can overlap with each other and act as the microvalve discussed above. Although initial lymphatics may appear collapsed and show no contractile activity, a pressure gradient from the interstitial fluid to the lymphatic lumen deforms the endothelial cells so that the microvalves open and fluid enters the initial lymphatic during the expansion phase (see Fig. 20-11A). During this time, the secondary lymph valves are closed.
External pressure (e.g., from skeletal muscle) shuts the microvalves and causes fluid to enter larger lymphatics through the now open secondary lymph valves (see Fig. 20-11B).
Most organs contain both initial and collecting lymphatics, but skeletal muscle and intestine have only initial lymphatics within their tissue. Lymphatics are absent from the brain. They are most prevalent in the skin and the genitourinary, respiratory, and gastrointestinal tracts.
As we have already seen, filtration at the arteriolar end of capillaries is estimated to exceed absorption at the venular end by 2 to 4 L/day. However, fluid does not normally accumulate in the interstitium because this excess fluid and protein move into the lymphatics. Thus, each day, the lymphatics return to the circulation 2 to 4 L of interstitial fluid, maintaining a steady state. In a model of congenital lymphedema, mice with genetic absence of initial lymphatics have elevated Pif and πif as well as interstitial volume expansion (i.e., edema), a finding that emphasizes the role of the lymphatics in returning fluid and protein from the interstitial space to the blood.
Flow in Initial Lymphatics
Hydrostatic pressure in the initial lymphatics (Plymph) ranges from −1 mm Hg to +1 mm Hg. Inasmuch as the mean interstitial fluid pressure is somewhat more negative than these values, what provides the driving force for interstitial fluid to move into the terminal lymphatics? Transient increases in Pif temporarily raise Pif above Plymph. Indeed, increases in mean Pif cause an increase in lymph flow (Fig. 20-12).
FIGURE 20-12 Dependence of lymph flow on interstitial pressure.
Because the interstitium exhibits a variable compliance (see p. 470), fluid added to the interstitium in its low-compliance range raises the Pif substantially, providing the driving force for fluid to enter the lymphatics. In this same range of Pif values, lymphatic flow is especially sensitive to increases in Pif (steep portion of curve in Fig. 20-12). Thus, lymphatic efflux nicely matches the excess capillary filtration, so that the interstitial fluid volume changes very little. The situation is very different if the interstitium is already expanded and in its high-compliance range. In this case, fluid added to the interstitium raises the already elevated Pif only moderately (e.g., from +2 to +4 mm Hg). In this range of Pif values, lymphatic uptake is not very responsive to increases in Pif (flat portion of the curve in Fig. 20-12). Thus, in this case, lymphatic return does not compensate well for the excess capillary filtration, so that interstitial fluid volume increases further (i.e., edema begets more edema).
Intermittent compression and relaxation of lymphatics occur during respiration, walking, and intestinal peristalsis. When Plymph in a downstream segment falls below that in an upstream segment, fluid aspiration produces unidirectional flow. This suction may be largely responsible for the subatmospheric values of the Pif observed in many tissues.
Flow in Collecting Lymphatics
Pressures in the collecting lymphatics range from +1 to +10 mm Hg, and they increase progressively with each valve along the vessel. As Plymph rises in the collecting lymphatic vessels, smooth muscle in the lymphatic walls actively contracts by an intrinsic myogenic mechanism that, as discussed below, also plays a role in blood vessels. Thus, downstream occlusion of a lymphatic vessel increases Plymph and hence the frequency of smooth-muscle contractions, whereas an upstream occlusion does the opposite. Because of the presence of one-way valves, smooth-muscle contraction drives lymph toward the veins. The rhythmic contraction and relaxation of VSMCs that we will discuss for blood vessels—vasomotion—also occurs in lymphatics and is essential for the propulsion of lymph.
In addition to vasomotion, passive processes also propel lymph toward the blood. As is the case for the initial lymphatics, skeletal muscle contraction, respiratory movements, and intestinal contractions all passively compress the collecting lymphatics. This intermittent pumping action moves lymph into the veins.
