Pathophysiology 17 (2010) 337–343

Review

Lung lymphatic anatomy and correlates

Dean E. Schraufnagel ∗
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine M/C 719, University of Illinois at Chicago,
840 S. Wood St., Chicago, IL 60612-7323, United States
Received 10 March 2009; received in revised form 12 June 2009; accepted 21 October 2009

Abstract
The pulmonary lymphatics do much more than keep the lung dry. They defend the lungs from airborne particles and microbes and allow a
local influx of liquid to clear and clean inflamed or damaged tissue. Lymphatic morphology, especially the three-dimensional structure, is best
demonstrated by casting the lymphatics, corroding the tissue, and viewing the casts by scanning electron microscopy. With this technique,
different lymphatic forms exist. On the pleural surface prelymphatics are simply tissue planes that connect with lymphatic channels. Reservoir
lymphatics are another form of initial lymphatics that have blind-ending pouches. They empty into conduit lymphatics. Lymphatics around
blood vessels and airways are generally tubular and saccular. In the last decade, lymphatic markers have been discovered that allow the study
of lymphatic development in health and disease. Modulators of these pathways could be potential therapeutics for diverse pulmonary problems
such as cancer and lung transplantation. The size of the lymphatic system expands manifold in response to an excess fluid load, cancer, or
inflammation. Immune cells move through the lymphatics, mature, and become activated there. The lymphatics enable the immune defense
system by allowing a sequestered place and close proximity for antigen presentation and lymphocyte maturation.
© 2009 Elsevier Ireland Ltd. All rights reserved.

Keywords: Pulmonary lymphatic system; Corrosion casting; Anatomy and histology

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
2. Cast structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
3. Pleural surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
3.1. Initial lymphatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
3.2. Conduit lymphatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
4. Lymphatics within the lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
4.1. Perivascular and airway lymphatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
5. Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
6. Lymphatic expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
7. Lymph flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
8. Lymph nodes and immune cell trafficking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

1. Introduction in thickness at its thinnest part. On the tissue side of this

barrier are blood capillaries and scant interstitial space that
The pulmonary alveoli in the normal lung are relatively contains several types of cells mostly of fibroblast and
dry. Alveolar fluid would reduce or prevent efficient gas immune lineage. Each day the human lung absorbs oxygen
exchange across the air–blood barrier, which is about 0.2 ␮m from about 10,000 L of air breathed in. Air contains particu-
lates and other inert and noxious matter. Fine particles may
∗ Tel.: +1 312 996 8039; fax: +1 312 996 4665. react with or pierce through the epithelium. The air also con-
E-mail address: schrauf@uic.edu. tains bacteria and viruses, which may gain a foothold in the

0928-4680/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.pathophys.2009.10.008
338 D.E. Schraufnagel / Pathophysiology 17 (2010) 337–343
lung. The body must rally it cellular defense against infection
and move a variety of immune cells into and out of the lung.
It must present antigens to lymphocytes and allow those cells
to mature into effector cells. The lungs regularly encounter
pharyngeal fluid, which may emanate from the stomach with
its acid or from the mouth with its microorganisms. The lung
responds to many forms of injury from local or systemic
insults by an outpouring of fluid—focal or diffuse pulmonary
edema. The interstitial space and thin epithelium are exposed
to osmotic, hydrostatic, and hydrodynamic forces of the tis-
sues and blood stream, and must adapt to a constant shifting
of fluid, protein, and cells. All of these challenges are met at
least in part by the lung lymphatics.
It is the job of the lung lymphatics to keep the lungs dry
even in the face of a massive fluid challenge, to clear inert
and toxic substances that penetrate the epithelium, and to
quarter, control, and regulate the pulmonary immune system.
With all this, it is amazing that the alveoli themselves do
not have lymphatics. Lymphatics around the alveoli would
impede gas exchange and would make gas exchange worse
in flood states where it would be most needed. When not
needed, the lymphatics are collapsed and hardly detectable.
When called upon, they swell to many times their resting
size.
