(The FASEB Journal. 2001;15:893-897.)
© 2001 FASEB
Are genetically modified mice useful for the understanding of acute pancreatitis?
CATHERINE M. PASTOR1 and
JEAN-LOUIS FROSSARD
Division d’Hépatologie et de Gastroentérologie, Geneva, Switzerland
1Correspondence: Division d’hépatologie et de gastro-entérologie, Hôpital Cantonal Universitaire de Genève, Rue Micheli-du-Crest, 24, 1211 Geneva 14, Switzerland. E-mail: Catherine.Pastor{at}medecine.unige.ch
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ABSTRACT
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Treatment of patients with acute pancreatitis has greatly improved due
to a better understanding of the pathophysiology of the disease. This
pathophysiology includes the activation and release of pancreatic
enzymes in the interstitium, the autodigestion of the pancreas, and a
multiple organ dysfunction after their release into the systemic
circulation. Moreover, significant evidence exists that synthesis and
release of proinflammatory cytokines and chemokines are also
responsible for the local injury and systemic dispersion of the
inflammation. The use of knockout mice devoid of active pro- or
anti-inflammatory mediators allows examination of the effects of a
specific cytokine without any drawbacks induced by pharmacological
manipulations. The results obtained from these genetically modified
mice show that numerous mediators have a major role in the
pathophysiology of acute pancreatitis. They also clearly demonstrate
that a single genetic deletion cannot completely prevent the occurrence
of pancreatic or distant organ injury. However, the fact that the
immune system is characterized by redundancies of ligands and receptors
complicates the full understanding of each report. The utility of such
experimental models might have limitations, and a full extrapolation of
experimental data from genetically modified mice to humans must be done
with caution.—Pastor, C. M., Frossard, J.-L. Are genetically
modified mice useful for the understanding of acute pancreatitis?
Key Words: IL-1 • metallothionein • tumor necrosis factor • NK1R • acute pancreatitis • knockout mice
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INTRODUCTION
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ACUTE PANCREATITIS IS an inflammatory process that
occurs in a normal organ and is diagnosed mainly by acute abdominal
pain associated with a concomitant rise of serum amylase and lipase
concentrations. Gallstone migration into the common bile duct and
alcohol abuse account for most of the etiologies of the disease.
Usually the injury is mild, but 20% of the patients have a severe
injury; among those, 15 to 25% will die.
Treatment of these patients has greatly improved owing to a better
understanding of the pathophysiology of the disease. This
pathophysiology includes activation and release of pancreatic enzymes
in the interstitium, autodigestion of the pancreas, and a multiple
organ dysfunction after their release into the systemic circulation. In
1988, Rinderknecht (1)
first hypothesized that cytokines
may play an important role and suggested that inappropriate activation
of the immune system might increase the severity of the local disease
and the systemic complications. Over the past few years, significant
evidence has accumulated that synthesis and release of proinflammatory
cytokines and chemokines are responsible for the local injury and the
systemic dispersion of the inflammation. Thus, inflammatory mediators
produced within the gland increase the pancreatic injury, and spread
out in distant organs, transforming a local inflammation into a severe
systemic disease. The effects of these mediators and/or their receptors
in the pancreas and remote organs have been evaluated using genetically
modified mice. Although these studies are important to consider for
increasing our knowledge, several drawbacks of these experimental
models have to be pointed out. In this study, we will review the
results of recent research dealing with genetically modified animals
and see how much they have changed our understanding of the disease
(Fig. 1
).
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Figure 1. Genetically modified mice and the pathophysiology of acute
pancreatitis. After a pancreatic insult, trypsinogen becomes activated
to trypsin in the presence of cathepsin B. Then, trypsin leads to the
activation cascade of other zymogens within the pancreas. The genetic
deletion of cathepsin B reduces the intrapancreatic concentrations of
trypsin. Substance P, which is a mediator produced by nerve ending and
is responsible for capillary leakage, is up-regulated during acute
pancreatitis, as well as the neurokinin 1 receptor (NK1R) on
endothelial and acinar cells. Deletion of the NK1R gene does not modify
the pancreatic cell responses but reduces the lung injury associated
with the disease. During acute pancreatitis, acinar cells and
macrophages produce tumor necrosis factor  (TNF-), which in turn
up-regulates the expression of intercellular adhesion molecules-1
(ICAM-1), an adhesion molecule responsible for the firm attachment of
neutrophils on endothelial cells. Deletion of TNF- protects mice
with pancreatitis. After tissue transmigration, neutrophils release
their deleterious enzymes and superoxide radicals, which are partly
scavenged by the superoxide dismutase and the metallothionein 1 (MT-1).
Mice overexpressing MT-1 have less severe pancreatitis. TNF-,
interleukin-1 (IL-1), and IL-6 are released by activated macrophages
primed by chemokines such as the chemoattractant cytokine receptor-1
(CCR-1). Deletion of CCR-1 has no effect on the severity of the
pancreatic disease but significantly reduces lung injury. TNF-,
IL-1, and IL-6 enhance the synthesis of the acute-phase proteins and
activate neutrophils and lymphocytes. Finally, mice overexpressing
IL-10 have a less severe pancreatic injury. Genetically modified genes
are in gray boxes; arrows are dotted when the mediator is beneficial
for the outcome of the pancreatic disease; arrows are plain when the
mediator is deleterious.
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INTERLEUKIN 1 (IL-1) AND TUMOR NECROSIS FACTOR
(TNF-)
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During pancreatitis, IL-1 and TNF- are produced in large
quantities. Evidence for their role in acute pancreatitis has been
shown by studies using pharmacological antagonism. IL-1 is a
proinflammatory cytokine whose deleterious effects might be attenuated
by a specific IL-1 receptor antagonist (2)
. The effects of
IL-1 are also suppressed by using IL-1 receptor-deficient mice
(3
, 4)
. Although the genetic deletion of IL-1 receptor
decreases the severity of acute pancreatitis, IL-1 mRNA increases in
organs known to produce the cytokines (4)
. Moreover, in
IL-1 and TNF- receptor knockout mice, the i.v. administration of
sterile, cytokine-free ascitic fluid collected from rats with
pancreatitis fails to induced lung injury as observed in normal
animals, suggesting that acute lung injury during acute pancreatitis
might be attributed to the pulmonary activity of IL-1 and TNF-
(5)
. When strains of knockout mice for IL-1 receptor or
TNF- receptor are used, the severity and the mortality of acute
pancreatitis are significantly attenuated in mice with a single genetic
deletion. Identical benefits are observed with the double knockout mice
(6)
. Animals devoid of receptors for both cytokines fail
to show further decrease in parameters of severity and have only a
modest decrease in the mortality rate. These observations strongly
demonstrate the numerous redundancies that characterize the cytokine
system.
Similarly, mice devoid of IL-1-converting enzyme, which is responsible
for the cellular export of mature IL-1, cannot secrete IL-1 and fail to
develop the acute pancreatic syndrome; pulmonary injury, pancreatic
necrosis, and mortality are decreased (7)
.
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Interleukin-6 (IL-6)
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Genes encoding for proinflammatory cytokines are regulated during
cerulein-induced pancreatitis via activation of the nuclear factor 
B
(NF-B) (8)
. As a result, the expression of proteins
such as IL-1, IL-6, and TNF- is enhanced. IL-6 is a multipotent
cytokine that influences numerous cells and several steps of the host
defense response, including hepatic acute-phase proteins. IL-6 has a
pivotal role in propagating the systemic inflammatory response and
subsequent multiple-organ dysfunction in patients with severe acute
pancreatitis. In experimental pancreatitis induced by cerulein, Suzuki
et al. (9)
demonstrate that pancreatic interstitial edema
is higher in IL-6 transgenic than in wild-type mice, while the
administration of anti-IL-6 receptor antibodies significantly decreased
the edema in normal mice. Thus, modulation of IL-6 expression in the
pancreas might be an interesting target.
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Interleukin-10 (IL-10)
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The mechanisms by which pancreatic inflammation acts on distant
organ function begins to be understood. Evidence exists that the
production of proinflammatory mediators (TNF-, IL-1, IL-6, and IL-8)
balances that of anti-inflammatory mediators (IL-10, IL-11, and IL-1
receptor antagonist). IL-10 is an anti-inflammatory cytokine that
inhibits the release of proinflammatory cytokines by macrophages from
all tissues. In the model of acute pancreatitis induced by a
choline-deficient ethionine-supplemented diet, the severity of lung
injury is greater in the IL-10 knockout than in the wild-type mice,
whereas the severity of pancreatitis is similar in both groups
(10)
. The transfection of a human IL-10 gene in normal
mice results in an effectively transcribed DNA into intact mRNA
(11)
. The transfer of this gene decreases the severity of
pancreatitis, demonstrating the benefit of gene therapy during this
acute inflammatory process (11)
. Endogenous IL-10 is
important in reducing the extent of inflammation in the pancreas as
well as in distant organs.
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CHEMOATTRACTANT CYTOKINE RECEPTOR-1 (CCR-1)
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The activation and trafficking of inflammatory cells involve a
multigene family of chemoattractant cytokines known as chemokines.
These chemokines are characterized by numerous redundancies of ligands
and receptors. Among them, the role of the CCR-1 was evaluated in the
murine model of acute pancreatitis induced by cerulein associated with
lung injury by developing mice lacking the CCR-1 (12)
.
Although pancreatitis has a similar severity in wild-type and knockout
mice, lung injury is significantly reduced in the mice lacking CCR-1 as
evidenced by the reduction of the alveolar membrane thickening, the
decreased leakage of albumin in broncho-alveolar lavage fluids, and the
decreased sequestration of inflammatory cells into the lungs
(12)
. Thus, genetic deletion of the CCR-1 reduces the
severity of cerulein-induced lung injury associated with pancreatitis
without influencing the severity of pancreatic injury. Thus, pancreatic
injury produces and releases chemokines in the bloodstream that can
activate circulating monocytes and neutrophils. Because pancreatic
injury was not modified in mice lacking CCR-1 while lung injury was
improved, CCR-1 plays a pivotal role in disseminating the injury from
the pancreas to the lungs.
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NEUROKININ 1 RECEPTOR (NK1R)
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The neuropeptide substance P released from nerve endings binds to
NK1R and plays an important role in asthma, inflammatory bowel disease,
arthritis, and other inflammatory processes. Because pancreatic acinar
cells isolated from guinea pigs and mice express NK1R and because
intrapancreatic content of substance P increases during
cerulein-induced pancreatitis, recent studies examined the role of this
neuropeptide in developing the disease and its complications (13
, 14)
. The deletion of the NK1R gene does not alter the pancreatic
cell responses to cerulein. However, in NK1R-deficient mice, both
pancreatitis and pancreatitis-associated lung injury are reduced in
comparison to the injuries observed in wild-type mice
(13)
. The increased lung permeability observed with
cerulein is prevented by the deletion of the NK1R gene. These results
indicate that neurogenic factors such as substance P play an important
role in determining the severity of pancreatitis. However, the
mechanisms by which substance P amplifies the severity of the
pancreatitis is unclear. Substance P acts on endothelial cells via the
NK1R, increasing the vascular permeability and promoting pancreatic
edema (14)
. Substance P might act directly on the NK1R
located on acinar cells; finally, substance P might directly injure
pulmonary tissues.
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INTERCELLULAR ADHESION MOLECULE-1 (ICAM-1)
|
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Leukocyte sequestration within the area of injury and inflammation
is a multistep process that begins with leukocyte activation, followed
with the adhesion of circulating inflammatory cells to the endothelium
via adhesions molecules such as ICAM-1. Under basal conditions, ICAM-1
is not constitutively expressed or is expressed only at low
concentrations in most tissues, but ICAM-1 expression increases during
inflammation. ICAM-1 interacts with CD11a/CD18 and CD11b-CD18 located
on lymphocytes and leukocytes. The interaction between ICAM-1 and
CD11/CD18 is a major determinant of leukocyte adhesion to the
endothelial cells and transmigration of leukocytes into the areas of
inflammation through the endothelial barrier. In two experimental
models of acute pancreatitis in mice (administration of cerulein or
feeding a choline-deficient, ethionine-supplemented diet), ICAM-1
concentrations in serum, pancreas, and lung increase (15)
.
Kaufman et al. (16)
also show that circulating
concentrations of ICAM-1 are elevated in patients with severe
pancreatitis. To confirm the pathophysiological role of the molecule,
we used mice that do not express ICAM-1 and mice depleted of
neutrophils by the administration of anti-neutrophil antibodies
(15)
. The severity of acute pancreatitis and associated
lung injury is partially decreased in mice deficient in ICAM-1.
Neutrophil depletion also reduces the severity of pancreatic and lung
injury, whereas the combination of both treatments does not further
reduce the severity of the injuries. Treatment of severe pancreatitis
with monoclonal antibodies against ICAM-1 also decreases both local
pancreatic and lung injuries (17)
. These observations
indicate that ICAM-1 plays an important role in pancreatitis and
pancreatitis-associated lung injury.
|
Cu/Zn SUPEROXIDE DISMUTASE AND METALLOTHIONEIN TRANSGENIC
MICE
|
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Free radical and lipid peroxide concentrations are increased in
pancreatic tissues from both human and experimental acute pancreatitis
(18
19
20)
. The possible sources of free radicals such as
invading inflammatory cells, xanthine oxidase, cytochromes P450, and
nitric oxide synthase are not yet clear. However, because
O2 radical scavengers improve the severity of
experimental acute pancreatitis and because prophylactic administration
of antioxidants diminish edema in pancreas, free radicals play an
important role in the pathogenesis of the disease (21)
.
For that purpose, transgenic mice overexpressing Cu/Zn superoxide
dismutase (an enzyme that catalyzes the dismutation of superoxide
radicals to H2O2) were
studied during acute pancreatitis. Overexpression of Cu/Zn superoxide
dismutase is strongly associated with a reduction of serum amylase
concentrations, pancreatic edema, and acinar cell injury in comparison
to wild-type mice (22)
.
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METALLOTHIONEIN 1 (MT-1)
|
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MT-1 are small, cysteine-rich, heavy metal binding proteins that
protect from heavy metal toxicity, particularly for Zn homeostasis
(23)
. MT-1 is an efficient scavenger of hydroxyl radicals
(24)
, and cells isolated from MT-1 knockout mice are more
sensitive to oxidative stress in vitro (25)
.
During cerulein-induced pancreatitis, the pancreatic concentration of
MT-1 is increased and might constitute a protective mechanism against
oxidative stress. Mice overexpressing MT-1 have less severe
pancreatitis than the wild-type, as evidenced by the decreased amylase
concentration in serum, decreased acinar cell injury, and less
pancreatic edema (26)
. Pancreatitis is more severe in mice
deficient for MT-1 (26)
. Thus, genetic manipulations of
MT-1 alter the outcome of cerulein-induced pancreatitis, but the exact
mechanisms of MT-1 protection are not assessed in these studies.
|
CATHEPSIN B
|
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Most researchers believe that autodigestion of the pancreas
by its own digestive proteases or zymogens prematurely activated is the
first event at the onset of acute pancreatitis. According to this
hypothesis, activation of these digestive zymogens follows the
redistribution of the lysosomal enzyme cathepsin B into a subcellular
compartment containing zymogens. Activation of trypsinogen into active
trypsin and subsequent activation of other zymogens then occur. A
mutation of the cationic trypsinogen gene responsible for a human form
of hereditary pancreatitis has recently been discovered, reinforcing
the link between these early events and the disease (27)
.
To test this hypothesis, Halangk et al. (28)
developed
cathepsin B-deficient mice. After induction of pancreatitis, the
pancreatic trypsin activity in these mice is more than 80% lower than
in wild-type mice and pancreatic injury is 50% lower. However, the
prevention of trypsinogen activation by genetic deletion of cathepsin B
was incomplete. Therefore, cathepsin B is not the only pathway involved
in premature intra-acinar activation of trypsinogen; trypsinogen
activation by other lysosomal enzymes has to be considered as an
alternative. In the cathepsin B-deficient mice, although the
reduction of trypsinogen activation correlates with a decrease of
acinar cell necrosis, the systemic inflammatory response as well as the
pancreatic leukocyte infiltration are not affected, indicating that
these events are not cathepsin B-dependent.
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PERSPECTIVES
|
|---|
These studies show that numerous cytokines have a major role in
the pathophysiology of acute pancreatitis. They also clearly
demonstrate that a single genetic deletion cannot completely prevent
the occurrence of pancreatic or distant organ injury. They show
numerous redundancies of ligands and receptors that characterize the
families of cytokines and chemokines.
During acute pancreatitis, the activation of leukocytes and
cytokine release are delayed after the primary pancreatic insult.
Consequently, the genetic deletion of genes involved in the early
events might have more beneficial consequences on pancreatic injury
than genetic deletion of genes encoding for cytokines or chemokines
that are produced later. However, although cathepsin B-deficient mice
were protected against cerulein-induced pancreatitis, the protection
was only partial, showing that other early pathways have to be
inhibited to provide a complete protection.
|
ADVANTAGES AND DISADVANTAGES OF USING THESE GENETICALLY
MODIFIED ANIMALS MODELS
|
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The ability to remove or alter with precision a single gene of
thousands in an animal is now a routine technique for creating animal
models that can be used to study the pathophysiology of various
diseases (29
, 30)
. The goal of the gene targeting
(knockout) method is to replace the specific gene of interest with one
that is inactive, altered, or irrelevant. The deficits present in a
knockout mouse can reveal or clarify the function of the mutant gene.
These experimental systems are of great value in studying the
pathogenesis and treatment of disorders in all fields of medicine.
Consequently, a knockout mouse corresponding to a particular genetic
disorder may help clarify the mechanism of the disease. The phenotype
of the knockout animal can usually be anticipated by previous knowledge
of the gene function but in some cases inactivation of a specific gene
such as IL-2 gene results in ulcerative colitis, an unexpected mutant
phenotype (31)
.
However, in light of recent advances, several considerations are
important in evaluating the phenotype of a knockout mouse. The fact
that a specific mutation has been present in the mice from the time of
its conception may enable a distinction between phenotypic changes due
to the mutation itself and changes caused by adaptation and
compensation for the mutation. Moreover, if a gene is expressed in
different tissues where it may have different functions, its alteration
may induce unexpected consequences. For example, the immune system is
characterized by many redundancies of ligands and receptors that
complicate the understanding of the action of a single cytokine or
chemokine. Mice deficient in E and P selectins, which are adhesive
receptors expressed on platelets and endothelial cells, expressed
higher concentrations of serum granulocyte monocyte
colony-stimulating factor (GMCSF), IL-3, and peripheral leukocyte
counts. Thus, one should take into consideration the role of high serum
concentrations of GMCSF, IL-3, and leukocyte counts when evaluating the
effect of P and E selectins. Conversely, the function of two genes may
overlap, and mutation in a single gene might not reveal an abnormal
phenotype. It must also be remembered that rodents have no homologue of
human IL-8 and, in contrast to humans, have abundant CCR-1 on
granulocytes, making a full extrapolation of experimental data from
genetically modified mice to humans difficult.
|
CONCLUSIONS
|
|---|
The use of knockout mice devoid of active pro- or
anti-inflammatory mediators allows examination of the effects of a
specific cytokine without any drawbacks induced by pharmacological
manipulations. In acute pancreatitis, several studies clearly identify
the role of these specific targeted genes. However, the immune system
is characterized by redundancies of ligands and receptors, which
complicates the full understanding of each report. The utility of such
experimental models might have limitations, and a full extrapolation of
experimental data from genetically modified mice to humans has to be
made with caution.
|
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2341 - 2351.
[Full Text]
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J. L. Frossard, A. K. Saluja, N. Mach, H. S. Lee, L. Bhagat, A. Hadenque, L. Rubbia-Brandt, G. Dranoff, and M. L. Steer
In vivo evidence for the role of GM-CSF as a mediator in acute pancreatitis-associated lung injury
Am J Physiol Lung Cell Mol Physiol,
September 1, 2002;
283(3):
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TOP
ABSTRACT
INTRODUCTION
