Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3996_Библиотеки_им_академика_М_И_Перельмана
.pdf
Changes during chronic inflammation
Defined by swelling, redness, and heat, inflammation is a burden
of the medical world that has a number of initiators and as such can
be treated in a variety of manners. Lymphatic dysfunction is a key
mediator of inflammation as, through stagnation of fluid, cell-
derived molecules and infiltrated peripheral immune cells can be
exacerbated by and result in lymphatic dysfunction and further
inflammatory insult. Lymphatic contractile dysfunction is often
associated with tissue inflammation, a phenomenon first described
during endotoxin infusion in sheep where, through the hypothe-
sized actions of prostaglandins, edema formation was seen [103].
More recent work has focused on the role of NO by regional iNOS
positive cells regulating contractile function within collecting lym-
phatics [84]. These iNOS positive cells include the resident popula-
tions of immune cells such as macrophages, dendritic cells, or mast
cells that reside on and within the vessel wall and can respond to
lymphatically trafficked antigens [104,105]. These resident cells
can modulate contraction through mechanisms other than NO
including the release of prostaglandins [68], histamine [67], and
cytokines such as IL-1β [106] and TNFα [107], which negatively
impacts upon the vessel pumping and could also alter its barrier
function [108].
There is mounting evidence that interactions between lymphatic
vessel stromal cells and immune cells exist influencing localized
effects, migration, and adaptive immune stimulation. Active lym-
phangiogenesis occurring during inflammation is a process domi-
nated by the production of lymphangiogenic growth factors
secreted from tissue-resident macrophages [109–111]. In addition
to their paracrine function, macrophages are also able to induce neo-
lymphangiogenesis through transdifferentiation into lymphatic
endothelial cells incorporating themselves as such and into the lym-
phatic vessels [112,113], a phenomenon also observed by Wilting’s
group using transgenic mice during development [114]. During
inflammation, this transdifferentiation event is prominent, with
many groups recording macrophage to lymphatic endothelial tran-
sitions in LPS-induced peritonitis [115] and even diabetes [116].
Although the contribution of these resident immune cells in mod-
ulation of the lymphatic pump remains to be further investigated,
34 3. Lymphatic pumping and pathological consequences of its dysfunction
https://t.me/medicina_free
it is reasonable to hypothesize that during inflammation, these
populations of immune cells within the vessels may alter pumping
through chemotaxis of peripheral cells, production of inflammatory
mediators, and dedifferentiation processes within the vessels and
surrounding tissue altogether promoting inflammation. These cells
could also directly impact the flow of lymph through vessel relaxa-
tion, reduce contraction frequency, and permeate the endothelial
layer through modulation of tight junction proteins. Leakage of
lymph into the peripheral tissue could further drive inflammation
through promotion of a localized immunogenic response a feature
commonly seen in many chronic inflammatory conditions.
Arthritic diseases
Many inflammatory joint diseases are associated with lymphatic
alterations. Swelling, pain, joint remodeling, and endpoint surgical
intervention are common to many forms of arthritic diseases such as
rheumatoid arthritis (RA) and osteoarthritis (OA). However, in such
highly inflammatory and degenerative diseases, the changes in lym-
phatic structures are widely overlooked yet present. While the liter-
ature yields low numbers of studies linking lymphedema and
inflammatory rheumatological diseases, new approaches to treat-
ments have greatly improved the lives of those suffering. Lymph-
edema within this disease group is primarily isolated to the
highly inflammatory pathologies such as RA [117] but is observed
in smaller numbers in psoriatic arthritis [118] and ankylosing
spondylitis [119].
Studies demonstrating a possible link between joint disease and
lymphatic function occurred through the use of the transgenic
TNFα-overexpressing mice, which showed that the popliteal lymph
node enlarges during the prearthritic phase, subsequently collaps-
ing during active joint disease [120]. The prearthritic phase was
associated with contractile dysfunction, assumedly through the
buildup of inflammatory mediators, after which the pumping pres-
sure of the afferent lymphatics is diminished following lymph node
collapse resulting in severely compromised lymph flow [121].In
recent years, the involvement of the lymphatic system, primarily
the drainage function, has been identified as a potential model for
the treatment of human RA. The inflamed synovium (pannus)
35Lymphatic pumping in diseases
https://t.me/medicina_free
creates a highly localized inflammatory environment packed with
proinflammatory cytokines, degenerative enzymes, and immune
cells, which can all have direct effects upon the lymphatic architec-
ture. It is thought that through chronic disruption of the collecting
lymphatics, fluid accumulates within the joint leading to localized
swelling. In the context of our focus, chronic damage to the lym-
phatic endothelium and surrounding muscle cells leads to loss of
lymphatic vessel contraction and subsequent lymph node collapse.