2. Cast structures
Lymphatics are delicate and complex structures that arise
from the tissue spaces. In the absence of disease or stimulus,
and until the discovery of specific markers about a decade
ago, they were nearly unseen by light microscopy and dif-
ficult to detect even with transmission electron microscopy.
The clearest visualization of the structure of lung lymphatics
was attained by casting them and viewing the casts with the
scanning electron microscopy [1]. Even with this method, it
was necessary to induce a state of lymphatic expansion or
edema to visualize them well, although in the absence of an
edematous state they could still be seen under conditions of
microvascular leakage, such as the blood vessel angiogenesis
that occurs with neoplasia.
With such techniques, it is possible to delineate differ-
ent forms of lymphatics in the lungs. However, it is first
important to distinguish blood from lymphatic vessels [2].
Blood vessels are more cylindrical and generally have dis-
tinct endothelial cell nuclear impressions. Cast pulmonary
veins have round impressions caused by their endothelial
cell nuclei, regular ring-like constrictions, and do not run
with airways once they are away from the hila. Even rather
large pulmonary veins (>200 ␮m in diameter) may have cap-
illaries joining them at right angles. On the other hand, the
casts of pulmonary arteries have flattened, elliptic endothelial
cell nuclear impressions running in the same direction as the
blood stream. The pulmonary artery casts lack narrow ring-
like impressions and have greater space between their surface
and adjacent capillaries than pulmonary veins. Arteries often
lie near airways. Pulmonary arteries greater than 100 ␮m in
diameter usually have short branches before giving off cap-
illaries, which arise at acute angles. Systemic arteries such
as those of the bronchial circulation, have deeper nuclear
impressions and thicker walls than pulmonary arteries [3].
Although the pulmonary blood and lymphatic vascula-
tures have been cast in many species, most of the following
discussion and all images shows are derived from casts of rat
lung. The lymphatic cast structure has not been well studied
in other species. To expand the lymphatics, pulmonary edema
was induced in the rats by exposure to a toxic level of oxygen
or increased lung volume.
3. Pleural surface
3.1. Initial lymphatics
The lung interstitial space and the lymphatics that emanate
from it can be cast and visualized by scanning electron
microscopy. The tissue space leading into the lymphatics
is sometimes called prelymphatics. The space lies within
and just below the visceral pleura fills with fluid in edema
conditions. It is exterior to pleural blood capillaries but is
contained by the outer layer of pleura. The prelymphatic tis-
sue planes are marked by connective tissue strands indenting
a textured surface (Fig. 1). There is no sign of tubularity.
This structural form allows access of the fluid bathing all
tissues to lymphatics. Any substance in the interstitial space
can be swept into lymphatics; antigens can be trapped, bro-
ken down, and presented to lymphocytes in lymph nodes.
Prelymphatics blend into areas with specific architectural
lace-like structures termed reservoir lymphatics. Reservoir
lymphatics have a hierarchal shape. They are thin flat struc-
tures within and beneath the visceral pleura. In contrast to
prelymphatic casts, they are not sheets of plastic but have
open areas and quasi-tubular segments with frond-like, short
blind-ending side branches. Reservoir lymphatics are found
with prelymphatics and the two intermingle at times making
it difficult to distinguish them. The junctions of prelymphat-
ics with conduit lymphatics and reservoir lymphatics with
conduit lymphatics are structurally identical. Because of the
difficulty in distinguishing them at times, both structures have
been called initial lymphatics [4].
The pleural surface of normal animals seldom has lym-
phatic casts. (The experience with cast human material is
insufficient to draw conclusions.) In an experiment with
hyperoxic edema, almost two-thirds of the pleural surfaces
of rats had cast initial lymphatics [4].
