Antiproteases and the Pancreas

Motoji Kitagawa
1
, Tetsuo Hayakawa
2
1
Department of Nutritional Sciences, Nagoya University of Arts and Sciences. Nisshin, Japan.
2
Meijo Hospital. Nagoya, Japan
What Is the Target of a Protease Inhibitor?
There is no proven specific drug therapy for
the treatment of acute pancreatitis, including
protease inhibitors. In this virtual Round
Table, our invited authors reviewed the past,
present, and projected future clinical
relevance of protease inhibitors. Through
their discussion, protease inhibitors are
demonstrated to have broad inhibitory actions
on serine proteases, the coagulation system,
the complement system and the production of
pro-inflammatory cytokines, both in vitro and
in vivo. We are assured that proteases remain
an important and active field of study.
Several protease inhibitors, including
gabexate mesilate, nafamostat mesilate and
ulinastatin, have been used for the treatment
of acute pancreatitis in Japan [1, 2]. Camostat
mesilate, an orally active protease inhibitor,
has also been used for the treatment of
chronic pancreatitis [2]. Their major action in
suppressing pancreatitis is that of inactivating
trypsin and preventing autodigestion. In
recent years, several actions of a protease
inhibitor have been demonstrated in vitro and
in vivo studies. For example, gabexate has
been revealed to inhibit nuclear factor-kappaB
(NF-kappa B) activation in human monocytes
or human umbilical vein endothelial cells
(HUVECs) [3, 4]. NF-kappa B plays a crucial
role in inflammation, immunity, cell
proliferation, and apoptosis [5, 6]. Therefore,
gabexate has been hypothesized to have
various functions in the pathogenesis of acute
pancreatitis, chronic pancreatitis and
pancreatic cancer, if gabexate therapies target
NF-kappa B.
Protease Inhibitors and Acute Pancreatitis
Protease inhibitors can block premature
trypsin activation, but they were not as
effective clinically as expected for the
treatment of acute pancreatitis [7, 8, 9]. An
inappropriate conversion of pancreatic
zymogens to active enzymes within the
pancreatic parenchyma was hypothesized to
initiate the inflammatory process [5]. Cellular
events leading to pancreatitis involve an
inflammatory cascade with premature
activation of trypsin in acinar cells. Trypsin
activates a subset of enzymes, leading to the
release of cytokines from acinar cells and the
recruitment of inflammatory cells. Although
the exact mechanisms which trigger the
inflammation and necrotizing process are not
completely understood, activated leukocytes
play an important role in the pathogenesis of
acute pancreatitis. The initial phase of severe
acute pancreatitis depends on neutrophil
activation, accompanied by a systemic
inflammatory response syndrome (SIRS).
Pro-inflammatory cytokines including
interleukin (IL)-1beta, IL-6, IL-8, tumor
necrosis factor-alpha (TNF-alpha), platelet-
activating factor (PAF), and the anti-
inflammatory cytokines IL-2 and IL-10, were
implicated in the pathogenesis of SIRS in
acute pancreatitis [10, 11]. This understanding

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has led to the development of alternative
treatment strategies aimed at interrupting the
inflammatory response and reducing the
degree of SIRS and multiple organ
dysfunction.
Dr. Chen [12] demonstrated that protease
inhibitors could modulate inflammatory
cytokine responses in experimental
pancreatitis. Therapies which target cytokines
have been studied; anti-inflammatory agents
such as lexipafant are not sufficient to
ameliorate SIRS in severe acute pancreatitis.
Further research into novel anti-inflammatory
mediator therapies are warranted [13].
Another candidate for target therapy by
protease inhibitors could be protease-
activated receptor-2 (PAR-2). PAR-2 is a
widely expressed ligand receptor which can
be activated by trypsin and other trypsin-like
serine proteases [14, 15]. PAR-2 is widely
expressed in the gastrointestinal tract and is
also abundantly expressed in the pancreas.
PAR-2 is expressed in pancreatic acinar cells
and the luminal side of the pancreatic duct
cell. Both PAR-1 and PAR-2 were reported to
be expressed in pancreatic satellite cells,
vascular endothelial cells and vascular smooth
muscle cells in the pancreas. In the exocrine
pancreas, PAR-2 activation has been found to
accelerate acinar cell secretion of digestive
enzymes and to alter duct cell ion channel
function. PAR-2 may have a dual role in acute
pancreatitis: protecting acinar and duct cells
against pancreatitis-induced cell damage
and/or
aggravating
the
systemic
complications of acute pancreatitis, which are
the major cause of mortality in the early phase
of necrotizing pancreatitis [16]. Further
studies are required to reveal whether
protease inhibitor therapy targeting PAR-2
have a beneficial or a harmful effect on the
exacerbation of acute pancreatitis.
