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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3798_Библиотеки_им_академика_М_И_Перельмана.pdf
Chapter 9
Physiology – Lymph Flow
Waldemar L. Olszewski
It is in only a few centers that tissue fluid and lymph hydraulics have thus far been
studied under normal conditions in the soft tissues of the human limb and in lymphedema.
understanding the manual and pneumatic massage events in tissues and after surgical
lymphatico-venous anastomoses, few data are available in the pertinent literature.
Tissue Fluid Pressure and Flow
Lymph flow from normal and lymphedematous tissues cannot be analyzed without
some knowledge of mobile tissue fluid pressure and movement. Lymph is a product of plasma capillary filtrate. This filtrate forms tissue fluid. A number of tissue
humoral and cellular components derived from skin, subcutaneous tissue, fascia,
and muscle mix in the interstitial space with the capillary filtrate and flow into the
lymphatics. In the lymphatics, the tissue fluid becomes lymph. Forces driving tissue fluid to the lymphatics are responsible for filling vessels and initiating flow.
1-9
Although knowledge of extravascular fluid hydraulics is indispensable for
Pressures in the Normal Limb
Under normal conditions, tissue (interstitial) fluid pressure in the lower limb subcutaneous tissue at rest, when measured, ranges between −3 and +1 mmHg (Fig. 9.1).
It is slightly negative, which also has been observed in animals. Active movements
of the calf (contractions of muscles) may slightly decrease the pressure due to
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_9, © Springer-Verlag London Limited 2011
69
70 W.L. Olszewski
Fig. 9.1 Tissue fluid pressures in the subcutaneous tissues of a normal and a lymphedematous calf
in the horizontal position. Upper panel: pressure approximating zero, not affected by muscular
contractions. Lower panel: pressure approximating 2 mmHg, with minor fluctuations, during calf
muscle contractions. Tissue fluid pressure is low even in the advanced stages of lymphedema, due
to expansion of the interstitial space of the subcutis
emptying of the interstitial space; however, these differences are of no clinical
importance (Fig. 9.1).
Pressures in the Lymphedema
In obstructive lymphedema, the resting tissue fluid pressure increases above zero,
but remains within a low range, between 1 and 10 mm Hg9 (Fig. 9.2). Higher pressures are observed in advanced stages (III and IV). There are no significant changes
in pressure elicited by the change from a horizontal to an upright position. Moreover,
active contractions of calf muscles do not generate higher pressures (Fig. 9.1).
Manual massaging of lymphedematous calf soft tissues may even increase the pressure above 100 mm Hg. However, removal of the massaging hand brings about an
immediate drop in pressure to zero.
Normal Tissue Fluid Flow
In a normal subcutaneous tissue there is no detectable flow at rest or during walking
or massage.
6
9 Physiology – Lymph Flow
Fig. 9.2 Tissue fluid pressures recorded at the mid-calf (left panel) and ankle level in lymphedema,
stage IV. Minor differences depending on the level of measurement. Note lack of effect of muscular contractions and low levels of pressure
71
Tissue Fluid Flow in Lymphedema
Excess accumulated tissue fluid moves radially from the site of applied force during
muscular contractions and massaging, but not unidirectionally toward the root of
the extremity. This makes massage of soft tissues without immediate distal compression (bandaging) non-effective. Tissue fluid flow can be seen on lymphoscintigraphy, depicting artificial channels created by deformation of the subcutaneous
tissue by the compressed fluid.
Lymph Pressure and Flow
Extrinsic Factors that Propel Lymph
Normal Conditions
Muscular activity, respiratory movements, passive movements and arterial pulsation
have no effect on lymph flow.
with only a few microliters of lymph in some lymphangions. There is no hydrostatic
pressure in normal leg lymphatics in the upright position.
1-3,5,6
Generally, the lymphatics of the limb are empty,
3,6
72 W.L. Olszewski
mmHg
15
10
5
0
0
10
20
30
40
50
µl (1µl=1mm)
Fig. 9.3 Pressure (lateral) and flow recorded in a normal calf lymphatic vessel. Three pulse waves
are seen (red curve). They are of different amplitude. Also, the time intervals between contractions
are of different duration. The contraction of each lymphangion generated pressures propelling flow
(blue curve). The ascending component of the curve shows the stroke volume. Flow occurred only
during lymphangion contractions
Lymphedema Conditions
Muscular contraction of the foot and calf may increase lymph pressure to values
above 100 mmHg. In lymphedema, patent lymphatics are filled with lymph and
pressing of the muscles against the skin creates a pressure gradient between the
distal and proximal lymphatics.
3,6
Intrinsic Factors that Propel Lymph
Lymph is propelled by autonomous rhythmic contractions of lymphangions.
Tissue fluid enters the initial lymphatics to flow into the lymphangions. Stretching
of the lymphatic wall by inflowing tissue fluid evokes contractions of the lymphatic
wall muscles (according to Starling’s law) and generates flow.
Lymph pressures in normal limbs. Lymphatics contract rhythmically with a frequency that depends on the volume of the tissue fluid entering.