3.2. Conduit lymphatics
Initial lymphatics are boundary structures from which
conduit lymphatics arise. Conduit lymphatics occupy lit-
tle space compared to initial lymphatics, but are a more
consistent finding on normal pleural surfaces, although it
 D.E. Schraufnagel / Pathophysiology 17 (2010) 337–343 339

Fig. 1. Lymphatics on the pleural surface. (A) A cast of prelymphatics (P), or tissue planes crossed by collagen and other connective tissue. A conduit lymphatic
(C) arises from the prelymphatic. The free access to the lymphatics from the tissue space allows the immune system to sample the entire lung. (B) Casts of
reservoir lymphatics (R), which are in close association with prelymphatics (P). Reservoir lymphatics are characteristically flat structures with budding blind
pouches and (C) shows them joining with conduit lymphatics (C). (D) A conduit lymphatic (C) on the pleural surface. The lack of strict cylindrical shape is a
feature that distinguished conduit lymphatics from the pleural blood capillaries beneath it. A small patch of reservoir lymphatics (R) is present. These scanning
electron microscopic images are of vascular and lymphatic casts on the pleural surface of rats exposed to a hyperoxic environment.

is still necessary to survey the whole pleural surface at
low magnification to find them in normal animals. Cast
conduit lymphatics are tubular and have endothelium and
valves, but they are not as rigidly cylindrical as blood ves-
sels. They vary in diameter irrespective of their course; their
diameter can be twice what it was just upstream or down-
stream. Nor are their surfaces as smooth as those of blood
vessels. They may arise from either reservoir lymphatics
or prelymphatics on the pleural surface or saccular lym-
phatics of the perivascular, peribronchial or peribronchiolar
space [1].
4. Lymphatics within the lung
4.1. Perivascular and airway lymphatics
Saccular and tubulo-saccular lymphatics surround non-
capillary blood vessels and airways within the lung (Fig. 2A
and B). These large, thin-walled sac-like structures are often
more than 100 ␮m in width. Lymphatic filling varies greatly
depending on how edemogenic the condition is. They range
from surrounding the blood vessel wall with a thick double
layer to being only a scant patchwork on its surface. Aharine-
jad et al. showed that the lymphatics were increased around
pulmonary venous muscular constrictions (sphincters) more
than other areas of the vein. The lymphatic enlargement is
mainly in the adventitial space in lymphatic structures with-
out complete endothelialization [5].
In edema states, saccular lymphatic casts are found
surrounding digested bronchioles. These have the same
characteristics as the periarterial and perivenous saccular
lymphatics (Fig. 2C). Conduit lymphatic casts in the bron-
chovascular bundle are rarely seen if perivascular saccular
lymphatics are absent (Fig. 3A). In conditions of lymphatic
profusion, conduit casts can be identified along the bron-
chovascular bundle and in the interlobular septa. When these
vessels are in the bronchovascular bundle they are round or
oval. When they are away from the bronchovascular bundle
(usually in the interlobular septa) they may be thin, tortuous
and spiraling (Fig. 3C). The cast lymphatics of the inter-
lobular septa often have a medial notch. In rats exposed to
hyperoxia, the conduit lymphatic vessels in the bronchovas-
cular bundle are larger than the accompanying bronchial
artery and up to about 40% of the size of the pulmonary
artery. The surface of the lymphatic casts is textured with
diagonal and longitudinal indentations and oval outpouch-
ings. The diameter of the conduit lymphatics may vary greatly
within short lengths of the long axis [1], although this is more
typical of pleural conduit than parenchymal lymphatics and
in conditions of more moderate edema. Larger (more proxi-
mal) conduit lymphatics accept tributaries less frequently. At
times, the flat intrapulmonary lymphatics join in star-shape
figures with multiple tributaries coming together at one place.
340 D.E. Schraufnagel / Pathophysiology 17 (2010) 337–343

Fig. 2. Lymphatics within the lung occur around blood vessels and airways. (A) Saccular and tubulo-saccular lymphatics (S) found around blood vessels in
states of lymphatic expansion. They empty into conduit lymphatics that transport lymph to hilar nodes. (B) Another image of a cast conduit lymphatic (C)
traveling with a pulmonary vein. This conduit lymphatic around the vein is flatter than the one shown in (A). Veins and their lymphatics travel in the interlobular
septa. Pulmonary and bronchial arteries, bronchioles, and lymphatics lie in bronchovascular bundles in the center of a pulmonary lobule. (C) The cast of the
lymphatics around a bronchus (Br) that has been digested. The tubulo-saccular (S) and conduit (C) lymphatics have the same form as those around the artery
in the bronchovascular bundle. These scanning electron microscopic images are of the lymphatic casts of rats exposed to hyperoxia.