Protease inhibitors administered intravenously
are unlikely to reach the pancreas because of
their pharmacokinetics and impaired micro-
circulation in an inflamed pancreas. Protease
inhibitors were not as effective as expected
because of the timing of the administration,
the concentration of the protease inhibitor in
pancreatic tissue and the diminution of the
vasculature of the pancreas [2]. To increase
the concentration of the protease inhibitor,
arterial infusion of the protease inhibitor in
acute necrotizing pancreatitis was conducted
[17]. Continuous regional arterial infusion
(CRAI) of protease inhibitors and antibiotics
has been used in Japan [1]. Dr. Takeda [18]
reported excellent results in clinical studies on
the efficacy of CRAI therapy in severe acute
pancreatitis. However, randomized controlled
trials in multiple centers are necessary to
justify CRAI therapy of protease inhibitors in
the early stage of acute pancreatitis and to
recommend it as a standard of care. The
pancreas is susceptible to ischemic insult,
which can exacerbate acute pancreatitis.
There is also increasing evidence of
pancreatic and systemic microvascular
disturbances in the pathogenesis of
pancreatitis, including vasoconstriction,
shunting, inadequate perfusion, and increased
blood viscosity and coagulation [19, 20, 21,
22]. These processes may be caused or
exacerbated by ischemia-reperfusion injury
and the development of oxygen-derived free
radicals. Acute pancreatitis impairs the
pancreatic and systemic microcirculation,
which is a key pathological process in the
development of severe necrotizing disease.
Therapies targeted at mediators of micro-
vascular changes in acute pancreatitis, such as
endothelin 1, platelet-activating factor (PAF),
and intercellular adhesion molecule (ICAM) 1
are currently being investigated [20].
Gabexate was reported to improved micro-
circulatory environment after induction of
experimental acute pancreatitis [23].
Moreover, gabexate was seen to regulate
NF-kappa B and inflammatory cytokines,
which could have an effect on micro-
circulation, vascular permeability and
coagulation in acute pancreatitis.
Because
multiple
cascades
which
independently alter the course of acute
pancreatitis (protease activation, inflam-
matory cytokines, oxidant stress, and
apoptosis), it is unrealistic to expect that
blocking a single cascade will dramatically
abort human acute pancreatitis. However,
inhibition of protease activation may certainly

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constitute an important arm of a multi-drug
approach to acute pancreatitis.
Protease Inhibitor and ERCP-Induced
Pancreatitis
The potential benefits of protease inhibitors in
preventing post-endoscopic retrograde
cholangiopancreatography (ERCP) acute
pancreatitis have been frequently discussed
[24, 25, 26]. Several studies have
demonstrated that the prophylactic
administration of protease inhibitors is of
significant value [26]. Dr. Tsujino et al. [27]
focused on cost-effectiveness and the
prolonged administration of gabexate
compared with ulinastatin after ERCP.
Prolonged infusions for pharmacologic
prophylaxis against severe pancreatitis after
ERCP may need an additional hospital stay. A
short-term infusion of ulinastatin is
recommended in preventing post-ERCP
pancreatitis in high-risk patients. It is unclear
whether all patients undergoing ERCP would
benefit from the use of protease inhibitors or
only those who are at greater risk for
pancreatitis. Magnetic resonance cholangio-
pancreatography (MRCP) is now available for
the diagnosis of pancreatic diseases;
unnecessary ERCPs should be avoided in
routine practice [28].
Protease Inhibitors and Chronic
Pancreatitis
Mutations in the protease serine type 1
(PRSS1) gene encoding cationic trypsinogen
play a causative role in chronic pancreatitis
[29, 30]. It has been shown that the PRSS1
mutations increase autolytic conversion of
trypsinogen to active trypsin, and thus
probably cause premature, intrapancreatic
trypsinogen activation disturbing the
intrapancreatic balance of proteases and their
inhibitors. Other genes, such as anionic
trypsinogen (PRSS2), the serine protease
inhibitor, Kazal type 1 (SPINK1) and the
cystic fibrosis transmembrane conductance
regulator (CFTR) have been found to be
associated with chronic pancreatitis
(idiopathic and hereditary) as well.
Furthermore, a trypsin receptor of the
protease-activated receptor (PAR) family,
PAR-2, has been seen to influence the onset
and aggravation of pancreatitis [29].
Theoretically, protease inhibitors can inhibit
repetitive activation of intrapancreatic trypsin
if they can arrive at their target.
Camostat mesilate is an orally active protease
inhibitor and its primary effect is the
inhibition of trypsin. Dr. Motoo [31] reviewed
the potential effects of camostat on the
pathogenesis and exacerbation of chronic
pancreatitis, and evaluated several effects on
the pancreas, such as the suppression of
inflammatory mediators, its influence on
apoptosis and on regulating fibrosis. Jia et al.
[32] reported the suppressive effects of
camostat on the expression of IL-1beta, IL-6,
TNF-alpha, TGF-beta, and alpha-SMA in
spontaneous diabetic Otsuka Long-Evans
Tokushima fatty (OLETF) rats. They
suggested that camostat effectively inhibits
inflammation and fibrosis of the pancreas by
suppressing cytokines.
Pancreatic stellate cells (PaSCs) are
myofibroblast-like cells found in the areas of
the pancreas which have an exocrine function
[33]. The activation of PaSCs induces them to
proliferate, to migrate to sites of tissue
damage, to contact and possibly phagocytose,
and to synthesize extracellular matrix (ECM)
components to promote tissue repair. The
sustained activation of PaSCs leads to an
imbalance between extracellular matrix
protein synthesis and degradation, eventually
resulting in pancreatic fibrosis associated with
chronic pancreatitis and with pancreatic
cancer. Gibo et al. [34] demonstrated that
camostat prevented the progression of
pancreatic fibrosis in rats. These observations
that
camostat
inhibited
monocyte
chemoattractant protein-1 (MCP-1) and
TNF-alpha production by cultured monocytes,
the proliferation of PaSCs and MCP-1
production by PaSCs in vitro proved the
existence of the direct effect of camostat on
immunocompetent cells and PaSCs. PaSCs
could be another target of protease inhibitors.

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Protease Inhibitors and Pancreatic Cancer
Recently, many tumor-specific alterations
have been discovered and evaluated. These
alterations create a tumor-specific
environment with many potential targets for
therapy (targeted therapy). Proteases play an
important role in cancer invasion and
metastasis [35]. Serine proteases and matrix
metalloproteinases (MMPs) are the focus of
intense research, as they appear to be related
to the process of tumor progression [36].
Three classes of proteases have been
associated with focal degradation of the
basement membrane. These three groups
include the serine proteases (such as the
plasmin/plasminogen system), the cathepsin
proteases, and the matrix metalloproteinases.
These various proteases work both
independently and in concert to advance
tumor progression and metastases.
In this Round Table, Dr. Uchima et al. [37]
discussed the effect of protease inhibitors on
serine proteases and MMP, such as
urokinase-type plasminogen activator (u-PA)
and tumor associated trypsinogen (TAT),
MMP-2, MMP-9 and membrane type-MMPs
(MT-MMPs). Physiological serine protease
inhibitors,
such
as
urokinase-type
plasminogen activator (uPA), and its inhibitor,
plasminogen activator inhibitor-type 1
(PAI-1), play a key role in tumor invasion and
metastasis in many cancers. On the other hand,
gabexate is a well-known non-physiologic,
synthetic serine protease inhibitor. Several
studies from Dr. Uchima’s group [38, 39, 40]
reported the inhibitory effects of gabexate on
pancreatic cancer cell invasion by directly
antagonizing the activities of uPA and TAT.
On the other hand, Dr. Takahashi et al. [41]
discussed the effects of protease inhibitors on
NF-kappa B in pancreatic cancer. They
demonstrated the relationship between the
glial cell-line derived neurotrophic factor
(GDNF) and perineural invasion by human
pancreatic cancer cells, and confirmed that
NF-kappa B is a part of the signaling pathway
from the GDNF in human pancreatic cancer
cells. GDNF increased NF-kappa B activity in
human pancreatic cell lines and the invasive
potential is regulated by NF-kappa B
activation. They documented the inhibitory
effect of gabexate for pancreatic cancer
invasion. They also demonstrated that
gabexate suppressed TNF-alpha-induced
NF-kappa B activation and enhanced
apoptosis in human pancreatic cancer cell
lines [3]. Gabexate has been reported to
inhibit NF-kappa B activation in human
monocytes and umbilical vein endothelial
cells. NF-kappa B has various functions in
cancer cells, including the prevention of
apoptosis and promotion of chemoresistance,
cell invasion, and metastases.
