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Chapter 6
Physiology, Pathophysiology,
and Lymphodynamics: General Overview
Stanley G. Rockson
The lymphatic system is a component of both the circulatory and the immune systems. The principal functions of this system include the prevention of edema and
maintenance of interstitial fluid homeostasis, immune traffic (transportation of
white blood cells and antigen-presenting cells to the lymphoid organs), and lipid
absorption from the gastrointestinal tract.
Not surprisingly, this system requires a complex intersection of specific anatomy
and physiological function to accomplish these goals. Lymphatics are found
throughout the body, with the exception of the central nervous system, in which
cerebrospinal fluid fulfills the normal role of lymph. Lymphatic vasculature and
lymphoid tissue are prevalent in organs that come into direct contact with the external environment, such as the skin, gastrointestinal tract, and lungs.2 This distribution
likely reflects the protective role of the lymphatics against infectious agents and
alien particles. Absorption of fat from the intestine occurs through the lymphatic
system, which transports the lipids (chyle) to the liver. The lymphatic system also
transports cellular debris, metabolic waste products, and excess fluid (edema safety
factor) from local sites back to the systemic circulation.
In the extremities, the lymphatic system consists of a superficial (epifascial) system that collects lymph from the skin and subcutaneous tissue, and a deeper system
that drains subfascial structures, such as muscle, bone, and deep blood vessels. The
superficial and deep systems of the lower extremities merge within the pelvis,
whereas those of the upper extremity merge in the axilla. The two drainage systems
function in an interdependent fashion, such that the deep lymphatic system participates in lymph transport from the skin during lymphatic obstruction.
Lymphatic capillaries are lined by a single layer of overlapping endothelial cells
with a discontinuous basement membrane.4 These vascular structures, which lack
1
3
S.G. Rockson
Division of Cardiovascular Medicine, Stanford University
School of Medicine, Falk Cardiovascular Research Center,
Stanford, CA, USA
B.-B. Lee et al. (eds.), Lymphedema,
DOI 10.1007/978-0-85729-567-5_6, © Springer-Verlag London Limited 2011
59
60 S.G. Rockson
either pericytes or smooth muscle cell coverage, begin as blind-ended tubes that
interface with the interstitium. Tissue fluid can enter these initial lymphatic vessels
between discontinuous button-like cell junctions.
5
Interendothelial openings may allow cells (macrophages, lymphocytes, erythrocytes) and cellular debris to directly enter lymphatics.
6,7
Fluid transport into the
initial lymphatics apparently occurs against a pressure gradient. It is believed that
episodic increases in interstitial fluid pressure are created through tissue movement;
this combines with suction forces generated through the contraction of the collecting lymphatics.
8
The lymphatic capillary structures coalesce into progressively larger collecting
lymphatic vessels and, ultimately, the cisterna chyli and thoracic duct. Lymph returns
to the blood circulation through lymphaticovenous anastomoses. Since the lymphatics lack a central pump, lymph progresses through the concerted effects of respiratory motions, skeletal muscle contraction, and the autocontractility of the mural
smooth muscle of the vasculature itself. In skeletal muscle, lymphatics are usually
paired with arterioles, so that arterial pulsation can also contribute to the periodic
expansion and compression of initial lymphatics to enhance fluid uptake.
9
Lymph flow in the collectors depends predominantly on lymphatic contraction.
The rate of lymph transport can be augmented substantially by humoral and physical factors that influence the rhythm and amplitude of spontaneous contractions.
Lymph flow and lymphatic contractility increase in response to tissue edema, hydrostatic pressure (standing position), mechanical stimulation, and exercise.
2
Failure of adequate lymph transport promotes lymphedema and likely contributes to the pathological presentation of a wide variety of lymphatic vascular diseases. Accordingly, a detailed understanding of lymphatic anatomy, physiology, and
dynamics will certainly contribute to an informed response to diagnosis and therapeutic intervention. Similarly, a detailed understanding of normal lymphatic development should allow us to address pathological lymphatic conditions that lead to
inflammation, autoimmunity, cancer, and other forms of human disease.