Fig. 3. Conduit lymphatics. (A) An enlarged conduit lymphatic (C) adjacent to a blood vessel (BV) and saccular lymphatics (S); (B) An enlarged conduit
lymphatic adjacent to a pulmonary artery (a). The pulmonary artery has oval endothelial nuclear impressions and is more tubular than the conduit lymphatic,
which has a fluctuating diameter. (C) An intrapulmonary conduit lymphatic (IC) not in a bronchovascular bundle. These thin lymphatic vessels have central
grooves, stretch long distances, and often twist. At times, 4 or 5 branches may join at one place.These scanning electron microscopic images are of lymphatic
casts of rats exposed to hyperoxia.
 D.E. Schraufnagel / Pathophysiology 17 (2010) 337–343
5. Markers
Fortunately, several molecular markers have been found
on lymphatics to make their identification easier. These dis-
coveries in the last decade have had far-reaching implications
because they allow the study of lymphatic development in
health and disease. For example, since the lymphatics are
a major route for cancer metastases, controlling lymphatic
development might control neoplasia.
Prox-1 (prospero-related homeobox gene) is found only
on lymphatics. It is a transcription factor that has wide rang-
ing control of the development of lymphatic endothelial cells.
LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-
1) is a CD44 homologue and hyaluronan receptor. It is found
on lymphatic endothelial cells and macrophages but not
blood endothelial cells. This marker is useful for measur-
ing lymphatic density, which has been correlated with tumor
prognosis in some settings.
VEGF-C and VEGF-D (vascular endothelial growth fac-
tors C and D) and their cell surface receptor, VEGFR-3,
are found on lymphatic endothelial cells but not blood
vascular endothelial cells. VEGF-C and VEGF-D promote
lymphangiogenesis by interacting with VEGFR-3, which
activates an intracellular tyrosine kinase-dependent signal-
ing cascade. VEGF-C and VEGF-D also bind neuropilin-2
(Nrp2), a semaphoring receptor expressed on lymphatic ves-
sels. With the VEGFs, the semaphorins help define a pattern
of vessel growth by regulating cell and extracellular matrix
interactions. This makes the neuropilin receptors for vascu-
lar endothelial growth factors important in tumor biology.
Controlling neuropilin may downregulate tumor growth and
metastasis [6]. Knocking out Nrp2 in mice leads to lymphatic
hypoplasia.
Deletion of Prox-1 or VEGF-C leads to complete absence
of lymphatics in mice. VEGF-D knock out does not affect
lymphatic development, although if VEGF-D is given to
VEGF-C knockout mice, it can allow lymphatic develop-
ment. Prox-1, VEGF-C, and VEGF-D are important in the
normal development of lungs and their levels are elevated in
late neonatal life [7]. VEGF-C and VEGF-D are ligands for
integrin ␣9, which is required for normal lymph development
[8].
Other important markers include desmoplakin and
plakoglobin found in the adherent junctions of lymphatic
endothelial cells and LA102, another lymphatic endothelial
cell specific marker [9].
Podoplanin belongs to the family of type-1 transmem-
brane sialomucin-like glycoproteins and normally is found
only on lymphatic vascular endothelium, but it is also
expressed in different types of tumor cells. Prox-1 induces the
expression of podoplanin. Podoplanin/D2-40 in lymphatic
endothelial cells is also used to estimate lymphatic microvas-
cular density, which is greater in more aggressive neoplasms
[10].
It is interesting that herpesvirus-8, the cause of Kaposi
sarcoma, was first thought to infect lymphatic endothelial
341
cells because these endothelial cells had VEGFR-3 and
podoplanin, markers of lymphatic endothelial cells. However,
it is now known that they infect blood vascular endothelial
cells and upregulate Prox-1, which is the master regulator of
the lymphatic lineage. Prox-1 downregulates blood vascular
endothelial cell markers in favor of those of the lymphatic
endothelial cells [11].
6. Lymphatic expansion
The lymphatics expand in many ways. After continu-
ous exposure to 85% oxygen for 7 days, experimental rats
develop advanced pulmonary edema. Injecting a plastic resin
into the blood vasculature will result in extensive casting of
the lymphatics [4]. In these animals most blood vessels and
conducting airways will be extensively flanked by saccular
lymphatic casts. This resolves when the animals are removed
from the hyperoxic environment. After 14 days in ambient air,
the lymphatic casts are again uncommon with this injection
method [4].
Another model of pulmonary edema entails acute air-
way injury from excessive volume of mechanical ventilation.
Rats ventilated at high tidal volume (12–16 mL) for 25 min
showed more perivascular, interlobular septal, and alveolar
edema than those ventilated with low tidal volume. Most of
the lymphatic changes occurred in the perivascular lymphat-
ics, with little accumulation in pleural lymphatics. Larger
blood vessels had more edema in their surrounding lymphat-
ics than smaller blood vessels [12]. The pleural lymphatics
may be expected to show less filling that perivascular because
the acute insult was greater to the proximal airway and
alveoli, which are drained by perivascular lymphatics. The
importance of this model was that it showed the lymphatic
expansion can occur quickly—without time for lymphangio-
genesis.
Metastatic lung cancer may spread via lymphatics. Cells
were thought to gain access to existing lymphatic channels.
Part of the defense against lymphangitic metastases came
from lymph nodes that occur at regular intervals along the
lymphatic network. Although this is still true, recent work
has shown a more complex picture. For example, lung can-
cer can produce high levels of VEGF-C, which can stimulate
expansion of the lymphatics and facilitate spread of the
tumor. Several important molecules associated with lym-
phatic expansion are now potential targets for antineoplastic
therapy. It appears that patients with cancers with increased
lymphatic vessel density and higher levels of VEGF-C,
VEGF-D, and VEGFR-3 have a shorter survival [13].
Pulmonary lymphatic expansion occurs in a variety of dis-
eases besides edema states. In asthma and other conditions
involving chronic inflammation of the airway, mucosal and
submucosal edema is associated with an influx of inflam-
matory cells, mucus cell hyperplasia, subepithelial fibrosis,
and thickened basement membranes. McDonald and col-
leagues infected mice with Mycoplasma pulmonis to mimic
342 D.E. Schraufnagel / Pathophysiology 17 (2010) 337–343
a bronchitis state. Lymphangiogenesis associated with this
model was dependent of signaling of VEGF-C, VEGF-D,
and VEGFR-3. Inhibiting VEGFR-3 resulted in lymphatic
growth inhibition without affecting blood vessel growth [14].
In a rat model of lung transplantation rejection, transfer
of VEGF resulted in the doubling of the LYVE-1 positive
lymphatic vessels in the airway walls. Giving an inhibitor
of VEGFR resulted in a 50% reduction [15]. Accompany-
ing this was a reduction in CD4 and CD8 cells in the airway
walls. This highlights that an expanded lymphatic system can
traffic more lymphocytes and alter immunity. In transplanta-
tion, this may not be good because it could increase the risk
of rejection. On the other hand, it could result in a more
rapid clearance of infecting microbes in these immunocom-
promised hosts and be beneficial.
7. Lymph flow
Lymph flow in the lung proceeds in opposite directions.
Lymphatics in the lung perimeter flow to the pleura and the
rest flows toward the hilum. The pleural flow is more effi-
cient than the central flow, which explains the classic chest
radiographic “butterfly pattern” of acute pulmonary edema in
human patients [16]. Gravity and respiratory movement also
affect lymph flow; the lower lobes clear lymph four times
more than the upper [17].
India ink injected into the pleural cavity rapidly enters the
lymphatics. The material is taken up by preformed parietal
pleural stomata that enter directly into the chest wall lym-
phatics [18]. Although normal pleural fluid, which is present
in small amounts, may be produced and taken up by either
the visceral or parietal pleura, the parietal pleura is the main
agent to remove excess fluid in pathologic conditions.
Inhaled particle distribution is also probably affected by
lymph flow. With tidal breathing, the greatest air flow goes to
the lower lung zones but silica, for example, deposits in the
upper lung zones in humans. Animal experiments have shown
particles less than 1 ␮m in diameter are cleared from the
dependent parts and migrate to the upper zones after several
days [19]. Asbestos particles, which are more often found in
the lower lung zones in humans, pass through the epithelium.
The fibers that enter the interstitial space can be picked up by
the lung lymphatics, dumped into the blood stream, and be
distributed to all organs. Other asbestos fibers penetrate to the
viscera and even parietal pleura. Pleural fluid is preferentially
sucked into the parietal pleural stomata. Hard, needle-like
asbestos fibers accumulate on the parietal pleural and cre-
ate a reaction to this irritation, pleural plaques. Asbestos
fiber translocation takes place over decades in humans with
asbestos-related lung disease [20].
The heterogeneity of lymph movement suggests that addi-
tional factors, such as surface tension of the fluid, are
involved [21]. Although fluid especially in large lymphat-
ics can move by muscular contraction of lymphatic walls,
most lymph movement occurs by external forces, such as
contraction of muscle or respiratory movements because the
initial lymphatics have incomplete endothelia. Lymphatic
valves interestingly do not have moving parts but are eccen-
tric monocuspid, funnel-shaped structures [22]. In addition
to the pumping action of the lymphatics, the casting of lym-
phatics of dead experimental animals attests to the passive
role of lymphatic flow.
8. Lymph nodes and immune cell trafficking
If microbes transgress the upper respiratory tract barriers,
they come in contact with dendritic cells that extend to the
epithelial surface. Dendritic cells sample and capture micro-
bial antigens and then migrate to the lymphatic vessels. The
dendritic cells breakdown protein into peptides, which bind
to major histocompatibility complex (MHC) molecules, a
necessary process for presentation to T lymphocytes. While
transporting the antigens to the lymph nodes, the dendritic
cells mature. They lose their adhesiveness to the epithelium
and express chemokine receptor 7 (CCR7), which tracks them
to the T cell zones of the lymph node. Mature dendritic cells
express toll-like receptors that recognize microbial molecules
and activate cells to produce cytokines. They also produce
costimulatory molecules that are required to develop T cell
immune competence. Maturation of dendritic cells converts
them from cells that capture foreign protein to cells that can
present antigen to naïve T cells and activate lymphocytes
[23].
Antigens also may enter the lymphatics in a free form.
Lymph-borne antigens can be extracted from the lymph by
dendritic cells and macrophages residing in the lymph nodes.
Soluble inflammatory mediators produced at the sites of
infection also enter the lymphatics. Lymph nodes, which are
imposed along the lymphatics, filter and delay transport of
immune cells back to the blood. These lung lymph nodes
are sentinels that prevent bacterial pneumonia from becom-
ing bacterial sepsis. After lymph enters the node, it goes to
the subcapsular sinus and then the paracortical area. Here
the dendritic cells present antigens to naïve T cells and initi-
ate the adaptive immune response. The lymph channels and
nodes provide for other immune functions such as delivering
chemokines from the inflamed tissues. Chemokines, such as
CCL2 (C–C motif, ligand), contribute to the recruitment of
leukocytes into the nodes. Specialized lining within the node
separates molecules by size and chemical composition and
shunts them into the T cell zones for processing. The nodes
are separated into zones by reticular and collagen fibers and
other tissue that allow the antigen presenting cells to come
and remain in close contact with the lymphocytes. Different
classes of lymphocytes are segregated into different areas.