As such, does the reduced lymphatic drainage result in the observed
synovitis and joint erosion? In theory, restoration or increased lym-
phatic drainage from the affected site facilitates the removal of cat-
abolic factors, cytokines, and inflammatory cells from the pannus.
Mouse models of osteoarthritis (OA), such as the meniscal-
ligamentous injury model or the transforming growth factor β
(TGFβ) type II knockout mice, have associated lymphatic maladies
[122]. The severe cartilage loss and joint destruction, evident in the
disease, appear in tandem with capillary and mature lymphatic ves-
sel changes. It has been documented that a majority of lymphangio-
genesis occurs within the soft tissues surrounding the joint. Within
patients, lymphatic alterations can be noted to differentiate early to
mild OA, where lymphangiogenesis is rife with increased density of
vessels, to severe OA that shows a distinct loss in mature lymphatics
and increased swelling, due to decreased lymph clearance from the
afflicted joint [122]. Treatment targeting inflammation and degrada-
tion within the joints of OA patients may also affect associated lym-
phatics as nonsteroidal antiinflammatory drugs (NSAIDS) such as
ketoprofen, by blocking the action of COXs impeding lymphatic
contraction through the regulation of spontaneous smooth muscle
contraction [123].
As a multifactorial manifestation, lymphedema within arthritic
disease is incredibly complicated to dissect and study. The multifac-
eted disease itself proves to wax and wane in a cyclic rhythm of
chronicity in a manner common to many inflammatory diseases,
interestingly corresponding with the occurrence of lymphatic dys-
function. Mounting evidence suggests these changes include an ini-
tial compensatory expanding phase, in which the lymph node
expansion and contraction of collecting lymphatics are proficient.
Soon after, however, intrinsic lymphatic contraction fails, and the
lymph node decreases in volume entering a collapsed stage
36 3. Lymphatic pumping and pathological consequences of its dysfunction
https://t.me/medicina_free
corresponding with disease flare. This new information provides
hope for the targeting of lymphatics as a treatment during
arthritis-associated inflammation, whereby it appears that until
the lymphatic collapse, the joint swelling and acute phase of the dis-
ease has not taken hold. Stalling in this phase could be a poignant
treatment for many sufferers of RA although more studies need
to be performed.
Inflammatory bowel disease
Lymphatic vessels are not usually considered key players in any
disease whose pathologies are not directly linked, such as inflamma-
tory bowel disease (IBD). While not evidently visible, because
revealed only after surgical intervention, overloaded lymphatics,
lymphangiogenesis, and lymph node remodeling are hallmark fea-
tures of these diseases (reviewed in von der Weid et al. [124]).
Crohn’s disease is described as a “regional ileitis” whereby the dis-
ease can affect anywhere along the GI tract but primarily manifests
at the terminal ileum [125]. Interestingly, regional lymphatic dys-
function around the sites of tissue inflammation is regularly
reported (reviewed in D’Alessio et al. [126]). This observation led
to the suggestion that lymphatic vessel obstruction and ineffective
relocation of the immune response to the mesenteric lymph nodes
perpetuated the chronic localized inflammation. Through artificial
damage or blockade of the mesenteric lymphatics with silica parti-
cles, sutures, or cauterization, researchers were able to mimic many
of the phenotypes of Crohn’s disease ([127,128]. However, not
all features are conserved, and the use of such an artificial system
questions the accuracy of the models and will remain under scrutiny
by peers for years to come. Other than benign obstruction of
lymphatics, chemical treatment such as surgical instillation of
2,4,6-trinitrobenzenesulfonic acid (TNBS) in the guinea pig ileum
causes an inflammation recapitulating many common effects to
the lymphatic dysfunction, such as loss in contractions and dilation
of vessels [129]. Similar results have been demonstrated within the
rat TNBS model of colitis whereby an altered lymphatic microenvi-
ronment resulted in sustained inflammation within the ileum [105].