1
References
1. Oliver G. Lymphatic vasculature development. Nat Rev Immunol. 2004;4(1):35-45.
2. Szuba A, Shin WS, Strauss HW, Rockson S. The third circulation: radionuclide lymphoscin-
tigraphy in the evaluation of lymphedema. J Nucl Med. 2003;44(1):43-57.
3. Brautigam P, Foldi E, Schaiper I, Krause T, Vanscheidt W, Moser E. Analysis of lymphatic
drainage in various forms of leg edema using two compartment lymphoscintigraphy. Lymphology.
1998;31(2):43-55.
4. Cueni LN, Detmar M. The lymphatic system in health and disease. Lymphat Res Biol. 2008;
6(3–4):109-22.
5. Baluk P, Fuxe J, Hashizume H, et al. Functionally specialized junctions between endothelial
cells of lymphatic vessels. J Exp Med. 2007;204(10):2349-62.
6. Ikomi F, Hanna GK, Schmid-Schonbein GW. Mechanism of colloidal particle uptake into the lym-
phatic system: basic study with percutaneous lymphography. Radiology. 1995;196(1):107-13.
6 Physiology, Pathophysiology, and Lymphodynamics: General Overview
7. Higuchi M, Fokin A, Masters TN, Robicsek F, Schmid-Schonbein GW. Transport of colloidal
particles in lymphatics and vasculature after subcutaneous injection. J Appl Physiol. 1999;
86(4):1381-7.
8. Reddy NP, Patel K. A mathematical model of flow through the terminal lymphatics. Med Eng
Phys. 1995;17(2):134-40.
9. Schmid-Schonbein GW. Microlymphatics and lymph flow. Physiol Rev. 1990;70(4):987-1028.
61
Chapter 7
Lymphodynamics
Stanley G. Rockson
As a tributary of the arteriovenous blood circulation, the lymphatic vasculature
plays an exquisite, finely modulated role in the regulation of body fluid homeostasis
and interstitial fluid balance. It is estimated that approximately one-sixth of the
body’s total volume resides in the interstitium (the spaces between cells).
Accordingly, the lymphatic circulation is responsible for unidirectional fluid
transport, moving protein-enriched fluid from the interstitium through a complex
vascular network that converges upon the thoracic duct(s) and, ultimately, the great
2
veins.
Given the near inaccessibility of the lymphatic vasculature to direct visualization
or instrumentation, it is not surprising that insight into the dynamics of this vascular
system has been slow to accrue. Nevertheless, substantial strides have been made,
particularly in the last 20 years.
Interstitial fluid becomes lymph once it enters the terminal lymphatics. The protein content of lymph is determined by the parenchyma of its origin. In most of the
body’s tissues, interstitial fluid protein concentration approximates 2 g/dl, but mesenteric lymph protein content approaches 3–4 g/dl and that of the liver is even
higher. Accordingly, lymph derived from the thoracic duct reflects the contributions
of these various elements, and approximates concentrations of 3–5 g/dl.
At rest, it is estimated that there are 2–3 l/day of lymph formed in the human
body. Thus, it is apparent that, in the absence of intact lymphatic transport mechanisms, circulatory collapse would occur in little more than a single day.
Entry of interstitial fluid into the lymphatic capillary is governed chiefly by
prevailing interstitial fluid pressure. Under steady-state conditions, the interstitial
fluid pressure is typically subatmospheric.3 If the pressure declines below the
normal value of −6 mmHg, lymph flow becomes negligible. At the other end of the
1
S.G. Rockson
Division of Cardiovascular Medicine, Stanford University School of Medicine,
Falk Cardiovascular Research Center, Stanford, CA, USA
B.-B. Lee et al. (eds.), Lymphedema,
DOI 10.1007/978-0-85729-567-5_7, © Springer-Verlag London Limited 2011
63
64 S.G. Rockson
spectrum, any physical force that increases interstitial fluid pressure will increase
lymph flow. Such factors chiefly reflect the influence of Starling forces, such that
increased capillary hydrostatic pressure, decreased plasma oncotic pressure,
and increased interstitial oncotic pressure, along with increased capillary permeability can all result in an increase in tissue lymph production. Lymph flow becomes
maximal when interstitial pressure is slightly higher than the atmospheric pressure.