Follicles are the B cell zones, where both mature and naïve B
cells aggregate. Germinal centers develop in response to anti-
genic stimuli and are sites of B cell proliferation, selection of
B cells producing high-affinity antibodies, and the generation
of memory B cells. T cells aggregates are located beneath and
 D.E. Schraufnagel / Pathophysiology 17 (2010) 337–343
more central to the follicles in the paracortical cords. Naïve T
and B cells enter the node through high endothelial venules in
response to chemokines and their receptors. The chemokines
bind to their cell surface receptors and set off a cascade of
signaling to exert several intracellular changes.
Another important component in the lymphatic system is
the bronchus associated lymphoid follicles. In addition to the
defense of the dendritic cells, lung microbial invaders may
encounter specialized secondary lymphoid tissue situated in
aggregates below the bronchial or bronchiolar epithelium.
These lymphoid follicles have access to the epithelial sur-
face as well as both the blood stream and lymphatics and
contain specialized dendritic cells, called follicular dendritic
cells. The follicles thus can monitor immune stimuli from
all three sources. Follicular dendritic cells can present anti-
gens to previously sensitized B cells in germinal centers. The
immune stimuli do not have to be bacteria. Dendritic cells can
ingest tumor cells and virus infected host cells and present
them to CD8 T cells instead of the usual CD4 T cells (cross
presentation).
Different lymphocytes traffic through the blood stream,
lymphatics, lymphoid organs, such as the spleen, special-
ized lymphoid tissue, such as the aggregates associated with
bronchi, bronchioles, and nonlymphoid tissue at different
frequencies and paces. This allows a constant sampling of
the body for antigens. The lymphocytes’ remarkable ability
to home back to the site of the inflammation results from
well-orchestrated set of molecular events involving adhesion
molecules, including selectins and integrins, and lymphocyte
homing receptors that bind to endothelial cells. The adhesion
and detachment to extra cellular matrix along with chemokine
concentrations determines how long the lymphocytes reside
in the tissue before recirculating back through the lymphatics
[24–27].
The lung lymphatics, thus, do far more that clear fluid
and particulates. The facilitate and orchestrate the immune
response that involves neoplasia and transplantation as well as
infection. The availability of markers and better understand-
ing of the process heralds a new era of lymphatic research
and potential for medical monitoring and treatments.
References
[1] D.E. Schraufnagel, Forms of lung lymphatics: a scanning electron
microscopic study of casts, Anat. Rec. 233 (1992) 547–554.
[2] D.E. Schraufnagel, Microvascular corrosion casting of the lung. A state-
of-the-art review, Scanning Microsc. 1 (1987) 1733–1747.
[3] D.E. Schraufnagel, D.B. Pearse, W.A. Mitzner, E.M. Wagner, Three-
dimensional structure of the bronchial microcirculation in sheep, Anat.
Rec. 243 (1995) 357–366.
[4] D.E. Schraufnagel, J. Llopart Basterra, K. Hainis, J.I. Sznajder, Lung
lymphatics increase after hyperoxic lung injury: an ultrastructural study
of casts, Am. J. Pathol. 144 (1994) 1393–1402.
343
[5] S. Aharinejad, P. Böck, W. Firbas, D.E. Schraufnagel, Pulmonary lym-
phatics and their spatial relationship to venous sphincters, Anat. Rec.
242 (1995) 531–544.
[6] A. Bagri, M. Tessier-Lavigne, R.J. Watts, Neuropilins in tumor biology,
Clin. Cancer Res. (2009).
[7] S. El-Chemaly, S.J. Levine, J. Moss, Lymphatics in lung disease, Ann.
N. Y. Acad. Sci. 1131 (2008) 195–202.
[8] N.E. Vlahakis, B.A. Young, A. Atakilit, D. Sheppard, The lymphangio-
genic vascular endothelial growth factors VEGF-C and -D are ligands
for the integrin alpha9beta1, J. Biol. Chem. 280 (2005) 4544–4552.
[9] T. Ezaki, K. Kuwahara, S. Morikawa, K. Shimizu, N. Sakaguchi, K.