Unfortunately, due to the lack of pumping within the mouse mesen-
teric collecting lymphatics, no data are available in relation to
37Lymphatic pumping in diseases
https://t.me/medicina_free
contractile function changes in genetic or treatment models of
Crohn’s disease in this animal. However, mouse models do provide
valuable insights into lymphatic alteration during associated GI
inflammation. For example, a vast array of lymphatic alterations
has been observed in the mesentery of the TNFdeltaARE model of
Crohn’s disease [130] and in the dextran sodium sulfate (DSS)-
induced colitis model [130].
Lymphatic vessel dilation and associated edema seen within IBD
patients undergoing surgery are theorized to be a consequence of
lymphatic obstruction, impaired lymphatic contraction, or a combi-
nation of both [124,127,131,132]. Tissue fluid accumulation would
suggest issues in fluid drainage, which can lead to local mucosal
hypoxia, systems commonly associated with CD [133]. Furthermore,
the lack of clearance of other particulate matter, such as macromol-
ecules, dead cells, bacterial components, and antigen-bearing innate
immune cells, can promote site-directed infection and a delay in
adaptive immune response [134]. However, the exact mechanisms
behind lymphatic contractile dysfunction are still not fully charac-
terized. Regardless of the mechanism, fluid buildup ultimately
results in lesions within the intestinal mucosa such as those seen
in IBD [135]. Although lymphatic dysfunction was observed in
human cases of IBD, it was rarely thought of as a causative agent,
especially where more aggressive symptoms lay upstream. Granu-
loma formation within the lamina propria, along with potent lym-
phangiogenesis, is seen as more targetable areas of therapy in
prevention of primary lesions in CD and UC [136].
Metabolic syndrome and diabetes
In recent years, metabolic syndrome and diabetes have become
one of the largest global health issues with the International Diabe-
tes Federation (IDF) estimating 25% of the world’s population
present with metabolic syndrome [137]. Chronic inflammation
underlying these diseases drives remodeling of collecting lym-
phatics and impairs their functions, which ultimately results in
inadequate lymph flow. While the effect upon blood microvascula-
ture had been associated with metabolic syndrome, it was only
recently that Zawieja’s group noted lymphatic alterations in a rat
model of metabolic syndrome and suggested their possible contri-
bution to disease pathogenesis. They demonstrated severely
38 3. Lymphatic pumping and pathological consequences of its dysfunction
https://t.me/medicina_free
reduced lymphatic capacity within rats suffering from metabolic
syndrome and a reduced diameter of prenodal collecting lym-
phatics under pressurization resulting in a significantly reduced
ability to generate pumping force [138]. With the apparent distur-
bance of the lymphatic system within the mesentery, the contribu-
tion of surrounding adipose tissue and resident cells has come
under scrutiny. Notably, high-fat diet-fed mice have been shown
to display functional impairment of collecting lymphatics consistent
with remodeling of the associated tissue lymphatics [139].
It therefore draws into question whether diet-induced obesity
and involved conditions such as metabolic syndrome and diabetes
are drivers of lymphatic dysfunction or rather a consequence. Addi-
tionally, with the importance of the lymphatic system in the trans-
port of dietary fats and lipid mediators such as LDL, what effect
could these alterations have on the body at distant sites? An exem-
plar study in support of this concept occurred through the use of
LDL receptor knockout mice, which suggested that the accumula-
tion of cholesterol in arteries and skin from mice was a resultant fac-
tor of poor lymphatic drainage, a phenomenon re-established by the
restoration of lymphatic flow [140]. Scallan et al. also revealed that
NO contributes to collecting lymphatic vascular integrity distur-
bance in a type II diabetic model of mice. Through a novel advanced
imaging technique, the lab demonstrated that the leptin receptor-
deficient (db/db) obese mice had “leakier” collecting lymphatic ves-
sels than wild-type counterparts [141]. It was also noted that the
decreased function and enhanced permeability were due to a low
bioavailability of NO, a factor as previously mentioned, to be impor-
tant in the regulation of pumping.
