The formation and composition of lymph

Lymph begins as an ultrafiltrate of blood at the arteriolar, high-pressure region of the capillary. Towards the venular end of the capillary, the hydrostatic pressure of the blood is much lower and this, together with the osmotic 'pull' of the blood plasma proteins, allows some of the water and crystalloids of the ultrafiltrate to be readsorbed (Figure 1). However, the protein component of the ultrafiltrate is not readsorbed and remains in the tissue spaces until it is carried away in the lymph. By virtue of its own colloid osmotic pressure (sometimes referred to as the 'oncotic' pressure) the protein retains some water and crystalloids with it, and it is this somewhat concentrated ultrafiltrate that constitutes the tissue fluid proper, which is the fluid that enters the peripheral lymphatics.

The composition of the tissue fluid varies some what from tissue to tissue, and with the level of activity, and hence blood pressure, of the individual. In general terms, the total protein concentration of the tissue fluid is about 25-30% of that of the blood plasma. It contains the whole range of blood plasma proteins, but their relative concentrations are different from those of the blood. This is because the ultrafiltration process functions as a molecular sieve so that smaller molecules, such as albumin (66 kDa) pass through relatively easily, but immunoglobulin G (IgG) is less well represented (150-170 kDa), and the large IgM molecule (970 kDa) is present at a concentration less than 8% of the blood plasma value.

The physiological basis for ultrafiltration and molecular sieving is unknown. It is explained best by the 'Pappenhiemer pore theory', which postulates that the capillary endothelium has the characteristics of a semipermeable membrane provided with 'pores' of graded sizes. The theory envisages that there arc more small pores through which albumin can pass than large ones that allow the escape of, for example, IgM. However, the pore theory is really a mathematical abstraction used to explain experimental results and it was not meant to imply that obvious pores exist as observable microanatomical entities. The structural basis of the 'pores' is debatable. Some workers believe that they consist of transient gaps between endothelial cells. Others believe that the real ultrafiltration apparatus resides in the basement membrane which surrounds the outer surface of the capillary endothelium. It has also been proposed that the extravasation of fluid and protein is brought about by the transcytosis of endocytic vesicles that traffic across the cytoplasm of the endothelial cell. So far, there is really no satisfactory detailed explanation of the observation that the ease with which plasma proteins escape from the circulating blood, across the capillary wall and into the tissue fluid, is inversely proportional to their mean diffusion diameters.

Despite these conceptual difficulties, it is relatively easy to measure the permeability characteristics of a given capillary bed. This is done by injecting intravenously a dose of plasma protein, usually albumin, labeled with, for example, a radioisotope. Lymph is then collected from the region under study at appropriate intervals and compared with corresponding samples of venous blood plasma. When the amount of radioactivity per unit weight of protein in the lymph is equal to that in the blood, 'equilibration' is said to have occurred. The elapsed rime between the initial injection and the equilibration is known as the 'equilibration time' and gives a relative measure of the permeability of the particular capillary bed.

For most mammalian somatic tissues, the equili-

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Low-prossuris venolar end of cap:lla/y

Lymphatic vassal wilh bfttcmen┬╗ mernbrnnc muscular coal and bicuspid voIvm

Figure 1 The principles of lymph formation. The high hydrostatic pressure at the arterial end of the capillary forces proteinaceous fluid through the capillary wall. At the venular end the hydrostatic pressure is low, and the colloid osmotic pressure of the plasma proteins causes the readsorption of water, electrolytes and crystalloids. The protein cannot be readsorbed and together with some water and solutes, it is drained away by the lymph. Note that the diagram is not to scale and in reality the diameter of the capillary just permits the passage of a red cell, while the larger white cells have to deform to pass through. This imposes a resistance to flow which helps to create the pressure drop between the arterial and venous ends of the capillary. (Reproduced with permission from Hall JG (1988) Lymphatic system in drug targeting. In: Gregoriadis G and Poste G (eds) Targeting of Drugs, Anatomical and Physiological Considerations, pp. 15-28. NATO ASI series Life Sciences, vol 155. New York: Plenum Press.)

Low-prossuris venolar end of cap:lla/y

Lymphatic vassal wilh bfttcmen┬╗ mernbrnnc muscular coal and bicuspid voIvm

Figure 1 The principles of lymph formation. The high hydrostatic pressure at the arterial end of the capillary forces proteinaceous fluid through the capillary wall. At the venular end the hydrostatic pressure is low, and the colloid osmotic pressure of the plasma proteins causes the readsorption of water, electrolytes and crystalloids. The protein cannot be readsorbed and together with some water and solutes, it is drained away by the lymph. Note that the diagram is not to scale and in reality the diameter of the capillary just permits the passage of a red cell, while the larger white cells have to deform to pass through. This imposes a resistance to flow which helps to create the pressure drop between the arterial and venous ends of the capillary. (Reproduced with permission from Hall JG (1988) Lymphatic system in drug targeting. In: Gregoriadis G and Poste G (eds) Targeting of Drugs, Anatomical and Physiological Considerations, pp. 15-28. NATO ASI series Life Sciences, vol 155. New York: Plenum Press.)

bration time for albumin is between 12 and 24 h, depending on the activity of the individual. There are, however, some major variations. For example, the endothelium of the portal sinusoids in the liver is fenestrated by ultrastructurally observable discontinuities. For this reason, there is no continuous barrier to impede the egress of the plasma proteins; the hepatic lymph plasma has a protein concentration almost as high as that of the blood, and the equilibration time is only 1-2 h.

At the other end of the scale is the central nervous system, which has no conventional lymphatic apparatus at all. The endothelial cells of the intracerebral capillaries are very tightly joined, so virtually no protein escapes. What little protein there is in the cerebrospinal fluid is provided by specialized tufts of vasculature in the choroid plexuses that lie on the floor of the ventricles. Nonetheless, there is a flow of fluid into the confines of the skull and an equivalent amount has to be removed to maintain the status quo.

Fluid is removed in two ways. First, small villous structures from the arachnoid membrane of the brain bulge into the main venous sinuses, and these arachnoid villi can be envisaged as a sort of private lymphatic system for the brain because they transmit excess fluid back into the venous blood. Second, some fluid tracks down the sheaths of the cranial nerves, particularly the olfactory nerves, and so gains entry into the nasal submucosae, where it is absorbed by conventional lymphatic vessels.

Fluid exchange in the lungs presents particular problems. The perfusion pressure is low, the blood pressure in the pulmonary arteries being much lower than in the arteries of the systemic circulation. Accordingly, in spite of the large blood flow, relatively little lymph is formed. Similarly, the low blood pressure makes the lung vasculature vulnerable to embolic phenomena. For example, white cells or tumor cells that are infused intravenously may be arrested temporarily in the lungs because there is not enough pressure to push them through the capillaries at the usual rate.

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