Transport of Proteins and Cells
Proteins that entered interstitial fluid from the capillary cannot return to the circulation because of the adverse chemical gradient across the capillary endothelial wall. The buildup of these macromolecules in the interstitium creates a diffusional gradient from the interstitium to the lymph that complements the convective movement of these macromolecules (along with fluid) into the lymphatic system. In an average person, the lymphatics return 100 to 200 g of proteins to the circulation each day. Even before lymph reaches lymph nodes, it contains leukocytes—which had moved from the blood into the interstitium—but no RBCs or platelets. Cycles of lymphatic compression and relaxation not only enhance fluid movement but also greatly increase the leukocyte count of lymph.
The circulation of extracellular fluids involves three convective loops: blood, interstitial fluid, and lymph
Extracellular fluid moves in three convective loops (Fig. 20-13). The first is the cardiovascular loop. Assuming a cardiac output of 5 L/min, the convective flow of blood through the circulation at rest is 7200 L/day. The second is the transvascular loop, in which fluid moves out of the capillaries at their arteriolar end and into the capillaries at their venular end. Not counting the kidney, whose glomeruli filter a vast amount of fluid (see p. 739), Landis and Pappenheimer estimated that all the other tissues of the body filter ~20 L/day at the arteriolar end of their capillaries and reabsorb 16 to 18 L at the venular end. As noted above (see pp. 472–474), both the filtration and absorption values are probably vast overestimates. Nevertheless, the difference between filtration and absorption, 2 to 4 L/day, is a reasonable estimate of the third fluid loop, the lymphatic loop.
FIGURE 20-13 Convective loops of extracellular fluid and protein.
In addition to convective exchange, a diffusional exchange of water and solutes also occurs across the capillaries. The diffusional exchange of water occurs at a much higher rate than does convective movement. Using deuterium oxide as a marker, investigators have found that this diffusional exchange is ~80,000 L/day across all of the body's systemic capillaries. This value is about an order of magnitude greater than blood flow in the cardiovascular loop and three orders of magnitude larger than the convective flow in the transvascular filtration/absorption loop of the microcirculation. However, the diffusion of water molecules is an exchange process that does not contribute appreciably to the net movement of water. In other words, every day, 80,000 L of water diffuses out of the capillaries and 80,000 L diffuses back.
For small solutes that can diffuse across the capillary endothelium, the traffic is quite different from the convective loops for water. Take glucose as an example. The plasma contains ~100 mg/dL glucose, RBCs have little glucose, and the cardiac output of plasma is ~2.75 L/min (assuming a hematocrit of 45%). Therefore, each day, the heart pumps ~4000 g of glucose. This glucose can enter the interstitium by two mechanisms. First, glucose is dissolved in the water filtered from the arteriolar end of the capillaries. Each day, this filtration process carries 20 L × 100 mg/dL = 20 g of glucose into the interstitium. Second, each day, ~20,000 g of glucose enters the interstitium by diffusion. Convection can supply only a small fraction of the ~400 g of glucose that the body consumes each day. Instead, diffusion supplies the majority of the glucose. Nevertheless, the 400 g/day of metabolized glucose is a minuscule fraction of the amount that enters the interstitium by diffusion. Thus, most of the glucose that diffuses into the interstitium diffuses back out again.
Protein traffic provides yet another pattern of circulatory loops. Plasma contains 7 g/dL of proteins, and—assuming a plasma volume of 3 L in a 70-kg human—total plasma protein content is ~210 g. Given a cardiac plasma output of 2.75 L/min, the heart pumps ~277,000 g of protein through the circulation every day. Of this protein, 100 to 200 g—nearly the entire plasma content of proteins—moves daily across the capillary walls through the large-pore system via a transcellular route (see p. 467) and to a lesser extent by solvent drag (see p. 467). Because only very small amounts of filtered protein return to the circulation by solvent drag at the venular end of capillaries (~5 g/day), nearly all of the filtered protein (95 to 195 g/day) depends on the convective lymphatic loop for its ultimate recovery.