Nevertheless, paradoxically, the prevailing pressure gradients do not seem to favor
fluid entry into the terminal lymphatics.2 It is conjectured, based upon available
evidence, that cyclical changes in prevailing pressure gradients create transient
forces that favor fluid entry.
4-6
Beyond hydrodynamics, in order to drive fluid transport through the vasculature,
the lymphatic circulation relies upon the effects of both intrinsic7 and extrinsic
pumps. The latter effect arises through cyclical lymphatic compression and expansion, through the operation of extrinsic tissue forces.2 Extrinsic forces can include
movement of parts of the body, contraction of skeletal musculature, arterial pulsation, and tissue compression by extrinsic forces.
Historically, the effect of physical activity on lymph flow was deduced from
direct measurements after direct thoracic duct cannulation but, previously, there
have been no studies of thoracic duct flow as a function of exercise intensity. It has
now become feasible to surgically instrument the canine thoracic lymph duct with
ultrasonic flow transducers and, after surgical recovery, to determine the effect of
exercise intensity.
8
Growing insights such as these are necessary in order to envision our full ability,
in future, to harness the forces of lymphatic physiology for enhanced lymphatic
imaging, diagnostics, and therapeutics.
References
1. Hall J. Guyton and Hall Textbook of Medical Physiology. 12th ed. Philadelphia: Saunders;
2010.
2. Zawieja DC. Contractile physiology of lymphatics. Lymphat Res Biol. 2009;7(2):87-96.
3. Aukland K, Reed RK. Interstitial-lymphatic mechanisms in the control of extracellular fluid
volume. Physiol Rev. 1993;73(1):1-78.
4. Negrini D, Moriondo A, Mukenge S. Transmural pressure during cardiogenic oscillations in
rodent diaphragmatic lymphatic vessels. Lymphat Res Biol. 2004;2(2):69-81.
5. Moriondo A, Mukenge S, Negrini D. Transmural pressure in rat initial subpleural lymphatics
during spontaneous or mechanical ventilation. Am J Physiol Heart Circ Physiol. 2005;289(1):
H263-9.
6. Grimaldi A, Moriondo A, Sciacca L, Guidali ML, Tettamanti G, Negrini D. Functional
arrangement of rat diaphragmatic initial lymphatic network. Am J Physiol Heart Circ Physiol.
2006;291(2):H876-85.
7. Olszewski WL, Engeset A. Intrinsic contractility of prenodal lymph vessels and lymph flow in
human leg. Am J Physiol. 1980;239(6):H775-83.
8. Desai P, Williams AG Jr, Prajapati P, Downey HF. Lymph flow in instrumented dogs varies
with exercise intensity. Lymphat Res Biol. 2010;8(3):143-8.
Chapter 8
Physiology, Biology, and Lymph Biochemistry
Waldemar L. Olszewski
Tissue Fluid
Tissue fluid is the basic fluid forming lymph. It is the capillary filtrate derived from
plasma by diffusion, filtration, and vesicular transport mixed with the preexisting
mobile intercellular fluid, containing local cell-produced proteins. It contains all
the protein fractions of plasma, but at lower levels. Because of the sieving mechanism that occurs during transport of macromolecules across the capillary wall, the
percentage of the total protein that is contributed by the small molecular weight
proteins tends to be greater than that in serum. There is still a lack of evidence that,
in the steady state, the protein concentration in afferent prenodal lymph differs
from that of interstitial fluid. Most authors assume that the lymph protein concentration is identical to that in the interstitium. This applies to both normal and
lymphedema conditions.
Tissue fluid proteins under normal conditions
and in obstructive lymphedema
Normal mobile tissue fluid is difficult to obtain because of its miniscule volumes. Its
mean total protein concentration ranges from 0.5 to 3.5 g%. In lymphedema there is
an excess of fluid and large volumes can be collected, allowing changes in protein
level to ensue because of the functional changes in the limb. The mean total protein
concentration is 2.3 g%, tissue fluid/serum (TF/S) 0.25; of immunoglobulin (Ig) G
0.65 g%, TF/S 0.47, and of C-reactive protein 0.6 mg/L, TF/S 1.2.