Matsushima, K. Matsuno, Production of two novel monoclonal anti-
bodies that distinguish mouse lymphatic and blood vascular endothelial
cells, Anat. Embryol. (Berl). 211 (2006) 379–393.
[10] M. Raica, A.M. Cimpean, D. Ribatti, The role of podoplanin in tumor
progression and metastasis, Anticancer Res. 28 (2008) 2997–3006.
[11] H.W. Wang, M.W. Trotter, D. Lagos, D. Bourboulia, S. Henderson, T.
Makinen, S. Elliman, A.M. Flanagan, K. Alitalo, C. Boshoff, Kaposi
sarcoma herpesvirus-induced cellular reprogramming contributes to the
lymphatic endothelial gene expression in Kaposi sarcoma, Nat. Genet.
36 (2004) 687–693.
[12] D.E. Schraufnagel, N.P. Agaram, A. Faruqui, S. Jain, L. Jain, K.M.
Ridge, J.I. Sznajder, Pulmonary lymphatics and edema accumulation
after brief lung injury, Am. J. Physiol. Lung Cell Mol. Physiol 284
(2003) L891–L897.
[13] M.G. Achen, S.A. Stacker, Molecular control of lymphatic metastasis,
Ann. N. Y. Acad. Sci. 1131 (2008) 225–234.
[14] D.M. McDonald, Angiogenesis and remodeling of airway vasculature
in chronic inflammation, Am. J. Respir. Crit Care Med. 164 (2001)
S39–S45.
[15] R. Krebs, J.M. Tikkanen, A.I. Nykanen, J. Wood, M. Jeltsch, S.
Yla-Herttuala, P.K. Koskinen, K.B. Lemstrom, Dual role of vascu-
lar endothelial growth factor in experimental obliterative bronchiolitis,
Am. J. Respir. Crit Care Med. 171 (2005) 1421–1429.
[16] F.G. Fleischner, The butterfly pattern of acute pulmonary edema, Am.
J. Cardiol. 20 (1967) 39–46.
[17] N.C. Staub, “State of the art” review. Pathogenesis of pulmonary edema,
Am. Rev. Respir. Dis. 109 (1974) 358–372.
[18] N.S. Wang, The preformed stomas connecting the pleural cavity and
the lymphatics in the parietal pleura, Am. Rev. Respir. Dis. 111 (1975)
12–20.
[19] P.A. Valberg, R.K. Wolff, J.L. Mauderly, Redistribution of retained
particles. Effect of hyperpnea, Am. Rev. Respir. Dis. 131 (1985) 273–
280.
[20] G. Miserocchi, G. Sancini, F. Mantegazza, G. Chiappino, Translocation
pathways for inhaled asbestos fibers, Environ. Health 7 (2008) 4.
[21] H. Bachofen, S. Schurch, R.P. Michel, E.R. Weibel, Experimental
hydrostatic pulmonary edema in rabbit lungs. Morphology, Am Rev.
Respir. Dis. 147 (1993) 989–996.
[22] J.M. Lauweryns, Morphological studies of the blood and lymphatic
microcirculation of the lung, Acta Cardiol. 19 (Suppl.) (1974) 157–167.
[23] D.N. Cook, K. Bottomly, Innate immune control of pulmonary dendritic
cell trafficking, Proc. Am. Thorac. Soc. 4 (2007) 234–239.
[24] A.K. Abbas, A.H. Lichtman, S. Pillai, Cellular and Molecular
Immunology, Elsevier, Philadelphia, 2007.
[25] O. Ohtani, Y. Ohtani, Structure and function of rat lymph nodes, Arch.
Histol. Cytol. 71 (2008) 69–76.
[26] L.M. Ebert, P. Schaerli, B. Moser, Chemokine-mediated control of T
cell traffic in lymphoid and peripheral tissues, Mol. Immunol. 42 (2005)
799–809.
[27] J. Bienenstock, M.R. McDermott, Bronchus- and nasal-associated lym-
phoid tissues, Immunol. Rev. 206 (2005) 22–31.