Cancer
Metastasis, described as the development of secondary tumors at
a distance from the site of primary cancer establishment, is the most
common reason for fatality in many forms of cancer [142]. The
movement of cancerous material throughout the body primarily
occurs through the lymphatic vasculature and is evident by the sec-
ondary sites of metastasis being most often the peripheral lymph
nodes. Primarily occurring through the lymphatic system, cancer
metastasis can elicit effects upon the system itself, modulating many
factors that can result in impaired immune responses, susceptibility
39Lymphatic pumping in diseases
https://t.me/medicina_free
to infection, and modulation of cancer growth. Tumor
microenvironment-derived growth factors such as VEGFC and
VEGFD promote lymphangiogenesis within and close to the pri-
mary tumor, thereby accelerating its potential to spread (detailed
in Wang et al. [143]). It is seen that the expansion of initial and col-
lecting lymphatics around solid tumors requires key remodeling of
smooth muscle cells, a process that can ultimately result in rapid
expansion of cancer correlated to altered lymphatics [144].
The generation of new lymphatic vessels and modification of pre-
existing lymphatic structures are thought by many to be an impor-
tant step in metastasis due to the prevalence of incidence in
numerous forms of cancer. However, it is a sign of poor prognosis
as the cancer has more than likely spread and colonized within sen-
tinel lymph nodes and distal organs. With such an apparent involve-
ment of the lymphatics in cancer metastasis, it has been suggested
that modulating the changes within lymphatics may be beneficial
to prevent cancer progression. Lymphangiogenesis at the primary
tumor site is a common phenomenon in many forms of primary
human cancers such as melanoma [145]. Originally, it was thought
that tumors were devoid of lymphatics and that the importance of
blood vasculature was the preferred method of transport of shed-
ding tumor cells into the periphery, a theory only debunked within
the last 15 years [146]. However, it has become apparent that tumor-
derived growth factors including VEGFC and VEGFD drive the
formation of intratumoral lymphatic vessels, an important process
in cancer establishment and metastasis seen in many tumor types
and an observable clinical feature. VEGFC was noted to be a predic-
tive marker for aggressive metastasizing cancers over a decade ago
with even low-grade intratumoral lymphangiogenesis being predic-
tive of the progression of laryngopharyngeal carcinoma, promoting
its use as a predictive diagnostic tool [147]. Later, the analysis of
solid tumors within gastric cancer, by Ikeda and colleagues, demon-
strated that lymphangiogenesis correlated to increased incidence of
metastasis and a significantly lower survival rate [148]. While all
cancers may not present with lymphangiogenesis, the importance
of the system in the context of cancer proliferation and metastasis
makes it a hot topic of research to this day additionally displaying
the importance of lymphatics in the context of cancer.
Beyond the primary tumor, distant collecting lymphatics
undergo substantial remodeling. While many studies implicating
40 3. Lymphatic pumping and pathological consequences of its dysfunction
https://t.me/medicina_free
VEGFC and VEGFD with tumor lymphangiogenesis focus primarily
on the tumor microenvironment and structural alterations held
therein, the knock-on effects this has on the lymphatic vasculature
as a whole are still being discovered. Observations in altered antigen
uptake, flow, and presentation during tumor metastasis have
directed studies into focusing on antitumor immunity in the context
of being lymphatically modulated (reviewed in Lund [149]).
As described in “Lymphangiogenesis” section, lymphatic dys-
function in the form of cancer-acquired secondary lymphedema is
one of the most common secondary conditions affecting patients
that have undergone surgical intervention. One of the most com-
monly acquired forms of lymphedema is a consequence of breast
cancer treatment, where, after surgical excision of the axillary lymph
nodes, a classical treatment during breast cancer surgery, fluid accu-
mulates. The accumulation of fluid, while not lethal, can be debili-
tating, and due to the stretching of dermal layers, prolonged
presence of immune cells and chronic inflammation is susceptible
to infection such as cellulitis [150]. Prominent lymphatic alterations
are an observed clinical phenomenon within cancer patients.
Whether this be through lymphangiogenesis at the sites of inflam-
mation, failure in collector pumping, or localized infection as a
product of failed antigen clearance, the disturbed lymphatic system
can have many detrimental effects. Ongoing research into this area
and novel treatments and surgical interventions such as lymph node
transplant has been somewhat successful although not universally
effective. Confounding these results is the evidence suggesting that
the incidence of secondary lymphedema within the patient cohort is
not direct, and as such, the exact cause and importance of the lym-
phatic system are still debated [151].