3,6
In regions with
high capillary filtration rates and tissue fluid formation, the frequency is high. The
recorded pressures at rest, without regard to whether they are obtained in the supine
or upright position, with free proximal flow (lateral pressure), range between 7 and
30 mmHg and during foot flexion, between 10 and 30 mmHg (Fig. 9.3). The pulse
amplitudes are 3–20 mmHg and 5–17 mmHg and the pulse frequencies are 0.6–6/min
and 2–8/min respectively.
responding to lymphatic obstruction in postsurgical lymphedema) range between
15 and 55 mmHg, and during foot flexion 15– 50 mmHg. The pulse amplitudes are
3,6
The resting end pressures with obstructed flow (e.g. cor-
3–35 mmHg and 3–14 mmHg and the pulse frequencies are 2.5–10/min and 3–12/min
respectively. Massaging of the foot or tapping of lymph-laden tissues has no effect
1-6
9 Physiology – Lymph Flow
Lymph flow and pressure
40
30
20
LATERALEND
Pressure (mmHg)
10
0
40
50
IND 239
Lymphedema II
flow 1 mm = 5µl
30
20
10
0
Fig. 9.4 Lymph pressure recorded in a patient with lymphedema, stage III. Spontaneous pressure
waves generated by a damaged lymphangion are low and unable to create flow (flat blue line)
73
on lymph pressure. Heating of the foot significantly increases the pressure, amplitude, and frequency of lymphatic contractions.
Pressures in Lymphedematous Limbs
In obstructive lymphedema only a few lymphatic collectors remain patent.
The recorded pressures during rest range from 5 to 45 mmHg depending on the
surviving contractility force of the damaged lymphatic musculature.
muscular contractions, pressures are generally low, ranging from 10 to 25 mmHg,
although tiptoeing may, in some cases, generate pressures exceeding 200 Hg.
Lymph Flow in Normal Limbs
Flow occurs only during spontaneous contractions of lymphangions.
Lymph Flow in Lymphedematous Limbs
As most collectors are partially or totally obliterated, there might be only some
spontaneous flow in patent vessel segments at different levels of the limb.
Correlation of pressures and flow, in most cases, demonstrates the ineffectiveness of
the lymphangions’ contractions (Fig. 9.4). This is the consequence of the destruction of vessel musculature and valves.
7-9
During calf
3
7,8
74 W.L. Olszewski
General Remarks
In post-inflammatory, post-surgical, and post-traumatic lymphedema, as well as in
the so-called idiopathic lymphedema (i.e., lymphedema of unknown etiology), the
intra-lymphatic pressures and flow are abnormal due to: a) destruction of lymph
vessel muscle cells, b) destruction of valves, or c) partial or total lumen obstruction.
Tissue fluid finds its way to the non-swollen parts of the limb along hydraulically
created tissue channels.
References
1. Olszewski WL, Engeset A. Intrinsic contractility of leg lymphatics in man. Preliminary com-
munication. Lymphology. 1979;12:81-4.
2. Olszewski WL. Lymphatic contractions. N Engl J Med. 1979;8(300):316.
3. Olszewski WL, Engeset A. Intrinsic contractility of prenodal lymph vessels and lymph flow in
human leg. Am J Physiol. 1980;239:H775-83.
4. Armenio S, Cetta F, Tanzini G, Guercia C. Spontaneous contractility in the human lymph ves-
sels. Lymphology. 1981;14:173-8.
5. Sjöberg T, Norgren L, Steen S. Contractility of human leg lymphatics during exercise before and
after indomethacin. Lymphology. 1989;22:186-93.
6. Olszewski WL. Lymph vessel contractility. In Lymph stasis – pathomechanism, diagnosis and
therapy. Boca Raton: CRC Press; 1991:115-154.
7. Olszewski WL. Contractility patterns of normal and pathologically changed human lymphatics.
Ann NY Acad Sci. 2002;979:52-63.
8. Olszewski WL. Contractility patterns of human leg lymphatics in various stages of obstructive
lymphedema. Ann NY Acad Sci. 2008;1131:110-8.
9. Olszewski WL, Jain P, Ambujam G, Zaleska M, Cakala M. Tissue fluid pressure and flow dur-
ing pneumatic massage of lymphedematous lower limbs. Lymphatic Res Biol. 8; 2010
(in press).
Chapter 10
Pathology and Histochemistry
Waldemar L. Olszewski
Immune processes in lymphatics and nodes
The pathological changes observed in the lymphatics in lymphedema can be caused
by infection or trauma and include damage of the endothelial and muscular cells,
subsequently leading to obliteration of the lumen by fibroblasts, the price the lymphatic system pays for its own function in the body changes. The system is devoted
to elimination of microbes and clearance of damaged cells and, in a feedback fashion, to the healing of parenchymatous tissues. The inflammatory process has a
destructive effect on the host’s cells. The pathological events in the skin and reaction of the regional lymphatic system are shown schematically in Fig. 10.1. The
lymph cells participating in the immune response are presented in Fig. 10.2.
1-3
Classification of Lymphedema of Lower Limbs
The pathological changes observed on lymphoscintigrams, magnetic resonance
images and histological specimens depend on the factors responsible for the development of lymphedema. Today, the sole term “lymphedema” does not provide
enough information about the etiology of the condition. Lymphedema is not a separate entity, it is a symptom. The term “lymphedema” should be preceded by a qualifying term that refers to the cause (Fig. 10.3). The histological pictures of lymphatics
and tissues differ depending on the primary cause.
Human limb lymphedema is characterized by tissue changes
Obstructive lymphedema: (1) obliteration of lymphatic collectors and fibrosis of
lymph nodes (Fig. 10.4), (2) hyperkeratosis of epidermis (Fig. 10.5), (3) immune
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_10, © Springer-Verlag London Limited 2011
4-6
:
75
76 W.L. Olszewski
Bacteria
Teichoic
acid
LPS Hsp CpG DNA
Wound
Epidermis
PMN
MF
LC
KC
TLR
CD80/86
Hsp
Cytokines
Antimicrobial peptides
Defensins
Chemokines
Cytokines
N
K
VEGF-C
VEGF
Dermis
Cytokines
Chemokines
Coagulation
Factors
Complement
Antimicrobial peptides
VEGF-R
CLUSTER
LC
HEV
FDC
CD4
+25+
TLR
LYVE1
CCL 21
CCL 19
CCR 7
LTβ
TLR2,4
Fig. 10.1 Schematic presentation of immune events in the skin, draining lymphatics and nodes.
Bacteria and/or trauma of the epidermis damage the superficial layers of keratinocytes. The bacterial antigens and cellular debris are immediately recognized by Langerhans’ cells present among
keratinocytes. A cascade of natural immune events is initiated. Multiple non-specific humoral and
cellular factors participate in the process. Yellow cells line out afferent lymphatics. LPS lipopolysaccharide, hsp heat-shock protein, CpG DNA bacterial DNA fragment, LC Langerhans’ cell,
KC keratinocytes, TLR toll-like receptor, MF macrophage, NK natural killer cell, VEGF vascular
endothelial growth factor (R-receptor), LYVE 1 hyaluronate receptor specific for lymphatic
endothelial cells, CCL lymphocyte chemoattracting cytokine, LT lymphocytotoxin attracting lymphocytes, FDC follicular dendritic cells in B-cell follicles, HEV high endothelial venules – sites of
extravasation of blood lymphocytes, CD4
+25+
regulatory lymphocytes
cell infiltrates of epidermis, dermis, and subcutaneous tissue (Fig. 10.5), (4) fibrosis
of the peri-lymphatic tissues and muscular fascia (Fig. 10.6), (5) growth of skin and
fat tissue.
lymphatic collectors, (2) acellular deposits under the endothelium narrowing, or
fibrotic structures obstructing the lumen (Fig. 10.7), (3) slow fibrotic process in the
So-called primary or idiopathic lymphedema: (1) normally structured wall of
subcutaneous tissue, (4) small but normally structured lymph nodes.
Remarks
In lymphedema, tissues deprived of tissue fluid and lymph drainage are the site of
a continuous inflammatory process. Fluids accumulating in skin and subcutaneous tissues in lymphedema contain cytokines, chemokines, activated immune cells,
10 Pathology and Histochemistry
Fig. 10.2 Histological analysis of lymph cell smear from a normal human calf lymphatic vessel.
The large cell in the middle is a Langerhans’ cell (dendritic, veiled) with attached CD4 T-helper
(rosy) lymphocytes forming a so-called immune cluster. Antigen (bacterial, own tissue-specific) is
processed by Langerhans’ cells and presented to the T-helper lymphocytes. In close vicinity are the
CD8 cytotoxic lymphocytes (brown), which also participate in the immune prosesses. The type of
cells in lymph is totally different from that of blood. Extravasation of specific cell precursors takes
place in the dermal and lymph node blood capillaries. These cells further migrate to the initial
lymphatics
77
Fig. 10.3 Classification of
lymphedema. Adding the
causative term in front of
“lymphedema” provides
information necessary for a
proper understanding of the
mechanism, establishing the
treatment protocol and
formulating prognosis
and, most importantly, microorganisms. Microorganisms normally penetrate the
epidermis in small numbers and are quickly eliminated by the circulating immune
cells. However, in conditions of lymph stasis, they are not removed and may
proliferate, evoking a host reaction. This is the reason for clinical attacks of
dermato-lymphangio-adenitis (DLA) and histological changes such as infiltrates
and formation of fibrous tissue.
78 W.L. Olszewski
T.Z.
hysterectomy
LIV
DLA frequent
Fig. 10.4 Pathological changes in lymphatics in a patient with postsurgical, postradiation lymphedema stage IV. Left panel – lymphoscintigram showing lack of lymphatics in the swollen limb.
Right panel – histological pictures from tissue at levels indicated by arrows. Dilated, irregular struc-
tured subepidermal lymphatic (lower panel), obliterated lymphatic collector (middle panel) and
remnants of an inguinal lymph node (upper panel) with few remaining lymphocytes (red). This is a
typical picture of changes in the lower limb lymphatic system in a long-lasting lymphedema