W.L. Olszewski
Department of Surgical Research and Transplantology,
Medical Research Centre, Warsaw, Poland
B.-B. Lee et al. (eds.), Lymphedema,
DOI 10.1007/978-0-85729-567-5_8, © Springer-Verlag London Limited 2011
65
66 W.L. Olszewski
0.8
α1-ACID-GLYCOPROTEIN
44 000 M.W.
49 000 M.W.
69 000 M.W.
81 000 M.W.
α
2
-HS-GLYCOPROTEIN
ALBUMIN
PLASMINOGEN
10:00
0
0.2
0.4
LYMPH/SERUM RATIO
0.6
CLOCK
HOURS
DAY
POSITION
AND
ACTIVITY
22:00 7:00 19:00
21
22:00 7:00
Lymph
Physiological Observations
Limb lymph protein concentration undergoes continuous changes depending on the
capillary filtration rate. This in turn depends on the capillary hydrostatic pressure,
which changes at various body positions, and the metabolic rate of tissues (muscular activity, temperature) increasing the number of dilated capillaries (increase in
filtration surface area; Fig. 8.1). The concentration of lymph in individual proteins
is inversely proportional to their molecular weight and molecule radius. The larger
the molecule the less of it in lymph (molecular sieving mechanism).
1-7
Fig. 8.1 Fluctuation of lymph protein level in the soft tissues of a normal human calf during normal limb activity, expressed as a lymph to serum ratio (L/S). A calf superficial lymphatic was
cannulated and lymph was collected over days and nights in various limb physical positions. Lying,
standing up, and contracting calf muscles changed the physical conditions for lymph formation,
which were expressed at different flow/concentration levels. High venous capillary pressure in an
upright position enhanced tissue fluid and lymph formation and subsequently more water with less
protein transport, whereas the horizontal position with low capillary pressure acted in an opposite
direction. Additionally, the concentrations differed depending on the molecular weight and size of
a given protein (see peak levels). The small acid glycoprotein was transported faster than the large
IgM. The tissue fluid and afferent lymph protein concentrations change, in contrast to the flowing
plasma, from minute to minute in various tissue regions, depending on the actual blood capillary
filtration rate (depending on intracapillary hydrostatic and oncotic pressures and filtration surface
area), local cell metabolism, the contractility of the lymphangions, and active lymph transport, as
well as extrinsic forces propelling lymph (striated muscle contractions)
8 Physiology, Biology, and Lymph Biochemistry
67
The mean concentration and lymph to serum ratio (L/S) of some immune proteins
in normal lymph, estimated in 24-h collected samples, are listed below. Total protein:
3.5 g% (0.5 during fast walking and 3.8 during night rest), L/S 0.39, and albumin
1.7–3.2 g%, L/S 0.13–0.48. Individual proteins arranged in order of increasing
molecular weight reach the following levels: alpha-1-glycoprotein 0.22 g%, L/S
0.45; prealbumin 0.12 g%, L/S 0.35; haptoglobin 0.15 g%, L/S 0.17; beta-lipoprotein
1.11 g%, L/S 0.2; IgM 0.23 g% L/S 0.08. Complement components: C3 0.191 g%,
L/S 0.21, and C1q 0.034, L/S 0.15. Cytokines: TNFbeta 12 mg/ml, L/S 1.0; IL1 beta
3.9 pg/ml, L/S 1.4; IL6 8 pg/ml, L/S 1.4; VEGF C 262 pg/ml, L/S 1.1.
Mobile tissue fluid and lymph protein concentration is low and oscillates between
10 and 50% of that of plasma. Admixture of locally synthetized proteins, like cytokines, raises their level to that above plasma with an L/S ratio above 1.0. Protein
concentration may be different in different regions of the limb soft tissues because
of the local capillary filtration and metabolic rate.
Proteins in Obstructive Lymphedema
Our data are: mean total protein 1.7 g%, L/S 0.25; IgG 350 mg%, L/S 0.28, IgM
23 mg%, L/S 0.1.
8-13
Generally, tissue fluid and lymph total protein concentration in lymphedema is
low. Moreover, there are no statistically significant differences in protein and
cytokine concentrations in tissue and fluid lymph between lymphedema and normal
samples. This contradicts the anecdotal notion of protein-rich edema. Our studies
are the first to be carried out in humans, clearly showing that the homeostatic mechanisms prevent generation of excessive protein concentrations and oncotic pressures. Starling’s law clearly shows that an increase in tissue fluid protein leads to a
rise in oncotic pressure. The effect of higher tissue oncotic pressure is an immediate
attraction of capillary water and dilution of tissue proteins. Increase in water volume
expands the tissue space, which is clinically recognized as edema. Expansion of
the tissue space is possible because of the high compliance of skin and subcutaneous tissue. Taken together, the total mass of accumulated protein in a lymphedematous tissue is high, but its concentration remains within physiological limits. High
tissue fluid and lymph concentrations may be seen only in inflamed tissues with
high capillary permeability and an excessive flux of plasma proteins.
Lymph Cytokines in Obstructive Lymphedema
Our data are: TNFalpha 6 pg/ml, L/S 3.5; IL1beta 4.5 pg/ml, L/S 1.4; IL6 60 pg/ml,
L/S 20; VEGF C 780 pg/ml, L/S 4.0.
Cytokines are low molecular proteins that easily penetrate the capillary wall.
However, they are also produced locally, in the case of skin and subcutaneous tissue,
68 W.L. Olszewski
by keratinocytes, fibroblasts, dermal macrophages, dendritic cells, and lymphocytes. The local contribution evidently increases lymph cytokine levels to those
above plasma. For example, the lymphatic endothelial-cell-produced VEGF C may
be 4–40 times higher in lymph than in plasma.
References
1. Olszewski WL, Engeset A, Sokolowski J. Lymph flow and protein in the normal male leg dur-
ing lying, getting up, and walking. Lymphology. 1977;10(3):178-83.
2. Olszewski W, Engeset A, Jaeger PM, Sokolowski J, Theodorsen L. Flow and composition of
leg lymph in normal men during venous stasis, muscular activity and local hyperthermia. Acta
Physiol Scand. 1977;99(2):149-55.
3. Olszewski WL, Engeset A, Lukasiewicz H. Immunoglobulins, complement and lysozyme in
leg lymph of normal men. Scand J Clin Lab Invest. 1977;37(8):669-74.
4. Olszewski WL, Engeset A. Haemolytic complement in peripheral lymph of normal men. Clin
Exp Immunol. 1978;32(3):392-8.
5. Olszewski WL, Engeset A. Immune proteins, enzymes and electrolytes in human peripheral
lymph. Lymphology. 1978;11(4):156-64.
6. Olszewski WL. Lymph protein concentration. In Lymph stasis – pathomechanism, diagnosis
and therapy. Boca Raton: CRC Press; 1991:243-56.
7. Interewicz B, Olszewski WL, Leak LV, Petricoin EF, Liotta LA. Profiling of normal human leg
lymph proteins using the 2-D electrophoresis and SELDI-TOF mass spectrophotometry
approach. Lymphology. 2004;37(2):65-72.
8. Plachta J, Olszewski WL, Grzelak I, Engeset A, Cholewka W. Identification of interleukin-1 in
normal human lymph derived from skin. Lymphokine Res. 1988;7(2):93-7.
9. Olszewski WL, Loe K, Engeset A. Immune proteins and other biochemical constituents of
peripheral lymph in patients with malignancy and postirradiation lymphedema. Lymphology.
1978;11(4):174-80.
10. Olszewski WL, Jamal S, Lukomska B, Manokaran G, Grzelak I. Immune proteins in periph-
eral tissue fluid-lymph in patients with filarial lymphedema of the lower limbs. Lymphology.
1992;25(4):166-71.
11. Olszewski WL, Pazdur J, Kubasiewicz E, Zaleska M, Cooke CJ, Miller NE. Lymph draining
from foot joints in rheumatoid arthritis provides insight into local cytokine and chemokine
production and transport to lymph nodes. Arthritis Rheum. 2001;44(3):541-9.
12. Olszewski WL. Pathophysiological aspects of lymphedema of human limbs: I Lymph protein
composition. Lymphat Res Biol. 2003;1(3):235-43.
13. Olszewski WL, Jain P, Ambujam G, Zaleska M, Cakala M. Cytokines in various types of lower
limb lymphedema. J Clin Invest 2010 (submitted).