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54 3. Lymphatic pumping and pathological consequences of its dysfunction
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CHAPTER
4
Hydrodynamic regulation of
lymphatic vessel transport
function and the impact of aging
Anatoliy A. Gashev, David C. Zawieja
Department of Medical Physiology, College of Medicine, Texas A&M
University Health Science Center, Temple, TX, United States
Concepts of intrinsic and extrinsic lymph pumps
There are several driving forces, varying by their origin, that sup-
port lymph flow. Historically these forces are divided into two
groups by reference to their sources: inside or outside of the spon-
taneous contracting lymphangions (the sections of lymphatic ves-
sels between adjacent valves) [1–3]. The term “active” or
“intrinsic” lymph pump describes the lymph driving force that is
generated by the active spontaneous contractions of lymphangions
themselves. The term “passive” or “extrinsic” lymph pump summa-
rizes together the influences of all other forces that are not generated
by active phasic and tonic contractions of lymphatic muscle cells
across lymphatic vessel wall. These latter forces may support more
or less the lymph flow in different regions of body.
Intrinsic lymph pump
There is no single pump in the lymphatic system similar to the
cardiovascular system where the energy of heart contractions is
enough to move blood through the whole blood circulation. Due
to the fact that the beginnings of lymphatic capillaries (initial
55Lymphatic Structure and Function in Health and Disease
https://doi.org/10.1016/B978-0-12-815645-2.00004-6
Copyright © 2020 Elsevier Inc. All rights reserved.
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lymphatics) do not normally have direct connections with blood
capillaries, the energy of contractions of the heart cannot be used
directly to create a pressure gradient in the lymphatic system suffi-
cient enough to propel lymph centripetally all way toward the
central veins. Moreover, a negative net pressure gradient exists in
the lymphatic system, as lymph pressures closer to their final output
(central veins) are higher than the basal intralymphatic pressures
near the lymphatic capillaries [4] (described in more details later).
Therefore, the lymphatic system possesses its own chains of serially
arranged intrinsic pumps—lymphangions, the contraction energy
of which is absolutely necessary for lymph flow in humans and
majority of mammals. Since the driving force created by one such
small pump (i.e., a single lymphangion) is not enough to propel
lymph all way down through the lymphatic system, lymphatic
vessels are organized in chains of these pumps. Coordinated
contraction of these serial pumps appears important to effective
lymph flow as there are numerous reports that have demonstrated
the coordinated propagation of peristaltic-like contractile waves
along lymphatic vessels [5, 6], while there is little to no evidence that
either simultaneous contraction of the lymphatic vessel occurs
momentarily along all of its length from capillaries toward the local
“output” of this regional net nor that the lymphangion contractions
are completely independent of one another. For some of regional
lymphatic nets (like in lower limbs), the presence of interrupted
fluid column in lymphatic vessels was demonstrated during the
normal contractile activity of lymphangions [7–9], and for such
situations, adjacent lymphangions contract in counterphase fashion
[9]. As such, each lymphangion can be principally described as a
short-distance local intrinsic pump whose primary “task” is to drive
bolus of lymph only to fill next one long or few shorter lymphangion
pumps. However, altogether, the chains of such pumps are capable
of maintaining effective long-distance transport of lymph. During
the active contractions of lymphangions, the lymphatic muscle cells
create an increase of intralymphatic pressure and form a local
positive pressure gradient to propel lymph centripetally. As a result
of such intrinsic spontaneous pumping activity of lymphangions, a
positive (supportive to lymph flow) pressure gradient occurs near
56 4. Hydrodynamic regulation of lymphatic vessel transport function
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the downstream front of propagating contraction zone in lymphatic
vessels (whether this zone includes one or several lymphangions
contracting at the same time is unknown). At the upstream edge
of contracting zone, a negative (opposing to lymph flow) pressure
gradient exists between contracting lymphangions and upstream
relaxing lymphangions. This gradient generates the short-lasting
local reversed flow and following valves closure at the input edge
of the contracting zone in lymphatic vessels [5,10,11].
The majority of lymphangions’ systolic contractile force is used to
produce an increase of intraluminal pressure and propel lymph.
However, some part of energy generated by lymphatic contraction
will be utilized to produce deformation of collagen and elastic fibers
in lymphatic wall. During diastole, these fibers will release their
remaining tension and lead lymphatic wall to expand. To provide
experimental evidence of this hypothesis, measurements of the pres-
sure inside single isolated bovine mesenteric lymphangions have
been performed in conditions when diastolic pressure inside lym-
phangions was set to 0 cm H
2
O [12,13]. The pressure tracings
obtained in this study demonstrated the development of negative
fluctuations of pressure inside these lymphangions of up to 5 cm
H
2
O during diastole. It was concluded that at low levels of lymphan-
gions filling (seen during the relatively low lymph formation states),
such negative pressure waves may produce a suction such that the
energy of active lymphatic pump will be used not only for emptying
of the lymphangion during systole but also for the lymphangion
refilling during diastole. More detailed measurements of intralum-
inal pressure performed recently [11] strengthen these conclusions
on the existence of “suction pressure” in collecting lymphatic vessels,
which manifests as a transient drop in pressure downstream of the
inlet valve following systolic contraction. This suction opens the inlet
valve and is required for filling in the presence of low upstream
pressure. A positive transmural pressure is required for this suction,
providing the energy required to reopen the vessel. Alternatively,
external vessel tethering can serve the same purpose when the
transmural pressure is negative. Suction is transmitted upstream,
allowing fluid to be drawn in through initial lymphatics from
interstitial space [11].
57Concepts of intrinsic and extrinsic lymph pumps
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Extrinsic lymph pump
The unique feature of the lymph dynamics is that the driving
forces generated by the active lymphatic pump are greatly influ-
enced by the action of different extralymphatic forces. These forces
can sometimes have a greater impact on lymph flow than active
pump does, and the sum vector of these forces is not always favor-
able to lymph flow. The action of variable extralymphatic forces
complicates pressure and flow patterns in the lymphatic network
and may vary dramatically [14,15], even in the same region of the
body depending on the level of activity of tissues and organs
surrounding lymphatic vessels.
The term “passive” or “extrinsic” lymph pump combines all
extralymphatic forces that influence lymph flow. The origin of these
forces is not connected with the active contractions of muscle cells in
lymphatic vessel wall. But the use of the term “passive” is correct
only in referral to the active contractions of lymphangions and is
not completely correct from the point of view that all of these forces
are generated by different active processes that are just nonrelated to
the lymphangion contractions. Extrinsic lymph driving forces
include driving forces of lymph formation (historically also called
as “vis a tergo”); influences of the surrounding tissues (affected
by cardiac and arterial pulsations, contractions of skeletal muscles
adjacent to the lymphatic vessels, gastrointestinal peristalsis, and
respiration); and forces affecting outflow/afterload, that is, central
venous pressure fluctuations. All of these forces may affect
the hydrostatic gradients in the lymphatic network that could effec-
tively propel lymph, even sometimes in the absence of lymphatic
vessels contractions. Some of these extrinsic lymph driving forces,
such as influences of lymph formation and central venous pressure
fluctuations, affect lymph flow in the whole body; influences of
others are more or less localized.
Lymph flow directly depends on the intensity of lymph forma-
tion. In general, lymphatic capillaries have their own capacity limits.
Therefore, the faster the volume of recently formed lymph rises
inside the certain regional lymphatic capillary network, the quicker
excessive lymph volumes will move downstream into correspond-
ing collecting lymphatic vessels. Other extralymphatic forces may
influence the emptying of lymphatic capillaries and the pumping
58 4. Hydrodynamic regulation of lymphatic vessel transport function
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lymphatic vessels too. In gastrointestinal lymphatic network, intes-
tinal peristalsis has a great impact on lymph formation and
transport. An increase in intraluminal pressure in the gut directly
increases the rates of lymph formation and pressure in intestinal
initial lymphatics with subsequent increase in lymph flow through
a network of mesenteric collecting lymphatics [16]. In the thoracic
cavity, cardiogenic and respiratory tissue motions have a direct
influence on lymphatic pressure by the generation of rhythmic
expansions and compressions of lymphatic wall [14,15,17].Many
lymphatic vessels are affected by contractions of adjacent or
surrounding skeletal muscles, which cause alternate compression/
re-expansion of the lymphatics and create additional forces to empty
and refill the lymphatic vessels. That has been demonstrated through
the direct correlation of the local values of lymphatic pressure and
levels of lymph flow with the intensity of skeletal muscle activity
in legs [18].
Thus, the values of intraluminal pressure and its gradients
in lymphatic networks depend upon the contractile activity of lym-
phangions and actions of extrinsic forces. Pressure measurements in
the different parts of lymphatic system demonstrated the presence
of pressure fluctuations that are connected with contraction of
lymphangions. Although it was demonstrated that increments of
pressure of 1–1.5 cm H
2
O is sufficient to open a closed valve, lym-
phatic vessels generate pressure peaks about 5–10 cm H
2
O higher
than baseline diastolic intralymphatic pressure [12,19–21].
As there are tremendous difficulties to measure pressures in
different parts of lymphatic system in situ, only a few observations
can present a comparatively complete range of pressures along lym-
phatic system or along some of its comparatively long parts. Until
now, the most inclusive representation of pressure patterns was
done by Szabo and Magyar [4]. These authors published the results
of their systematic measurements of pressure in major lymphatic
trunks in dogs that were obtained during cannulations of different
lymphatic vessels. The authors demonstrated that mean intralym-
phatic pressure in thoracic duct was 5.11 mmHg (6.95 cm H
2
O)
and in right lymphatic trunk was 2.13 mmHg, while jugular venous
pressure was 5.83 mmHg. In more peripheral lymphatic vessels, the
mean intralymphatic pressure were as follows: left jugular
trunk 0.85 mmHg, efferent lymphatic trunk of heart 2.91 mmHg,
59Concepts of intrinsic and extrinsic lymph pumps
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bronchomedial trunk 2.09 mmHg, hepatic trunk 3.43 mmHg, intes-
tinal trunk 3.60 mmHg, left lumbar trunk 2.72 mmHg, and femoral
lymph vessel 0.51 mmHg. This study was the first in which detailed
evidence has been presented for the fact that there is no constant
positive (supportive to lymph flow) pressure gradient along the
entire lymphatic network. The data of this study confirmed that
the action of so-called vis a tergo (or force of lymph formation) is
limited probably by the initial capillary segments of lymphatic net
and by the actual levels of lymph formation there. Majority of the
time, the lymphangions in collecting lymphatic vessels are faced
to produce the extra force needed to prevail over the usual negative
pressure gradient between the segments. These pressure differences
are dependent on the action of gravitational forces, the wide vari-
ability of influences of skeletal muscles contractions, and the pres-
ence of competent valves along the lymphatic vessels [4].
In bipedal humans, the negative pressure gradient along lym-
phatic net may be even much higher than in animals. Olszewski
and Engeset [18,22,23] performed lymphatic cannulations using
T-shape tubes to measure the lateral pressures. At rest, the mean lat-
eral systolic pressure in the leg lymphatic vessels with free lymph
flow (measurements of side-pressure) was 13.5 8.01 mmHg, the
lymph pulse amplitude was 8.8 4.6 mmHg, and contraction fre-
quency was 2.42 1.88/min. All these values rose sequentially from
a horizontal rest position, to a horizontal position with flexing of
the foot, to an upright rest position, to upright with rising toe posi-
tion. In the last case, these values were as follows: peak
pressure 23.8 6.15 mmHg, the lymph pump pulse amplitude
9.67 4.08 mmHg, and contraction frequency 5.5 1.04/min.
The authors calculated mean lymph flow by measuring the move-
ment of a minute air bubble introduced into tubing inserted
into both ends of leg lymph vessel. It was 0.25 0.04 mL/h
(0.004 mL/min) in the horizontal position at the rest and
0.76 0.26 mL/h (0.012 mL/min) in the upright position rising on
toes. Lymph flow was only observed during the pump pulse waves,
and there was no flow in between the pulses, even when massaging
was applied. Several other groups performed measurements of lym-
phatic pressures in the human legs, and these data presented in
general the same order of magnitudes of intralymphatic pressure
in this region of body. In 1991, Krylov et al. [24] published
60 4. Hydrodynamic regulation of lymphatic vessel transport function
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measurements of lymphatic pressure before lymphography when
they catheterized leg lymphatic vessels and immediately measured
the end-lymphatic pressure in them. The values of these pressures
measured on dorsal surface of foot were low, 0.86–1.1 mmHg.
Then, during the catheterization of more downstream lymphatic
vessels in the leg, lymph pressure pulses have been recorded about
2–20 mmHg in amplitude from basal levels of 8–17 mmHg.
The authors visibly correlated the elevations of lymph pressure with
the contractions of lymphatic vessel. Zaugg-Vesti and others pub-
lished [25] measurements of lymphatic capillary pressure in healthy
volunteers. Pressure was measured using the servo-null technique
in the distal forefoot proximal to the base of the first and second toes.
Mean lymph capillary pressure was 7.9 3.4 mmHg, and pressure
fluctuations of more than 3 mmHg were found. In another study,
this group described the influences of postural changes on cutane-
ous lymph capillary pressure at the dorsum of the foot [26]. Mean
lymph capillary pressure was 9.9 3.0 mmHg in the sitting and
3.9 4.2 mmHg in the supine position.
In general, the comparatively high values of resting intralym-
phatic pressures and peak pressure fluctuations described earlier
reflect much higher outflow resistance for the leg lymphatic net-
work in humans and the physiological demands for local lymphan-
gions to develop much stronger contractions than in animals.
Pressure measurements in the human thoracic duct are much more
limited, and some of them represent the tracings only of end-
lymphatic pressure [27] with pressure fluctuations of about
5–10 mmHg in amplitude from a basal level near 30 mmHg. But
even in those pressure measurements that could be considered
as measurements of side-pressure [28], the majority of thoracic
duct pre ssures fluctuated between 14 and 22 mmHg on average.
These levels are much higher than the basal resting pressures in
leg lymphatic network and represent the outflow lymph pressures
within the lymphatic network. However, during inspiration, the
intralymphatic pressure in the thoracic duct may drop to slightly
negative or slightly positive values [28], which could temporarily
make the net pressure gradient favorable to lymph flow. However,
it is not completely clear if these short temporal patterns of pres-
sure changes in thoracic duct directly influence lymph flow only
locally in thoracic cavity, but not in the legs which lymphatic
61Concepts of intrinsic and extrinsic lymph pumps
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vessels located as far as on almost all height of human body and
many times possess interrupted fluid column in them [7–9].
Modulation of the lymphatic vessel contractility by
pressure/stretch
Transmural pressure is an important physical factor of lymph
dynamics, which influences the contractile activity of lymphangions
causing inotropic (changes in the strength of contraction) and chron-
otropic (changes in the contraction frequency) effects. Transmural
pressure is defined as the pressure gradient across vessel wall
and is affected by intralymphatic and extralymphatic forces. In col-
lecting lymphatics, two main forces may produce increases in intra-
vascular (intraluminal) pressure and cause lymphangion filling and
distension of lymphatic wall. These forces are the driving force of
lymph formation and pressure pulses generated by contractions
of upstream lymphangions. The influences of several extralympha-
tic forces on the lymphatic wall may help to expand lymphatics but
in other situations may lead to vessel compression. Since the studies
of Florey [29,30], Smith [31], and Horstmann [32,33], it has been pos-
tulated that the generation and distribution of lymphatic contrac-
tions depend exclusively on mechanical stimuli. Traditional
paradigms postulate that distension of the lymphatic wall activates
the lymphatic contraction, which generates a pressure pulse suffi-
cient to propel lymph to the next lymphatic segment. Later in
numerous studies performed both in vivo and in vitro [5,34–41],it
was shown that increases in transmural pressure caused positive
inotropic and chronotropic effects in lymphatic vessels. Lymphatics
from different tissues and species reach the maximums of their
pumping at the different values of intravascular pressure. These
values found for most tissues are comparatively low and vary in
different species and different regions between 3 and 15 cm
H
2
O. Further increase of intraluminal pressure causes overdisten-
sion of the lymphatic wall and diminishes pumping.
McHale and Roddie particularly demonstrated [5] that isolated
bovine mesenteric lymphatic segments that contained five to seven
lymphangions were able to increase frequency of contractions and
stroke volumes during the increase of transmural pressure from
62 4. Hydrodynamic regulation of lymphatic vessel transport function
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1 to 4 cm H
2
O. These lymphatic vessels reached their maximums of
pumping at transmural pressures of about 4–5cm H
2
O. Further
increase in transmural pressure led to a decrease in stroke volume.
Frequency of lymphatic contractions continued to rise, but this
positive chronotropic effect of the increase in transmural pressure
did not compensate for the negative inotropic influences of continu-
ing distension and flow felt at transmural pressures 6 cm H
2
O and
higher. Principally, the same patterns of lymphatic contractile
behavior in response to increased transmural pressure were
observed by Ohhashi et al. [36] Isolated one- or two-lymphangion
segments of bovine mesenteric lymphatic vessels with outer
diameters 0.5–3 mm had their pumping maximums between 5
and 10 cm H
2
O of intraluminal end-diastolic pressure.
Typical bell-shaped curves of the pressure/pumping relationship
was shown for different regions and for different species. But it is
important to mention that for smaller lymphatic vessels located
more peripherally, the maximums of lymphatic pumping occurs
at higher values of transmural pressure. Such was demonstrated
for the rat mesentery there: the lymphangions located nearer
the intestinal wall had five times greater lymph propulsion ability
thanlymphangions nearer the outflow from the mesentery [42].
For another example, in the maximum pumping in sheep prenodal
popliteal lymphatic vessels, the greatest pumping ability was
observed at values of transmural pressure near 18–26 cm H
2
O,
and greater than 50% pumping occurred between 12- and 43-cm
H
2
O [41]. Recent studies demonstrated the same tendency in the
bovine mesenteric lymphatic network [43]. Bovine prenodal mesen-
teric lymphatic vessels are able to increase contractility during the
increases in transmural pressure and reach the pumping maximums
at transmural pressures 6–9cm H
2
O. During further increases in
transmural pressure, their contractility and pumping were not sig-
nificantly depressed up to 15 cm H
2
O, whereas pumping in bovine
postnodal mesenteric lymphatic vessels is typically depressed
at transmural pressures higher than 10 cm H
2
O. Thus, when
comparing the pumping capacities of pre- and postnodal lymphatic
vessels, the bovine prenodal mesenteric lymphatic pumps appear to
be adapted to overcome the fluid resistance of the lymphatic nodal
architecture. Together, these data appear to indicate that
more peripheral lymphatic vessels may develop higher pressures
63Modulation of the lymphatic vessel contractility by pressure/stretch
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