Recently, another synthetic trypsin inhibitor,
nafamostat mesilate (FUT-175), has been
reported to disrupt interconnected signaling
pathways both by suppressing the NF-kappa
B antiapoptotic activity and inducing tumor
necrosis factor receptor (TNFR)-mediated
apoptosis [42]. They found that nafamostat
inhibited NF-kappa B activation by
suppressing I-kappa B kinase complex
(IKK)-mediated
I-kappa
B-alpha
phosphorylation and simultaneously induced
TNFR1-mediated caspase-8 activation. Both
of these effects resulted in apoptosis.
Nafamostat is both a potent inhibitor of
NF-kappa B activity by blocking
IKK-mediated phosphorylation of I-kappa
B-alpha, and a strong inducer of apoptosis by
up-regulating the expression of TNFR1,
thereby
enhancing
TNFR1-mediated
apoptosis. These results suggest a possible
mechanism by which nafamostat suppresses
NF-kappa B antiapoptotic activity and
induces TNFR-mediated apoptosis. Both
gabexate and nafamostat can function as
NF-kappa B inhibitors and apoptosis
inducers; however, their mechanisms of
actions are not fully understood. The effects
of protease inhibitors may involve
TNFR1-mediated signaling cascades which
activate NF-kappa B and the suppression of
inflammatory responses, largely attributed to
its inhibitory effect on proteases. Moreover,
synthetic protease inhibitors could be a
potentially therapeutic agent for pancreatic
cancer.
Knowledge regarding the role of proteases in

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tumor progression, invasion and metastasis
should be used in the development of specific
inhibitors to block their molecular
mechanisms of action. Continuous inhibition
of the molecular mechanism of pancreatic
cancer by gabexate or nafamostat should be
effective, but both protease inhibitors should
be administered intravenously and have a
very short half-time in the blood. An orally
active protease inhibitor (camostat) seems be
easy to use and has inhibitory effects on
serine proteases, MMP, and NF-kappa B,
modulating pancreatic cancer cell invasion or
metastasis in vitro and in vivo studies.
Conclusion
Proteases have various effects on the onset
and multiple cascades which independently
alter the course of pancreatitis and pancreatic
cancer. It does not seem to be enough to
prevent a single cascade for the treatment of
pancreatic diseases. Further research is
needed for a multi-drug approach including
protease inhibitors. In the treatment of acute
pancreatitis, the timing, dosage and route of
administration of a protease inhibitor are also
important. Some justification exists for the
use of protease inhibitors in the early stages
of acute pancreatitis, but the data are
insufficient to recommend it as a standard of
care. Protease inhibitors could be involved in
several therapeutic methods of targeting at
NF-kappa B. NF-kappa B comprises a family
of transcription factors which activate the
expression of a wide array of genes involved
in tumor-genesis, metastasis, differentiation,
embryonic development, apoptosis and
inflammation in pancreatitis and pancreatic
cancer.
In conclusion, we believe that protease
inhibitors may constitute an important and
active field of study through the discussion in
this virtual Round Table; therefore, we should
continue to study protease inhibitors for
clinical use in pancreatitis and pancreatic
cancer.
Keywords
NF-kappa B; Pancreatic
Neoplasms; Pancreatitis; Protease Inhibitors;
Receptor, PAR-2
Abbreviations CRAI: continuous regional
arterial infusion; GDNF: glial cell-line
derived neurotrophic factor; MCP: monocyte
chemoattractant protein; MMP: matrix
metalloproteinase; MT: membrane type;
OLETF: Otsuka Long-Evans Tokushima
fatty; PAF: platelet-activating factor; PAI
plasminogen activator inhibitor; PAR:
protease-activated receptor; PaSC: pancreatic
stellate cells; TAT: tumor associated
trypsinogen; TNFR: tumor necrosis factor
receptor; u-PA: urokinase-type plasminogen
activator
Conflict of interest The authors have no
potential conflicts of interest
Correspondence
Motoji Kitagawa
Department of Nutritional Sciences
Nagoya University of Arts and Sciences
57 Takenoyama, Iwasaki-Cho
Nisshin-City (Aichi-Pref)
470-0194, Japan
 
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