Research Article
Prospect on the Therapeutic Effect of Vascular Endothelial Growth Factor from the Perspective of the Pathogenesis of Pancreatitis
Muna Palikhe1, Jun Zhan1*, Rajiv Kumar Jha2 and Xudong Zhang2
*Corresponding author: Jun Zhan, Division of Gastroenterology, The second Affiliated Hospital of Xi’an Jiaotong University, No.157, XiWu Road, Xi’an, China
Published: 22 Oct, 2018
Cite this article as: Palikhe M, Zhan J, Jha RK, Zhang
X. Prospect on the Therapeutic
Effect of Vascular Endothelial Growth
Factor from the Perspective of the
Pathogenesis of Pancreatitis. Clin Surg.
2018; 3: 2174.
Abstract
Many theories on the pathogenesis of severe acute pancreatitis (SAP) cannot fully explain the
pathophysiological mechanism of SAP, with many unexplainable contradictions, hence the need for
further investigation. Vascular Endothelial Growth Factor (VEGF), the most effective proangiogenic
and vascular endothelial protective agent found by far, plays critical roles in the processes of
angiogenesis, vascular development and vascular protection. In recent years, many scholars have
investigated the therapeutic effect of VEGF on pancreatitis, but the results are inconclusive. This
study intends to explore the prospects of VEGF on the treatment of SAP from the perspective of the
pathogenesis of pancreatitis.
Keywords: Acute pancreatitis; Pathogenesis; Vascular endothelial growth factor
Background
Between the two types of Acute Pancreatitis (AP), Severe Acute Pancreatitis (SAP) accounts for
approximately 20% and tends to cause Multiple Organ Dysfunction Syndrome (MODS). In spite of
continuous improvements in medical conditions, the mortality rate of SAP is still as high as 20% to
40% [1,2]. This situation is mainly due to an insufficient understanding of the pathogenesis of SAP,
which also leads to the lack of substantial progress in its clinical treatment. Further exploring the
pathogenesis of SAP and then carrying out an intervention on the key steps from the disease onset
may lead to therapeutic breakthroughs.
As the most effective proangiogenic and vascular endothelial protective agent found by far,
Vascular Endothelial Growth Factor (VEGF) specifically acts on endothelial cells to promote the
proliferation and differentiation of vascular endothelial cells and facilitate angiogenesis. VEGF plays
crucial roles in the processes of vascular development and formation and vascular protection. VEGF
is often widely used as a specific factor of vascular endothelial cells in the studies on tumorigenesis,
progression and metastasis, and treatment of ischemic diseases [3]. Due to its powerful roles in
promoting angiogenesis and vascular protection, scientists have started to study the therapeutic
effect of VEGF on AP in recent years and have obtained preliminary research results. This review
intends to focus on the therapeutic effect of VEGF on AP from the perspective of the pathogenesis
of AP, to address the gap in the understanding of AP, in order to provide a new clinical treatment
concept.
Current Research Status and Inadequate Understanding of Acute Pancreatitis
Self-digestion of pancreatic enzymes
In 1896, Chari proposed that pancreatitis was caused by the ectopic activation of pancreatic
enzymes; this has been considered the classic theory of AP pathogenesis ever since. Under normal
circumstances, trypsin is activated in the duodenum. However, in AP, the normal isolation mechanism
of lysosomal enzymes and trypsinogen is disrupted, causing the ectopic activation of trypsinogen
in the pancreas and leading to the self-digestion of pancreatic tissues. Coelho et al. confirmed that
the blood levels of TNF-α and IL-6 were positively correlated with the blood concentration of
proteases during SAP, and decreasing the blood concentration of proteases significantly reduced
the degree of liver injury [3]. This finding suggests that trypsin plays an important role in AP and the
associated multiple organ damage. In 2000, Lundeberg [4] reported
that trypsin is the most important mediator of the inflammatory
response in SAP. Meanwhile, Leonhardt et al. [5,6] also confirmed
Lundeberg’s conclusion. In fact, the discovery by Lundeberg et al. is
an extension of Chari’s pancreatic enzyme theory. However, Chari’s
theory is limited to the pathological changes of the pancreas itself and
lacks a reasonable explanation for the damage to the organs other
than the pancreas. Therefore, Chari’s theory has certain limitations.
Foitzik and others proposed that SAP-activated pancreatic enzymes
not only digest the pancreas itself but also continue to exert their
destructive effects as they enter the blood circulation with blood flow,
triggering a series of pathological changes, such as microcirculatory
disturbances, excessive activation of leukocytes and inflammatory
factors, and secondary infections. However, how does trypsin cause
these pathological phenomena? What is their specific mechanism of
action? Further research is needed to address these questions.
Excessive release of inflammatory mediators and
cytokines
The theory of inflammatory factors and cell mediators was first
proposed by Ringerknecht et al. in 1988 [7]. Since its introduction,
this theory has become a hot topic for research in the field around
the world. In recent years, substantial research results have been
achieved, which suggest that the overstimulation of neutrophils
causes the increased production of toxic substances such as oxygen
free radicals and TNF-α, resulting in varying degrees of Systemic
Inflammatory Response Syndrome (SIRS), which in turn leads to
multiple organ failure. The main idea of this theory is that the over
activation of leukocytes leads to the release of large amounts of
cytokines and inflammatory mediators into the blood upon the onset
of AP, resulting in a respiratory burst, the production of oxygen free
radicals, and the initiation of a cascade of inflammatory cytokine
activation. These events lead to microcirculatory disorders, which
further aggravates pancreatic tissue injury and triggers SIRS and
MODS [8].
Microcirculatory dysfunction
The occurrence and development of AP are believed to have a
crucial association with circulation. Thromboxane A2 (TXA2) is a
potent capillary vasoconstrictor and platelet contraction enhancer
that can cause tissue ischemia; coagulation disorders, leukocyte
activation, and the release of oxygen free radicals, resulting in damage
to the vascular endothelium and in turn microcirculatory dysfunction.
Endo Thelin (ET) can cause vasospasm, promote calcium influx,
damage tissue cells, and reduce cardiac output, leading to ischemia
and oxygen free radical production. Ischemia, hypoxia, and increased
oxygen free radicals also promote ET production in endothelial cells,
resulting in a vicious cycle [9].
However, the role of blood circulation in the pathogenesis and
progression of AP remains controversial. Some scholars believe that
the changes in pancreatic blood flow is only a secondary manifestation
of AP, and studies have demonstrated that changes in pancreatic
blood flow and systemic hemodynamics are caused by hypovolemia
after the onset of AP. Therefore, the role of blood circulation in the
pathogenesis and progression of AP and its exact mechanism await
further research.
Bacterial infection and the “Second Strike” theory
Infections in pancreatic and para pancreatic tissues following
AP are one of the major causes of mortality in the late stage of AP.
A large number of studies have shown that the barrier function of
the intestinal epithelium is seriously impaired in AP, resulting in
the translocation of bacteria and toxins in the intestinal tract and
thus infections in pancreatic and para pancreatic tissues and even
sepsis [10]. Endotoxins also promote the second cascade of cytokine
activation, causing the body to suffer a second strike, aggravating
organ damage and further worsening the symptoms.
The above theory explains to some extent some phenomena in the
pathogenesis of AP. However, many special phenomena cannot be
reasonably explained by existing theories. (1) What are the criteria to
distinguish between the two pathological types of AP? In the two types
of pancreatitis, the pathological changes of edematous pancreatitis
are mainly edema and inflammatory cell infiltration in pancreatic
tissues. In addition to hemorrhage and necrosis in the pancreas
itself, SAP also causes serious damage to other organs. According to
the current theory of the “waterfall-like” cascade effect, and in the
absence of specific treatment measures, there should be only one type
of AP, which is SAP. In fact, less than 20% of all pancreatitis patients
fall into this category. This phenomenon cannot be explained by
the current theories. (2) Why are the pathological changes of other
organs similar to those of the pancreas itself? We know that the
pathological changes of the pancreas in AP mainly include necrosis,
hemorrhage, and inflammatory cell infiltration in pancreatic tissue.
In fact, the pathological changes in the liver, kidney, lung, intestine
and brain tissues are consistent with those in the pancreas in AP
[11,12]. This phenomenon is also currently unexplainable using the
existing theories. (3) Why does the occurrence of multiple organ
damage have an obvious decreasing trend along the pancreatic blood
flow circuit? Our literature review clearly found that the incidence
of organ damage has a close relationship with the location of the
involved organ on the route of pancreatic venous drainage, namely,
liver (80-100%) >heart (48.9-60.7%) >lung (15-50%) >kidney (15-
35.8%) >brain (9-20%). What causes this phenomenon?
Establishment of a Medical Hypothesis
With the above questions in mind, we developed the following
hypothesis after long-term animal experiments and an extensive
review of the literature: a large amount of pancreatic proteases are
ectopically activated upon AP, especially SAP, and enter the blood
circulation through venous blood flow while destroying the structure
of the pancreas itself. These proteases can destroy the protein skeleton
structure on vascular wall, causing impaired vascular wall integrity
and increased vascular permeability. Therefore, large amounts of
vascular contents pass through the damaged vascular wall and enter
the interstitial space or body cavity. This leads to early circulatory
dysfunction in AP patients, which is an important cause of early
death in AP patients. Because the liver is the first recipient organ in
pancreatic venous drainage, the concentration of activated pancreatic
protease is the highest in the liver, where the extent of damage caused
by these proteases is also the most serious. With the consumption
of these pancreatic enzymes in the liver, the concentrations of these
proteases in post hepatic venous blood are significantly lower than the
prehepatic concentrations, and thus, the degree of damage to other
organs along this venous drainage circuit shows a decreasing trend.
According to this hypothesis, we can easily explain the questions we
raised earlier. Distinguishing between AP and SAP, the two types of
pancreatitis, mainly depends on the amount of activated pancreatic
proteases and whether they enter the blood circulation and then cause
a wider range of damage.
According to our inference, from the current point of view on
AP treatment, once the vascular wall is damaged, it is apparently
impossible to fundamentally address the issue using the current
traditional treatment measures. This is also the main reason why the
mortality rate of AP patients remains high. Therefore, it is only possible
to achieve better therapeutic effects when we start from the root cause
of the disease and repair the damaged vascular endothelium as soon
as possible, to maintain the stability of the circulatory function and
then improve the impaired organ functions. This treatment strategy
is likely to become a breakthrough for AP treatment in the future.
Prospect on the effect of vascular endothelial growth
factor on the treatment of pancreatitis
As the most potent substance that promotes angiogenesis
and vascular endothelial protection, VEGF specifically acts on
endothelial cells to promote the proliferation and differentiation of
vascular endothelial cells, thus promoting angiogenesis. VEGF plays
important roles in the process of vascular development, formation,
and myocardial and cerebral ischemia. VEGF is often widely used as
a vascular endothelial-specific factor in research on tumorigenesis,
tumor progression and metastasis, and the treatment of various
ischemic diseases [13]. Recent studies have found that VEGF has the
following functions: 1) Promote endothelial cell proliferation: VEGF
stimulates vascular endothelial cell division and proliferation, with
a chemotactic effect. VEGF activates phospholipase C, hydrolyzes
phosphatidylinositol, and induces calcium release to promote
endothelial cell proliferation and inhibit endothelial cell apoptosis.
2) Promote angiogenesis: VEGF promotes mitosis in vascular
endothelial cells and regulates the factors involved in angiogenesis.
VEGF has the functions of stimulating cell migration, blood vessel
formation, and intimal repair and thus maintaining vascular
integrity. In addition, VEGF induces the activation of fibrinogen
and the expression of metalloproteinase and interstitial collagenase
in endothelial cells. These proteases stimulate matrix degradation,
which is an important step in angiogenesis. VEGF also promotes
the growth of endothelial cells derived from arteries, veins, and
lymphatic vessels. 3) Vascular protection: (1) Vascular maintenance
function: VEGF dose-dependently stimulates the production of
Nitric Oxide (NO) in animal or human endothelial cells to exert its
vascular maintenance function. (2) Inhibition of Smooth Muscle
Cell (SMC) overgrowth: VEGF promotes SMC proliferation and
inhibits endothelial cell apoptosis and thus has protective effects on
endothelial cells. (3) Protection of endothelial cells: VEGF induces
the expression of survivin and X-linked Inhibitor of Apoptosis
Protein (XIAP) through inducing the expression of anti-apoptotic
protein Bcl-2 and its family member A1 and suppresses the upstream
pathway of the caspase family and inhibits endothelial cell apoptosis.
(4) Alteration of extracellular matrix: In endothelial cells, VEGF
induces the expression of plasminogen activator and plasminogen
activator inhibitor, as well as the expression of other proteases,
matrix collagenase and the tissue factor. VEGF also stimulates the
release of factor VIII from endothelial cells. These effects change
the extracellular matrix, which is conducive to the bud growth of
blood vessels to the surrounding areas [13]. (5) Anti-inflammatory
effect: Inflammation is a defensive response characterized by exuding
circulating leukocytes and plasma proteins to the site of tissue damage.
Adhesion of leukocytes to the surface of the vascular endothelium
is the starting step of the chemotactic migration of leukocytes, their
crossing of the vascular wall and forming inflammatory foci. VEGF
weakens the interaction between leukocytes and the endothelium,
performing anti-inflammatory activities. (6) Inhibition of thrombosis:
VEGF inhibits platelet aggregation and adhesion and thus has an
antithrombotic effect. The specific mechanisms of VEGF are shown
in (Figure 1).
Based on the therapeutic effect of VEGF, we believe that the use
of VEGF in AP patients to promote neovascularization and vascular
endothelial protection and intervene in AP from the onset may have
unexpected therapeutic effects. Therefore, in subsequent studies, we
will use VEGF as a therapeutic drug to observe the therapeutic effect of
VEGF on SAP in rats and further explore the associated mechanisms.
Based on the experimental results, we will strive to conduct clinical
studies, in the hopes of finding new effective treatment options for AP
and improving patient prognosis.
Fortunately, the therapeutic effect of VEGF on SAP has already
received some attention and has been preliminarily confirmed in
experiments. As early as 2006, Ueda et al. demonstrated that VEGF
alleviated the degree of organ damage during SAP by inhibiting
apoptosis in liver and kidney tissues via the examination of serum
VEGF levels in SAP patients and VEGF intervention in animal
experiments [14]. Nakajima et al. also demonstrated in animal
experiments in 2007 that VEGF mitigated intestinal mucosal
functional impairment and the resulting shift in bacterial colonization
in SAP rats through improving microcirculation and inhibiting
intestinal mucosal cell apoptosis [15]. Unfortunately, these studies
were limited to studying the conditions, without further exploration
on the related mechanisms. With progress in relevant research, VEGF
will have a new breakthrough in the treatment of pancreatitis in the
near future.
Acknowledgment
The authors express their gratitude to the Nature Natural Science Foundation of China for financial support (Grant NO 81550110256).
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