Targeting the lymphatic pump for therapeutic benefits
The potential for the manipulation of the lymphatic system as a
therapeutic approach has been a dream of many in the research com-
munity. Current treatments for lymphedema are insufficient and
usually limited to resolving symptoms rather than targeting the
cause. Skin care, manual lymph drainage, compression, and exercise
remain the frontline therapies for all suffering from lymphedema
41Targeting the lymphatic pump for therapeutic benefits
https://t.me/medicina_free
despite the underlying cause. In the treatment of inflammatory dis-
eases such as RA, the introduction of disease-modifying drugs does
not always resolve the lymphatic alterations and is therefore com-
monly seen as an unlinked phenomenon. Interestingly, however,
several studies into the use of anti-TNF therapy within the treatment
of rheumatological diseases may be effective for lymphedema treat-
ment with etanercept significantly reduced lymphedematous swell-
ing in RA patients with associated inflammation [152–154]. The
therapy is thought to act by reducing inflammation within the
inflamed joint and thereby the adjacent inflammation within
affected lymphatics, thus reducing fluid accumulation. However,
in the same manner as many RA patients, the efficacy of this treat-
ment is poor and can aggravate other underlying issues with many
having reported the paradoxical effects of anti-TNF therapies pro-
moting underlying psoriasis, suggesting that its use should be care-
fully considered.
For IBD sufferers, the use of biologic treatments is limited due to
the varying efficacy on the resolution of symptoms. At the time of
writing this, six biologic agents are approved for the treatment of
IBD, four that target TNFα (infliximab, golimumab, and certolizu-
mab pegol) while the other two that target integrins (natalizumab
and vedolizumab). The full spectrum of effects that these treatments
have upon the lymphatics has not been characterized although with
the known effect of TNFα on lymphatic pumping modulation and
the involvement of α4β7 integrins in endothelial cell migration
and lymph node B-cell adherence, there could be significant over-
lap. Time and further analysis will demonstrate the efficacies of
these treatments upon IBD progression, although they may only
regulate the inflammatory symptoms of the disease rather than
the underlying cause, suggested by many to be lymphatically mod-
ulated. Currently, a base of research aims at resolving disease
through the restoration of correct lymphatic flow identifying it as
the primary source of pathogenicity. Several groups are investigat-
ing this avenue at the moment through the modulation of lymphan-
giogenesis and lymphatic pumping with varying results. While
the outcomes of these studies have been globally inconclusive, the
information gleamed from them has developed ideas into treat-
ments and new targets. Selective drug delivery through lipophilic
42 3. Lymphatic pumping and pathological consequences of its dysfunction
https://t.me/medicina_free
agents and regulation/restoration of the lymphatic flow through
pumping modulation are but some of the ideas [155].
In many inflammatory conditions, the accumulation of fluid
through lymphatic disruption creates many symptoms not associated
with the actual primary disease manifestation. Chronic damage,
matrix remodeling, and tissue necrosis are all common side effects
to several inflammatory diseases such as IBD, RA, OA, and cancer,
and targeting the lymphatics to aid in the resolution of the condition
is an innovative novel strategyfor therapeutic intervention.However,
the purpose of lymphatic remodeling within these diseases is still not
fully understood; as such, interfering with the natural process of
events may further exacerbate disease pathogenesis. Therefore, fully
understanding the consequences of lymphangiogenesis, lymphan-
giectasia, and other such lymphatic changes is paramount for
researchers and clinicians alike. It is through developing imaging
techniques such as near-infrared lymphoscintigraphy that the effi-
cacy of lymphatic pumping-targeted treatments can be monitored
in a clinical scenario further allowing us to understand the impor-
tance of this system, which until recently has been widely ignored.
With the recent recognition of the interstitium as an organ [156],
the development of research involving lymphatics are sure to expand
even further, relating to the close interplay of the system in almost
every facet of disease establishment and progression.
Conclusions
Divided into three major components, the lymphatic system is
seemingly rather simplistic. Collection of fluid through initial lym-
phatics is driven by hydrostatic pressure gradients, after which
transport to the lymph node is modulated by pumping of collecting
lymphatics where the fluid can be screened by the innate resident
cells and any antigen-presenting cells can promote an adaptive
response. However, if any step of this process is altered, the effects
can be unfavorable. The collection of lymph and transport of its
components are undoubtedly the most important step in this struc-
turally hierarchical system as without flow, the system is obsolete
and would solely rely on cellular migration and diffusion. During
diseases of lymphatic involvement, a common feature is a failure
43Conclusions
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана