Am J Physiol Gastrointest Liver Physiol 311: G343–G355, 2016.

First published July 14, 2016; doi:10.1152/ajpgi.00372.2015. Themes

Animal models of gastrointestinal and liver diseases. Animal models of acute

and chronic pancreatitis
Xianbao Zhan,1* Fan Wang,1* Yan Bi,2 and Baoan Ji1
1
Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida and 2Department of Gastroenterology and Hepatology,
Mayo Clinic, Jacksonville, Florida
Submitted 23 October 2015; accepted in final form 6 July 2016

Zhan X, Wang F, Bi Y, Ji B. Animal models of gastrointestinal and liver

diseases. Animal models of acute and chronic pancreatitis. Am J Physiol Gastro-
intest Liver Physiol 311: G343–G355, 2016. First published July 14, 2016;
doi:10.1152/ajpgi.00372.2015.—Animal models of pancreatitis are useful for elu-
cidating the pathogenesis of pancreatitis and developing and testing novel inter-
ventions. In this review, we aim to summarize the most commonly used animal
models, overview their pathophysiology, and discuss their strengths and limitations.
We will also briefly describe common animal study procedures and refer readers to
more detailed protocols in the literature. Although animal models include pigs,
dogs, opossums, and other animals, we will mainly focus on rodent models because
of their popularity. Autoimmune pancreatitis and genetically engineered animal
models will be reviewed elsewhere.
fibrosis; inflammation; pancreatic disorder

PANCREATITIS IS THE INFLAMMATORY disease of the pancreas that
causes significant morbidity and mortality throughout the
world (148). There are two main types of the disease: acute
pancreatitis and chronic pancreatitis.
Animal Models of Acute Pancreatitis
With ⬃275,000 hospitalizations in 2009 (an increase of
more than twofold since 1988) (177), acute pancreatitis (AP) is
the most common single gastrointestinal diagnosis, resulting in
an estimated 2.6 billion dollars per year in inpatient costs
(129). AP also ranks as the fifth leading cause of in-hospital
deaths (85). Unfortunately, there are no effective preventive or
therapeutic strategies for this disease due to the lack of a deep
understanding of its pathogenesis (80).
In the United States, alcohol abuse and gallstone disease
account for 70 – 80% of the cases of AP. Drugs, postendo-
scopic retrograde cholangiopancreatography (ERCP) proce-
dures, infections, and lipid metabolic disorders can also cause
AP (127). Eighty-five to 90% of AP cases are self-limiting and
respond well to conservative treatment. However, the remain-
ing 10 –15% of cases with severe acute pancreatitis (SAP) are
accompanied by local or systemic complications and organ
failure and have a grave clinical course. Although the overall
mortality in patients with AP is ⬃5%, the mortality of SAP is
between 25 and 50% (13).
The pathophysiology of this disease is not well understood,
and most of our current knowledge about the pathophysiology
of this disease is from animal studies. This is partially due to
the relative inaccessibility of human pancreatic tissue for
* X. Zhan and F. Wang contributed equally to this work.
Address for reprint requests and other correspondence: B. Ji, Dept. of
Cancer Biology, Griffin Bldg. 311, Mayo Clinic, 4500 San Pablo Rd S.,
Jacksonville, FL 32224 (e-mail: ji.baoan@mayo.edu).
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examination during the early phases of pancreatitis. However,
a variety of animal models have been developed to facilitate
our understanding of the pathophysiology of AP. In this re-
view, we will discuss several commonly used experimental
models of AP with focus on mice and rats. Although these
animal models of pancreatitis are widely used, researchers
should keep in mind that no model fully recapitulates the
human form of the disease. Therefore, understanding the
pathophysiology and limitations of each model will guide
investigators in selecting the specific model for their special
purposes. Other considerations important during model selec-
tion include the cost, ease of use, reproducibility, disease
severity, and clinically relevance.
It should also be noted that species, sex, and age can also
affect the severity of pancreatitis. Therefore, age- and sex-
matched controls should be used to offset those potential
influences. As for species differences, the cholecystokinin
(CCK) analog JMV-180 acts as a partial agonist in rats but a
full agonist in mice (72). Unlike rodent pancreatic acinar cells,
human counterparts don’t respond to CCK stimulation (71).
Age-dependent effects on experimental AP in mice have also
been observed (113). Male rats fed with high-fat diet have
shown marked, lower pancreas Mn-superoxide dismutase ac-
tivity and higher oxidative damage than females (50). These
observations support the role of male hormones in the regula-
tion of oxidative stress and pancreatitis. The evidence for
female hormones in the development of pancreatitis is even
more extensive. The choline-deficient, ethionine-supplemented
(CDE) diet induces acute hemorrhagic pancreatic necrosis only
in young female mice but not in young male mice (137).
The interplay between inflammation and the microbiome
suggests that housing conditions can affect the severity and
natural history of pancreatitis (181). The composition of the
model’s diet can also affect inflammatory signaling (133).
G343
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G344 PANCREATITIS MODELS
Analgesics can also interfere with pancreatitis-associated in-
flammation; indomethacin prevents postendoscopic retrograde
cholangiopancreatography pancreatitis (36). In contrast, opi-
ates may be a cause of pancreatitis (159). Although it has been
shown that caerulein-induced AP is associated with pain in
experimental animals, most experiments are carried out with-
out any pain-relieving treatment. However, in a recent study,
orally administered metamizol showed no influence on the
caerulein-induced AP and could be given as an analgesic to
increase animal welfare in experimental models with induced
AP (150).
AP is an inflammatory disease of the pancreas. The damage
to the pancreas can be evaluated by measuring the serum
pancreatic enzymes, such as amylase and lipase, that are
released into the blood from the damaged acinar cells. There
are commercially kits available that can measure these en-
zymes. However, the levels of these enzymes do not necessar-
ily reflect the severity of pancreatitis. A histological examina-
tion by an experienced pathologist in a blinded manner is
highly recommended to assess interstitial edema, acinar cell
death (apoptosis, necrosis, and autophagy), parenchymal loss,
hemorrhage, fat necrosis, inflammatory cell infiltration, and fat
and fibrotic tissue replacement. However, no consensus is
available regarding the criteria for scoring, and the parameters
used by different investigators to evaluate the severity of AP
have yet to be standardized, but most of these parameters are
described in detail by Nevalainen et al. (118) and Zhang and
Rouse (182). Additionally, pancreatic edema can be evaluated
by whole pancreas/body weight (body wt) ratio, wet/dry pan-
creas ratio, or (wet⫺dry)/dry weight ratio.
Systematic complications involving the lung are also asso-
ciated with the severity of the disease. Therefore, the histology
of the lung is often included in pancreatitis research. For
studies focusing on the acute respiratory distress syndrome
(ARDS) in severe AP, detailed measurements of histological
changes in parenchymal tissue, altered integrity of the alveolar
capillary barrier, inflammation, and abnormal pulmonary
function should be included. The analytical approaches,
pathological features, and common measurements have been
described in a recent review (3). In severe models of AP,
liver/kidney malfunction can also be monitored and has
been described (6, 12).
Finally, cytokine expression levels in the pancreatic tissue
and serum can also be used to reflect the severity of local and
systematic inflammation. It is worth emphasizing that the
severity of inflammation and damage to the pancreas is not
evenly distributed. Using a large piece of tissue will decrease
sampling error.
Secretagogue-induced AP. In 1895, Mouret (111a) reported
that excessive cholinergic stimulation was associated with the
development of pancreatic acinar cell vacuolization and necro-
sis. Since then, pancreatitis has been reported as a complication
of anticholinesterase insecticide intoxication in humans and
experimental animals (34, 44). Cholinergic nerve mediation of
low-dose caerulein- and alcohol-induced experimental pancre-
atitis has also been documented (102), and, because it stimu-
lates the release of acetylcholine from pancreatic nerves, scor-
pion venom has been found to induce AP in humans and dogs
(14, 46, 104). Similarly, carbachol (a cholinergic mimetic)
administration to rats produces a form of edematous pancre-
atitis (21, 38). However, due to systematic toxicity, the pan-
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creatitis induced by cholinergic agonists has never been widely
used in experimental settings.
Caerulein (ceruletide, also spelled as cerulein) and its struc-
ture were identified in 1967 by Australian and Italian scientists
from dried skins of the Australian green tree frog (Litoria
caerulea) (8). Sequencing of the peptide showed a strong
resemblance in the amino acid sequence to the carboxy termi-
nus of CCK (CCK octapeptide: Asp-Tyr[SO3H]-Met-Gly-Trp-
Met-Asp-Phe-NH2; caerulein: pyroGlu-Gln-Asp-Tyr[SO3H]-
Thr-Gly-Trp-Met-Asp-Phe-NH2). The seven amino acids of
the COOH-terminal of caerulein are identical to those of the
CCK octapeptide, except for a Thr residue that is a substitute
for Met. Both peptides bear a carboxy terminal amide group,
but caerulein also has a blocked amino terminal with pyroglu-
tamine as the initial amino acid. This blocking group reduces
susceptibility to inactivation by amino peptidases (173). Addi-
tionally, sulfation of the tyrosine in caerulein is necessary for
optimal physiological activity (76). In rodents, CCK receptors
are present both on pancreatic acinar cells and within the neural
system. Physiological levels of CCK in plasma act via stimu-
lation of the vagal afferent pathways. In contrast, supraphysi-
ological plasma CCK levels act on intrapancreatic neurons and
act directly to a larger extent on rodent pancreatic acini (124).
Caerulein is a potent pancreatic secretion stimulant. The
dosages used for secretion studies are 1–5 ng/kg through
rapid intravenous injection, 0.25–1 ng·kg⫺1·min⫺1 through
intravenous infusion, and 50 –100 ng/kg through subcutane-
ous injection (16, 33). At higher doses (20 ng·kg⫺1·min⫺1),
caerulein causes zymogen activation, large vacuole accumula-
tion, endoplasmic reticulum (ER) dilation and segmentation,
and mitochondrial swelling (155). In 1977, Lampel and Kern
(84) discovered that excessive doses (5 ␮g·kg⫺1·h⫺1) of caeru-
lein-induced acute interstitial pancreatitis in rats.
Supramaximal doses of caerulein induce a significant in-
crease in serum pancreatic enzymes, pancreatic interstitial
edema, and inflammatory cell infiltration. It has been tested in
rats, mice, dogs, and hamsters, and all of the animals survived
the induction of pancreatitis (172). The changes caused by
caerulein infusion occur within 15 min after infusion. Cyto-
plasmic vacuoles are the earliest histological alterations. As the
pancreatitis progresses, these vacuoles increase to an enormous
size. Electron microscopy showed both intact and degenerative
granules inside the vacuoles. Interstitial inflammation and
acinar cell necrosis were prominent 6 h after injection and
reached a maximum after 12 h. These changes usually resolved
within a week. During the regression of pancreatitis, focal
atrophy was a remarkable histological finding (119).
The mechanisms of secretagogue-induced AP have been
extensively exploited over the past few decades. For in vitro
studies, primary pancreatic acini can be isolated from mouse
and rat pancreata by mechanical dissection followed by puri-
fied collagenase digestion (174). These pancreatic acini can
then be treated with CCK or other secretagogues. CCK regu-
lates a complex array of cellular functions in pancreatic acinar
cells through its G protein-coupled receptor, which activates a
variety of intracellular signaling mechanisms. CCK couples
through heterotrimeric G proteins to activate phospholipase C,
increasing inositol trisphosphate and releasing intracellular
Ca2⫹. This pathway and protein kinase C activation leads to
the secretion of digestive enzymes by exocytosis. CCK also
activates Nuclear Factor of Activated T cells (NFATs), ERKs,

PANCREATITIS MODELS
JNKs, and p38 MAPK, which are involved in secretion and
growth (58, 175). In addition to Gq, CCK receptors also
activate G12/13, Rho, and Rac to regulate the cytoskeleton and
secretion (17, 88).
CCK elicits a concentration-dependent effect on pancreatic
enzyme secretion. At low physiological concentrations, CCK
stimulates pancreatic acinar cell secretion. However, at patho-
physiological concentrations, the secretion of the pancreas is
inhibited due to the altered influx of intracellular calcium,
diminished pancreatic enzyme secretion into the duct, patho-
logical basal-lateral secretion/leakage of active enzymes, pre-
mature intracellular zymogen activation, actin cytoskeleton
reorganization, ER stress, activation of NF-␬B and apoptosis,
and autophagy. Increased vascular permeability and increased
hydrostatic pressure may contribute to the extensive edema
associated with pancreatitis. Cytokine storms and active pan-
creatic enzymes lead to a systemic inflammatory response
syndrome (SIRS), which includes extrapancreatic damage,
such as pancreatitis-related lung injury (18, 73, 98, 103, 112,
142, 157).
In addition to the direct effect of CCK on acinar cells, CCK
also acts via the vagal afferent pathways to mediate pancreatic
secretion. Atropine, a muscarinic receptor antagonist, com-
pletely abolishes pancreatic enzyme responses to physiological
doses of CCK in rats, which suggests that CCK acts on a
presynaptic site along the cholinergic pathway (95). In healthy
human subjects, CCK infusions produce plasma CCK levels
similar to those seen postprandially and stimulate pancreatic
secretion by an atropine-sensitive pathway. These observations
suggest that both in experimental animals and in humans
cholinergic neural pathways, rather than pancreatic acini, rep-
resent the primary targets in which CCK acts to stimulate
pancreatic enzyme secretion (2). Cholinergic stimulation of
pancreatic amylase secretion is mediated in mice by a mixture
of M1 and M3 muscarinic acetylcholine receptors. Like CCK
receptors, these receptors are selectively coupled to G proteins
of the Gq family, which mediate the breakdown of phosphati-
dyl inositol lipids (47). Similarly, muscarinic-receptor agonists
stimulate trypsinogen and NF-␬B activation, two key signaling
pathways in the pathogenesis of pancreatitis. Interestingly,
ethanol enhances carbachol-induced protease activation and
accelerates Ca2⫹ waves in isolated rat pancreatic acini. These
observations support the key roles of the cholinergic system in
the mechanisms of alcoholic pancreatitis (59, 102, 123, 185).
The cholinergic signaling may be of particular importance in
humans because there are no functional CCK receptors on
human pancreatic acinar cells (71).
There are great variations among the protocols used in
different laboratories. Although jugular or tail vein infusion
was originally used, it was soon replaced by intraperitoneal
injection due to its convenience (119). Typically, caerulein (50
␮g/kg body wt; dissolved in phosphate-buffered saline or 0.9%
saline in a volume of 100 ␮l) is injected intraperitoneally every
hour for 8 –12 injections. The pancreata are usually harvested
1 h after the last injection or 24 h after the first injection. For
regeneration studies, the pancreata can be collected after 2–7
days. For early signaling studies, the pancreata can be removed
at a desired time after a single dose of injected caerulein.
Caerulein induces parallel activation of both NF-␬B and
trypsinogen in the pancreas in vivo as early as 15 min after
injection (64). Of note, caerulein is usually provided in 1-mg
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G345
aliquot powder, and the solubility of caerulein from different
providers may vary. If the powder does not completely dis-
solve, then it will result in a low concentration of caerulein and
may fail to induce pancreatitis.
The secretagogue overstimulation model of experimental
pancreatitis is so far the most commonly used AP model. The
model has several advantages, including noninvasiveness, high
reproducibility, and applicability in multiple species. In addi-
tion, the in vivo experiment can be paralleled with in vitro
acinar cell studies, which makes this model extremely useful
for the investigation of intracellular signal transduction events,
protease activation cascades, and cell death pathways involved
in the early phase of AP. Moreover, this is a great model for the
investigation of recovery and regeneration of damaged tissue
after the toxic substances have been discontinued. However,
this model has several major disadvantages. Even with maxi-
mum dosage of caerulein, only mild, self-limited AP but not
severe necrotizing pancreatitis is recapitulated, which limits its
use in the study of severe pancreatitis, which carries the highest
morbidity and mortality. In addition, secretagogue overstimu-
lation is not a common cause of AP in humans, although AP
cases have been reported in patients who accidentally received
high concentrations of secretagogue (14), were exposed to
cholinesterase inhibitors such as insecticides (149), or were
exposed to Trinidadian scorpion toxin (14). Moreover, major
differences exist between the human and rodent pancreas: CCK
plays a major role in regulating exocrine pancreatic secretion in
rodents; however, human pancreatic acinar cells are mostly
regulated by cholinergic pathways that involve neurogenic
CCK stimulation (71, 124).
Basic amino acid-induced AP. In an effort to study the
effects of arginine on normal tissues, Mizunuma et al. (110)
unexpectedly found that single intraperitoneal injection of
L-arginine (500 mg/100 g body wt) in rats selectively destroyed
pancreatic acinar cells. The model was further studied by Tani
et al. (154) in 1990. From then on, several groups have used
this rat model. However, with this protocol the same dose of
L-arginine failed to induce reproducible pancreatitis in either
Balb/c or C57Bl/6 mice. In 2007, Saluja and colleagues (29)
developed a mouse model of acute necrotizing pancreatitis
using intraperitoneal applications of L-arginine hydrochloride
solution (8% in normal saline, pH 7.0).
The dosage of L-arginine on AP development is species
dependent. In mice, L-arginine has no effect on pancreatic
histology when administered at doses lower than 4 g/kg and
when administered twice (1 h apart). However, in rats, intra-
peritoneal administration of 2 g/kg L-lysine induced severe
acute necrotizing pancreatitis (20).
In rats given single intraperitoneal injections of L-arginine at
500 mg/100 g body wt, serum levels of amylase, lipase, and
anionic trypsin reached their peaks after 12–24 h but returned
to normal levels after 24 – 48 h. Histological examinations
revealed a number of small vesicles within acinar cells after 6
h, which were identified as markedly swollen mitochondria by
electron microscopy. Interstitial edema appeared after 12 h,
and acinar cell necrosis was seen after 24 h. The extent and
severity of necrotic changes of pancreatic exocrine tissue with
inflammatory cell infiltration was maximal after 72 h. After 7
days without treatment, pancreatic acinar cells began to regen-
erate, and pancreatic architecture appeared almost normal after
14 days without treatment (154). In this model, pancreatic
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G346 PANCREATITIS MODELS
necrosis was significantly increased in a concentration-depen-
dent manner and was accompanied by lung injury (29, 154,
169).
In the mouse model, the mice become sluggish after admin-
istration of the first dose of L-arginine (4 g/kg) in saline, and
their lethargy increases with the administration of the second
dose. The administration of L-arginine results in significantly
increased plasma amylase levels after 48 h and normalizes at
96 h. Histologically, acinar cell vacuoles appear as early as 6
h after treatment. Twenty-four hours after injection, zymogen
granules disappear in some areas. After 72 h, there is an
accumulation of interstitial fluid and necrosis of acinar cells.
After 96 and 120 h, the majority of the pancreas is replaced by
inflammatory and fibrotic cells, and only small areas of intact
acinar cells are visible. However, pancreatic islet cells remain
unaffected by L-arginine treatment (29).
Although the exact mechanisms of L-arginine pancreatitis
are not clear, the imbalance of amino acids and the subsequent
decrease of protein synthesis, the derangement of transamina-
tion and the urea cycle, and metabolic acidosis in the acinar
cells may all be involved. L-Arginine metabolites are also
involved in pancreatitis development as high doses of L-orni-
thine, a downstream product of L-arginine by L-arginase, have
also been reported to cause AP (136). Partial inhibition of
L-arginase ameliorates L-arginine-induced pancreatitis (19).
Oxidative stress may also contribute to L-arginine pancreatitis
because reducing oxidative stress ameliorates pancreatic injury
in this model of pancreatitis (61, 62). Additionally, hyperse-
cretion from the significant enhancement of neural sympathetic
and parasympathetic activity (50 mg) (61) and nitric oxide
(152) may also be involved in the development of this disease
(151, 153). These effects seem to be L-arginine specific as
D-arginine, L-lysine, L-alanine, and glycine failed to elicit AP.
The L-arginine model has been modified to a single injection
with varying results. Doses higher than 500 mg/100 g body wt
can induce death within a few hours (154). A single dose of
500 mg/100 g causes necrosis in up to 70 – 80% of the pancre-
atic acinar cells within 3 days, which increases to 90% after
three further doses over 10 days (154). Splitting the dose to two
injections can also be used to delay the onset of AP (169).
Single injection carries a higher mortality than double injec-
tion, and therefore double injection models are more com-
monly used. In brief, a sterile L-arginine solution (8% in PBS
or normal saline, pH 7) is administered intraperitoneally to
nonfasted mice at a dose of 400 mg/100 g body wt or to rats at
a dose of 250 mg/100 g body wt. One hour later, a second dose
of L-arginine is administered.
L-Arginine-induced AP provides a model for necrotizing
pancreatitis that carries a high morbidity and mortality. It is
highly reproducible, and the severity of pancreatic acinar
necrosis can be controlled by regulating the dose and time of
L-arginine. However, it is unlikely that human AP is caused by
basic amino acid overdose.
CDE diet-induced AP. Pancreatic damage caused by low-
choline diets was originally reported in 1937 (54). In 1950,
ethionine was first reported to induce AP in rats by Farber and
Popper (40) and Goldberg et al. (49). Since then, ethionine-
induced pancreatitis has been shown to occur in many other
species of experimental animals, including mice, hamsters,
cats, dogs, and monkeys (22, 30, 166). Ethionine-induced
pancreatitis is characterized mainly by local necrosis and
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atrophy with acinar cell regeneration. In 1975, Lombardi and
colleagues (100, 138) reported that female mice fed with the
CDE diet (a choline-deficient diet enriched with 0.5% ethio-
nine, a derivative of methionine) developed severe necrotizing
pancreatitis and had a mortality rate of 100% after 4 days.
The onset of CDE diet-induced AP is variable, but it usually
takes ⬃2–3 days to develop. This form of pancreatitis is
characterized by massive fat necrosis of the exocrine paren-
chyma, intense hemorrhaging, and an inflammatory reaction of
the stroma throughout the peritoneal cavity (99, 100, 120, 138).
The earliest changes are increased zymogen granules in pan-
creatic acinar cells. Pancreatic inflammation and necrosis occur
before activated proteolytic enzymes can be detected within the
pancreas. The necrosis of acinar cells develops 48 h after
treatment, and hemorrhaging starts 60 h after initiation of the
diet. In the animals who survived the AP, their pancreatic
function started to recover after 2–3 wk, and morphological
resolution usually took 4 – 6 wk.
The exact mechanisms of CDE on AP are unclear. However,
the obvious sex differences in this model suggest that estrogen
may play a role in the pathogenesis of AP and have been
evidenced by the fact that male mice pretreated with estrogen
can also develop AP on CDE diet. Additionally, zymogen-
granule secretion blockage and intraparenchymal trypsinogen
activation can be a result of a synergistic action of choline
deficiency with the basic toxicity of ethionine toward the acinar
cells. Ethionine may be toxic to the pancreas by interfering
with RNA, protein, and phospholipid metabolism (100). Au-
tophagy and crinophagy have also been suggested to be in-
volved in the vacuole formation.
The severity of the CDE AP model will vary depending on
the sex, age, and weight of the animals. Young, female mice
are prone to have more severe cases compared with older, male
mice. Generally, young female CD-1 mice (or NMR1, or Swiss
Webster mice; 4 – 6 wk old, 10 –14 g) are used for the CDE AP
model. Typically there are two approaches to generate this
model. In one approach, the animals are fed regularly with
regular chow and then switched to the CDE diet. The mortality
of the animals depends on the length of time the animal is on
the CDE diet: 33 h renders 10 –20% mortality, 48 h increases
the mortality to 40 –70%, 66 h is associated with 55–75%
mortality, and if the diet is administered for 72 h, then there
will be a mortality of over 80%. Another approach involves
animal starvation for 1 day followed by feeding with the CDE
diet at 3 g per mouse per day for 1–5 days depending on the
desired severity of AP. In this approach, the animals tend to eat
more of the CDE diet during the first 24 h and develop AP
faster because they have been starved for 24 h (120).
This model is a noninvasive AP model. Despite the differ-
ences in pathogenesis of the pancreatitis induced in this model
compared with the human disease, the gross and histological
appearance of the pancreatic and peripancreatic inflammation
and the clinical and biochemical course of the diet-induced
pancreatitis resemble the human disease. Both the model and
the human disease share several pathophysiological features,
including necrosis, systemic hypoxia, and hemoconcentration.
Therefore, the model may be suitable for studying these patho-
physiological aspects of this disease. The severity and mortal-
ity of the model can be modified by changing the duration of
CDE diet administration; for example, all of the mice fed with
the CDE diet for 5 days died of hemorrhagic pancreatitis;

PANCREATITIS MODELS
however, when the CDE diet was given for only 1 day, the
incidence of fatal hemorrhagic pancreatitis was reduced to
55– 65% (120).
Several pitfalls and problems have to be considered to obtain
valuable data. Due to the mortality associated with the amount
of the CDE diet ingested, the CDE diet implementation re-
quires careful monitoring of dietary intake and animal status. It
is also important to use large numbers of animals in each
experimental group. Young mice are affected more severely
than adult mice and females more than males (101). Thereby
age- and sex-matched animals should be used for homogeneity
and reproducibility of CDE diet-induced AP. Another point to
remember is that liver damage and hypoglycemia are also
observed in this model. Therefore, this model is not ideal for
studying multiple organ distress syndromes because the CDE
diet can trigger those syndromes by mechanisms that are
unrelated to the severity of AP. The high cost of the diet also
discourages the use of this model (120). Because of these
limitations, this model has been rarely used in recent years.
Retrograde ductal infusion-induced AP. Biliary pancreatitis
is one of the most common forms of AP. One theory is that
biliary obstruction permits the reflux of bile into the pancreatic
duct. The first experimental, retrograde ductal infusion-induced
AP model was established in 1856 by Bernard (15), who
injected bile and olive oil into a canine pancreas through the
ampulla of Vater. Since then, various bile salts have been
reported to induce AP in different species. Ductal infusion of
sodium glycodeoxycholic dose dependently induces edema-
tous pancreatitis and necrotizing pancreatitis in rats (156). An
infusion containing a combination of enterokinase with sodium
glycodeoxycholic induced necrotic pancreatitis with systemic
complications and rapid mortality (156). In 1992, Schmidt et
al. (145) modified the rat duct infusion model by using the
combined actions of very low concentrations of glycodeoxy-
cholic acid (5–10 mM) administered via ductal infusion and
caerulein (5 ␮g·kg⫺1·h⫺1 for 6 h) administered intravenously.
This model features a moderate onset of moderate injury
throughout the pancreas that lasts 24 h and provides the
potential for modulating disease severity (41). Recently, Lauk-
karinen et al. (87) established a retrograde ductal infusion-
induced AP model in mice by infusing sodium taurocholate
into the mouse pancreatic duct. In the head of the pancreas,
evidence of pancreatitis was observed 12–24 h after infusion of
20 –50 ␮l of 2–5% sodium taurocholate. The damage in the
pancreas was concentration and volume dependent. There was
no lethality found. In contrast, in a separate study using mice
(176), 2–5% sodium taurocholate solution was injected at a
volume of 2 ml/kg (⬃50 ␮l/mouse). All of the animals receiv-
ing 2 or 3% sodium taurocholate survived the experiment.
Animals receiving 4 and 5% sodium taurocholate showed a
significant increase of fatty tissue necrosis when compared
with animals receiving the 2% solution. Death within the first
24 h occurred in 10% of the animals receiving the 4% solution.
And death rate reached 60% when 5% taurocholate solution
was used.
Histological changes of the pancreas after 24 h of treatment
include large areas of acinar cell necrosis adjacent to morpho-
logically unaltered acinar lobes. Leukocyte infiltration, fatty-
tissue necrosis, and hemorrhage are typical. Taurocholate in-
fusion predominantly affects the pancreatic head. The pancre-
atic tail usually presents with extensive edema. Surprisingly,
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G347
despite the marked lethality associated with the 5% sodium
taurocholate treatment, no obvious pulmonary pathology was
detected after 24 h postinduction (176).
Bile salts exert detergent properties and primarily aid in the
absorption of fat and fat-soluble vitamins (65). It was initially
believed that pancreatic injury resulted from the detergent
properties of bile acids. Currently, bile acids are considered
crucial agonists that interact with several proteins, including
the nuclear receptor farnesoid X receptor (FXR) and G protein-
coupled bile acid receptor-1 (Gpbar1) to regulate many cellular
functions (39, 48). Bile acids can act on both duct cells and
acinar cells of the exocrine pancreas. Bile acids have dual
effects on the ductal secretion, and at low concentrations they
induce a dose-dependent elevation of intracellular Ca2⫹ con-
centration via an inositol 1,4,5-triphosphate receptor and a
phospholipase C-mediated pathway. This may help wash out
the toxic bile acids and thus protect the acinar cells. At high
concentrations, bile acids induce a toxic, sustained intracellular
Ca2⫹ concentration and decrease intracellular ATP, which
inhibits all of the acid-base transporters. Pathological Ca2⫹-
dependent trypsinogen and calcineurin activation causes cell
death in isolated pancreatic acinar cells (112). Loss of the flux
defense mechanism may also lead to high concentrations of
bile acids to reach the acinar cells. These effects at least in part
are mediated by Gpbar1. Genetic deletion of Gpbar1 signifi-
cantly reduces biliary but not secretagogue-induced experi-
mental AP, suggesting its role in the pathophysiology of the
biliary pancreatitis (130).
One of the most commonly used retrograde ductal-infusion
protocols in rats was described by Aho et al. (5). First, a
midline laparotomy is performed, the biliopancreatic duct is
then cannulated, and fluid (saline or saline containing bile acid
and blue dye) is infused. Flow rates higher than 10 ␮l/min
should be avoided to minimize any artifacts or injury due to the
rapid increase in intrapancreatic pressure. Detailed methods for
experimental acute biliary pancreatitis in mice induced by
retrograde infusion of bile acids have been published by
Perides et al. (132).
Biliary AP accounts for 30 –50% of all clinical cases of AP.
This model uses clinically relevant etiological insults of acute
biliary pancreatitis, and its severity can be manipulated by
altering the concentration, volume, and infusion pressure of the
injected bile acid. This model is useful for mechanistic studies
employing genetically modified mouse strains. The disadvan-
tage is that it is technically challenging to control the constant
pressure when retrograding ductal infusion, which is critical
for determining the severity of the induced pancreatitis. Pumps
may be needed to control the constant low pressure of infusion
to produce a standard degree of pancreatic injury and to avoid
high perfusion pressure-induced artifact (87).
Recently, Husain and coworkers (75) developed another
clinically relevant mouse model of AP. In this model, the
radiocontrast agent iohexol was injected to the common bile
duct and pancreatic duct of Swiss Webster mice by retrograde
infusion. Iohexol infusion causes acute damage and inflamma-
tion in the pancreas. Mechanistically, radiocontrast agents
cause a pancreatic inflammatory response through the activa-
tion of NF-␬B, calcium signaling, and calcineurin pathways.
These signaling pathways seem to be pancreatic acinar cell
specific because they were not elicited in HEK293 or COS7
cells. Calcineurin deficiency or inhibitors improved the pan-
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G348 PANCREATITIS MODELS
creatitis associated with this model, suggesting that targeting
these pathways may prevent post-ERCP pancreatitis in patients
(75).
Duct-ligation induced AP. This model is based on the
theory that duct obstruction will block pancreatic fluid and
enzyme flow and therefore lead to AP development. Initially
attempted in the early 19th century (81), duct ligation has
been used in various animals including dogs, rabbits, opos-
sums, rats, and mice. Opossums have a pancreatic main duct
that drains into a long common bile duct, and both enter the
duodenum at the papilla. The extraduodenal common bile
duct and the pancreatic duct are easily dissected in this
animal and as a result make it easier to study the effects of
ligation of specific ducts on the pathogenesis of AP. Liga-
tion of the pancreas duct or common bile duct in opossum
induced hemorrhagic AP with a 14-day mortality of 100%
(147). However, most other laboratory animals do not de-
velop AP with surgical ligation of the pancreatic duct alone,
but long-term ligation causes chronic atrophy of the exo-
crine pancreas (122, 167). In mice, the combination of bile
infusion into the pancreas followed by bile duct ligation also
causes a more severe, necrotizing pancreatitis (89). A sim-
ilar level of severity seen after obstructing the pancreatic
duct adjacent to duodenum (which also blocks the bile duct)
compared with ligation of both pancreatic duct and bile duct
adjacent to liver suggest that bile reflux may not be neces-
sary to induce AP (92). In another study in mice, the
pancreatic duct was blocked by placing a small metal clip
across the lower end of the duct. A suture was incorporated
within the clip during its placement for reversing biliary
obstruction as needed (82). Combining duct ligation with
both secretory stimulation or minimized arterial blood pro-
duced a more severe form of AP (135).
Pancreatic duct obstruction rapidly changes the physio-
logical response of the exocrine pancreas to a calcium
signaling pattern that has been associated with premature
digestive enzyme activation and the onset of pancreatitis
(111). It is postulated that intrapancreatic digestive enzyme
activation accounts for the major pathology of this model.
Altered intracellular targeting of endocytosed proteases
might be one mechanism by which digestive zymogens
reach an intracellular compartment where premature activa-
tion can occur (93).
The duct ligation-induced model closely mimics gallstone-
induced AP (1). It avoids the use of agents at nonphysiologi-
cally relevant concentration and dosage that could produce
unwanted systemic effects. However, the complexity, technical
difficulty, and limited reproducibility have made the duct
ligation model less popular for investigating AP. Duodenal
wall necrosis and pancreatic peritoneal sepsis often add com-
plexity to the model. Furthermore, the severity of AP varies
depending on the species and duration of obstruction (23, 122).
There are also species-dependent effects in this model. In
duct-ligated rats, apoptosis is the main mechanism of cell
death. By contrast, necrosis is the predominant mechanism in
duct-ligated opossums (56, 79).
Alcohol-related AP. Although alcoholism is one of the major
causes of human pancreatitis in the United States, a continuous
intragastric infusion of ethanol to rats over several weeks
produced only ethanol-induced liver injury, not alcohol-in-
duced pancreatitis. The failure to produce alcoholic pancreati-
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tis in animals suggests that the provision of ethanol may only
increase the predisposition to pancreatitis. In 1999, Pandol et
al. (126) found that an ethanol diet sensitized rats to the
pancreatitis caused by CCK-8. After intragastric feeding with
either a control or an ethanol diet for 2 or 6 wk, rats were then
infused for 6 h with either saline or CCK-8 at a dose of 3,000
pmol·kg⫺1·h⫺1, which by itself did not induce pancreatitis. All
measures of pancreatitis, as well as NF-␬B activity and cyto-
kines were significantly increased only in rats treated with
ethanol plus CCK-8 (126). In a later study, rats were fed with
control and ethanol-containing Lieber-DeCarli diets (discussed
in detail below: Alcohol-related CP models) for 6 wk followed
by four hourly intraperitoneal injections of caerulein at 0.5
␮g/kg. Caerulein alone induced only minor pathological
changes in control-fed rats. In contrast, in ethanol-fed rats,
caerulein induced marked acinar cell vacuolization, dilation of
the ER, and occasional patchy cellular necrosis (102).
Both oxidative and nonoxidative metabolisms of ethanol
(OME and NOME, respectively) mechanisms are used to
degrade alcohol in the exocrine pancreas. NOME combines
ethanol with fatty acids to yield lipophilic fatty acid ethyl esters
(FAEEs) via diverse FAEE synthase enzymes (55). FAEEs can
induce high sustained toxic calcium concentrations in pancre-
atic acinar cells and lead to acinar necrosis (27). To test the
effects of FAEE in the initiation of AP, adult CD1 mice
received two intraperitoneal injections of ethanol (1.35 g/kg)
and POA (palmitoleic acid, a monounsaturated fatty acid, 150
mg/kg) at 1-h intervals. Two hundred microliters of normal
saline were injected immediately prior to ethanol/POA injec-
tions to avoid local damage by ethanol to peritoneal organs at
the injection site. Mice received either saline, ethanol (1.35
g/kg), or POA (150 mg/kg) were used as controls (67). At 24
h after application, the combination of ethanol and POA
induced pancreatic damages including extensive acinar cell
edema, neutrophil infiltration, and necrosis. The combination
of ethanol/POA also elicited alveolar membrane thickening
and inflammatory cell infiltration in the lung but damages in
the liver, kidney, or heart are minimal (67). A similar pheno-
type was achieved with the use of C57BL/6J mice (170). Mice
are more tolerant to the treatment after one instead of two doses
of treatment (107).
Coxsackie B virus-induced AP. A wide variety of infections
have been associated with AP. These infections include viruses
(mumps, coxsackie, hepatitis B, cytomegalovirus, varicella-
zoster virus, herpes simplex virus), bacteria (Mycoplasma,
Legionella, Leptospira, Salmonella), fungi (Aspergillus), and
parasites (Toxoplasma, Cryptosporidium, Ascaris) (128).
Among these factors, coxsackie B virus-induced AP has been
well documented and studied (24, 60, 139).
Coxsackie virus-type B virus is a single-stranded RNA
picornavirus with six identified serotypes (serotypes 1– 6).
Mice infected with coxsackie viruses B1, B3, B4, or B5
produce a severe form of pancreatitis consisting of the degen-
eration of acinar cells, loss of zymogen granules, infiltration of
mononuclear and plasma cells, and the replacement of exocrine
tissue with fatty tissue. In contrast, coxsackie viruses B2 and
B6 do not cause these changes. Coxsackie viruses B3 and B4
exhibit more rapid action in the tissue and more severe lesions
than B1 and B5. In contrast, none of the coxsackie B viruses
examined elicited detectable microscopic changes in the islets
of Langerhans (86). In newborn mice infected with coxsackie

PANCREATITIS MODELS
B4 virus by intraperitoneal inoculation for 1–2 days, cytone-
crosis consistent with a picornaviral infection was observed
(60). Mice with coxsackievirus B3 infection developed necro-
tizing AP. This form of pancreatitis eventually led to complete
atrophy of the exocrine pancreas with the islets of Langerhans
and pancreatic ducts spared (165). These mice also developed
focal myocarditis (51). The viral infection also interacted with
other modifying factors. For example, it was observed that
infection of the virulent coxsackievirus B3 strain 28 in com-
bination with alcohol feeding resulted in a more severe form of
pancreatitis. Furthermore, infection with the avirulent strain
(GA) plus alcohol feeding caused severe pancreatitis, whereas
the infection alone did not result in any obvious pathological
effects in the pancreas (70). Alcohol also impaired pancreatic
regeneration following viral-induced injury in a dose- and
duration-dependent fashion (25).
Animal Models of Chronic Pancreatitis
Progressive inflammation of the pancreas leads to chronic
pancreatitis (CP), which is defined by the loss of parenchymal
(exocrine and endocrine) cells, inflammatory cell infiltration,
fat replacement, stellate cell activation and fibrosis, calcifica-
tion, and nerve enlargement. Clinical manifestations include
pain, maldigestion, and possible diabetes. Although pain is
common, exocrine insufficiency occurs late in the course of the
disease because the pancreas has a great functional reserve.
Steatorrhea occurs only when lipase secretion is reduced to less
than 10% of normal (162). In the absence of established
diagnostic criteria, early diagnosis of human CP is challenging
and often based on a combination of clinical presentation,
imaging results, and pancreatic function test results (35, 105).
There is also no consensus on the criteria for evaluating animal
models of CP. Because the purpose of pancreatitis research is
to eliminate the inflammatory response, prevent fatty/fibrotic
replacement, and preserve both exocrine and endocrine pan-
creatic functions, the parameters used to evaluate CP include
pancreatic weight, blood insulin/glucose levels, pancreatic am-
ylase content, inflammatory cell including macrophage and
lymphocyte infiltrations, ␣-SMA expression (a marker for
early stellate cell activation), and areas of fatty/fibrotic replace-
ment (45, 69, 74, 140, 141, 183).
The pathogenesis of CP is poorly understood. Accumulated
evidence suggests that the incidence of CP is increasing (77).
Alcohol is the major cause of CP in the Western world. Other
etiologies include smoking, obstructive lesions, other toxic
agents, and genetic factors (178). Ethanol has both direct and
indirect toxic effects on the integrity of pancreatic acinar cells
that are mediated by the ethanol metabolite acetaldehyde (7).
Oxidative stress caused by ethanol or nicotine can lead to the
peroxidation of the lipid bilayer of the cell membrane, which
consecutively disintegrates the membrane (108). Different eti-
ologies may have different pathogenic mechanisms, and di-
verse signaling leads to various phenotypic changes. For ex-
ample, prolonged activity of NF-␬B results in inflammatory
cell infiltration, activation of stellate cells, loss of acinar cells,
and fibrosis, which are characteristics of CP (66). Ras activa-
tion leads to acinar cell senescence and generates inflammation
and massive fibrosis resembling the histological features of CP
(28, 74, 97). In contrast, the primary response to intracellular
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G349
trypsin activity is the rapid induction of acinar cell death via
apoptosis and causes fat replacement in the pancreas (45).
Pancreatic fibrosis is a histopathological feature of CP. It is
now recognized that pancreatic fibrosis is mediated by the
activation of pancreatic stellate cells (PSCs) that normally
reside in the periacinar region of the pancreas in a quiescent
state (9). The mechanisms of PSC activation have been studied
and reviewed previously (11). It seems that fibrosis is an active
process mediated by the activation of PSCs. Acinar cell apo-
ptosis that is induced by intracellular trypsin caused extensive
fat replacement (45). In contrast, Ras-induced acinar cell se-
nescence led to a dramatic desmoplastic reaction in the pan-
creas (74).
In humans, acute and recurrent AP can develop into CP.
These diseases share similar genetic and environmental caus-
ative factors. Therefore, AP, recurrent AP, and CP are now
considered as a disease continuum (171). Indeed, many re-
searchers have tried to establish CP models by using modified
experimental protocols that cause AP.
Models based on repetitive induction of AP. In caerulein-
induced AP, the pancreas will recover from a single episode of
caerulein challenge within a week. Expression of TGF-␤1, a
key profibrogenic factor, is increased in acinar and stromal
cells of the rat pancreas in this model, indicating that repetitive
treatment with caerulein may cause fibrosis, a key feature of
CP (53). Indeed, repeated caerulein insult could induce exo-
crine deficiency, fibrosis, and diabetes (115). As in AP models,
this is the most commonly used and reproducible model for
CP. The procedures vary in different studies and can be used in
combination with many other insults. In one early study, rats
were treated with water immersion stress for 5 h and two
intraperitoneal injections of caerulein (20 ␮g/kg body wt) once
a week for 16 wk. Pancreatic atrophy, marked fibrosis, fatty
changes, and destruction of the lobular architecture were dem-
onstrated microscopically; diabetes was also present (52).
Acute pancreatic injury induced in mice by twice-weekly
caerulein treatment (50 ␮g·kg⫺1·h⫺1 ⫻ 6 h) for 10 wk in-
creased procollagen expression and progressive accumulation
of the extracellular matrix surrounding acinar units and in
interlobular spaces. Atrophy, transdifferentiation of acinar
units to ductlike tubular complexes, and dilatation of intra-
acinar lumina also developed (117). A more closely spaced
treatment strategy in which AP was induced three times weekly
instead of twice weekly produced an even more rapid accumu-
lation of periacinar fibrosis and altered acinar architecture 6 wk
after the initial AP induction (116, 158). After the insults were
stopped, the pancreatic fibrosis mostly resolved in 3– 6 wk,
suggesting that the processes responsible for matrix resolution
are potently active in the pancreas (116). Additionally, the
addition of lipopolysaccharide (LPS) increased the amount of
fibrosis (121). This may be because pancreatic stellate cells
express a variety of Toll-like receptors (TLRs) and respond to
TLR ligands (e.g., LPS), leading to the activation of signaling
pathways and proinflammatory responses (109).
Cyclosporin is a drug that binds to cyclophilin to inhibit
calcineurin and increases TGF-␤ expression. Although cyclo-
sporin accumulates at high concentrations in the pancreas, it
only produces minor morphological or functional derange-
ments. However, the combination of cyclosporin and caerulein
exacerbates the chronic inflammatory response in the pancreas
(161), but the doses and duration of caerulein treatment and the
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G350 PANCREATITIS MODELS
timing of tissue collection seem to be important in determining
the phenotype observed. In one study, pancreatitis was induced
nine times at intervals of ⬃20 days; 3 days after the last
injection of caerulein, inflammation was still observed. How-
ever, 6 wk later, the pancreas fully recovered (37). Using
higher frequencies of caerulein applications will likely lead to
more a dramatic formation of pancreatic fibrosis.
Serial intraperitoneal injections of arginine with initial dose
of 500 mg/100 g body wt followed by three injections at 250
mg/100 g over 10 days was also used to produce CP. After 24
h the pancreas had severe edematous AP. By day 5 there was
up to 90% acinar destruction with adipose tissue replacement,
but ductal and islet cells appeared undamaged. These changes
were still present 6 mo after injection (31). In another study,
male rats were intraperitoneally injected daily (350 mg/100 g
body wt) with L-arginine from 1 to 4 wk. At week 1, light
microscopy revealed areas of focal acinar cell degeneration. At
the end of week 2, acinar necrosis was evident throughout most
pancreatic lobules. At week 4, only isolated, single acinar cells
remained within a fibrous connective tissue matrix contiguous
with ducts, blood vessels, intrapancreatic nerves, and islets
(169). Instead of fibrosis, Yamaguchi et al. (180) showed that
85 to 90% of the acinar tissue was replaced by fatty tissue and
dilated pancreatic ducts on day 54 after the first intraperitoneal
arginine injection.
Mice fed with an intermittent CDE diet (3 days of CDE diet
alternating with 3 days of normal diet) for a prolonged period
of 24 wk can develop some histological features of CP. The
fibrosis in this model is mild (69).
In mice and rats, complete pancreatic duct obstruction
mainly results in atrophy of the organ and does not lead to the
typical morphology of CP. Several months after pancreatic
duct ligation, there is intralobular fatty replacement of the
exocrine pancreas (168). Therefore, duct ligation alone does
not cause typical CP. However, complete pancreatic duct
obstruction and daily caerulein hyperstimulation caused large
amounts of interstitial collagen expression after 72 h (114).
Recently, a modified-CP model by branch duct ligation in
combination with caerulein administration has been developed
and could be a valuable model (146). In this study, CP was
induced by ligation of the pancreatic duct at the junction
between the gastric and the duodenal lobe sparing the bile duct
and its concomitant artery. These animals then received a
single injection of caerulein (50 ␮g/kg body wt) 2 days after
duct ligation. Severe necrotizing pancreatitis developed in the
ligated part of the pancreas 3 days after surgery. Model-
associated mortality ranged from 10 to 15% and always oc-
curred within 48 h of caerulein injection. Areas of pancreatic
necrosis were replaced by fibrotic and fatty tissues, and max-
imal fibrosis was detected after 21 days.
The mortality rate is usually high in acute hemorrhagic
pancreatitis that is induced by retrograde infusion of sodium
taurocholate into the pancreatic duct system of the rats. In
animals surviving 72 h, there was marked acinar atrophy and
pancreatic fibrosis (5).
However, with a single retrograde intraductal infusion of 40
␮l/100 g body wt of 3% sodium taurocholate, the pancreas
appeared to be histologically normal 42 days after intraductal
infusion (180). The volume, concentration, pressure, and du-
ration may be factors that are complicated in these phenotypic
changes.
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Alcohol-related CP models. In 1967, Maki et al. (106)
studied the influence of the oral administration of alcohol on
the rat pancreas and the interaction of alcohol with various
dietary compositions. Alcohol with a concentration of 15%
was added to the drinking water of the study animals for 2 mo.
The alcohol intake caused increased serum amylase levels,
pancreatic edema, and vacuolization of acinar cells, but fat
necrosis or pancreatic necrosis was not noted. Interestingly, the
rats that were fed on a high-carbohydrate diet showed minimal
changes in the pancreas compared with those fed on high-
protein and high-fat diets and with those fed on low-protein
and high-fat diets. In 1971, Sarles et al. (144) fed rats with 20%
ethanol for 20 –30 mo. The average daily consumption of
alcohol was 4 g/rat. More than half of the animals developed
pancreatic lesions similar to those of human CP. The patho-
logical changes included reduced acini, duct multiplication,
protein plugs, sometimes calcified ducts, and sclerosis. Beta-
cell adenomata of the islets of Langerhans were also observed
in four of the rats exposed to ethanol.
Currently, the most popular protocol used to imitate the
effects of alcohol on various organs was developed by Lieber
and DeCarli in 1975 for alcohol liver injury (96). The feeding
regime was based on the supplementation of ethanol into a
liquid diet (referred as Lieber-DeCarli diet), and it allows an
increased total alcohol intake. Isocaloric substitution of carbo-
hydrates by ethanol (36% of total calories in rats) resulted in
the production of fatty liver disease, alcoholic hepatitis, and
eventually cirrhosis. This diet leads to severe organ damage in
the liver but pancreatic morphology changes are mild. Rather
than CP, only mild functional insufficiency develops in most
cases. These observations correlate with the clinical finding
that only a minority (less than 10%) of alcoholics ever develop
clinical CP (94). Therefore, alcohol alone is a very weak
inducer of CP, and other factors are necessary for the onset of
CP. However, the Lieber-DeCarli administration causes a num-
ber of changes that may predispose the gland to damage. These
changes include an increased concentration of digestive en-
zymes and the lysosomal enzyme cathepsin B, which is im-
portant in intracellular trypsinogen activation. It is believed
that alcohol “sensitizes” or “primes” the pancreas to pancre-
atitis; current studies are focused on the mechanisms respon-
sible for the sensitizing effects of alcohol, and Lieber-DeCarli
diet is usually used in combination with many other factors
(genetic, environmental, or dietary) to induce CP (10, 125).
The pancreata from rats fed ethanol for 9 –12 mo are more
susceptible to caerulein-induced activation of chymotrypsino-
gen than the pancreata from pair-fed control animals (134).
The combination of alcohol feeding with caerulein injections
exacerbates pancreatitis with increased fibrosis and loss of
parenchyma. Additionally, calcifications indicating severe CP
can be observed. Although pancreatic function was not directly
tested, there was evidence that digestive enzyme synthesis is
reduced after chronic ethanol feeding (32, 131).
Combining LPS and the alcohol model can be adopted
because of its potential clinical relevance. In one study, alco-
hol-fed rats receiving a single LPS injection displayed more
severe acinar vacuolization, acinar cell necrosis, inflammatory
infiltrates, and hemorrhaging. Negligible lesions were found in
the control diet-fed plus LPS group. These lesions mimic some
of the features of AP (164). When the rats fed Lieber-DeCarli
liquid diets for 10 wk were challenged with three repeated

PANCREATITIS MODELS
doses of LPS (3 mg/kg intravenously per week for 3 wk),
significantly greater pancreatic injury and pancreatic fibrosis
were seen in the alcohol-fed rats but not in control diet group.
In in vitro studies, alcohol and LPS exerted a synergistic effect
on PSC activation, and pancreata exposed to alcohol were
more sensitive to LPS-induced damage. This may be caused by
increased sensitivity to necrotic cell death rather than apoptotic
cell death (42). Withdrawal of alcohol led to the resolution of
pancreatic lesions including increased PSC apoptosis and de-
creased fibrosis (163).
Smoking is a strong and independent risk factor of pancre-
atitis. Cigarette smoke dose dependently potentiates the
amount of pancreatic injury generated by ethanol alone (63,
179). Pancreatic stellate cells can be activated by clinically
relevant concentrations of cigarette smoke components (90).
In a cyclosporin model of alcoholic CP developed by Guk-
ovsky et al. (57), the addition of cyclosporin and caerulein in
rats fed with ethanol led to a decrease of the pancreatic
parenchyma by ⬃86%. The combination markedly increased
NF-␬B activation and cytokine/chemokine expression, colla-
gen, fibronectin, the activities of matrix metalloproteinases,
and the activation of pancreatic stellate cells.
It has been found that, in animals fed on a high-protein and
high-fat diet, ethanol increased the amount of the excretory
enzymes in the pancreas (26). In Tsukamoto’s study (160), rats
implanted with gastrostomy catheters were fed with increasing
doses of ethanol (from 8 g·kg⫺1·day⫺1 to 15 g·kg⫺1·day⫺1)
plus corn oil unsaturated fat: 5% (low-fat), 25% (high-fat), or
35% (extra-high-fat) of total calories. With the low-fat diet,
chronic ethanol feeding produced only mild pancreatic pathol-
ogy, such as steatosis and interstitial edema. However, ethanol
with the high-fat and extra-high-fat diets caused increased
acinar cell apoptosis. Focal lesions of CP were also observed in
20 or 30% of ethanol-fed animals given the high-fat or extra-
high-fat diet. These lesions included fat necrosis, mononuclear
cell infiltration, fibrosis, acinar atrophy, ductal dilatation, and
intraductal mucinous or proteinaceous plugs (160). Interest-
ingly, although pancreatic damage was associated with unsat-
urated fat, medium-chain triglycerides (saturated fat) signifi-
cantly blunted the damage, suggesting that the dietary fat types
have different roles in pancreatitis (83).
Perspectives
There are many models available for both acute and chronic
pancreatitis. These models have been discussed in many ex-
cellent reviews (4, 43, 68, 78, 91, 143, 184). However, inves-
tigators studying pancreatitis face several challenges. The first
and most major challenge is the clinical relevance of the
models. Unfortunately, many models use non-clinically rele-
vant stimulants, while others fail to reproduce human diseases,
even with human-related etiological insults. Thus the mecha-
nisms found from these models should be interpreted with
caution. The second is that reproducible rodent models for
some forms of human pancreatic inflammatory diseases with
known etiologies (e.g., hereditary pancreatitis, cystic fibrosis)
have yet to be developed. Last, current research largely focuses
on the initiating mechanisms. Effective preventive and thera-
peutic drugs for the human pancreatitis are still lacking. Clin-
ically relevant models are urgently needed for developing and
testing interventions.
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G351
ACKNOWLEDGMENTS
We thank Kelly E. Viola for critical editing.
GRANTS
The project described was supported by P50 CA102701 and K12 CA90628
from the National Cancer Institute and W81XWH-15-1-0257 from the Depart-
ment of Defense. This publication was also made possible by the CTSA Grant
UL1 TR000135 from the National Center for Advancing Translational Sci-
ences (NCATS), a component of the National Institutes of Health. The content
is solely the responsibility of the authors and does not necessarily represent the
official views of the National Institutes of Health or the Department of
Defense.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author (s).
AUTHOR CONTRIBUTIONS
X.Z., F.W., Y.B., and B.J. drafted manuscript; Y.B. and B.J. conception and
design of research; Y.B. and B.J. edited and revised manuscript; B.J. approved
final version of manuscript.
REFERENCES
1. Acosta JM, Ledesma CL. Gallstone migration as a cause of acute
pancreatitis. N Engl J Med 290: 484 –487, 1974.
2. Adler G, Beglinger C, Braun U, Reinshagen M, Koop I, Schafmayer
A, Rovati L, Arnold R. Interaction of the cholinergic system and
cholecystokinin in the regulation of endogenous and exogenous stimu-
lation of pancreatic secretion in humans. Gastroenterology 100: 537–
543, 1991.
3. Aeffner F, Bolon B, Davis IC. Mouse models of acute respiratory
distress syndrome: a review of analytical approaches, pathologic features,
and common measurements. Toxicol Pathol 43: 1074 –1092, 2015.
4. Aghdassi AA, Mayerle J, Christochowitz S, Weiss FU, Sendler M,
Lerch MM. Animal models for investigating chronic pancreatitis. Fi-
brogenesis Tissue Repair 4: 26, 2011.
5. Aho HJ, Koskensalo SM, Nevalainen TJ. Experimental pancreatitis in
the rat. Sodium taurocholate-induced acute haemorrhagic pancreatitis.
Scand J Gastroenterol 15: 411–416, 1980.
6. Alhan E, Usta A, Turkyilmaz S, Kural BV, Ercin C. Effects of
glutamine alone on the acute necrotizing pancreatitis in rats. J Surg Res
193: 161–167, 2015.
7. Ammann RW, Heitz PU, Kloppel G. Course of alcoholic chronic
pancreatitis: a prospective clinicomorphological long-term study. Gas-
troenterology 111: 224 –231, 1996.
8. Anastasi A, Erspamer V, Endean R. Isolation and structure of caeru-
lein, an active decapeptide from the skin of Hyla caerulea. Experientia
23: 699 –700, 1967.
9. Apte M, Pirola R, Wilson J. The fibrosis of chronic pancreatitis: new
insights into the role of pancreatic stellate cells. Antioxid Redox Signal
15: 2711–2722, 2011.
10. Apte MV, Norton ID, Wilson JS. Ethanol induced acinar cell injury.
Alcohol Alcohol Suppl 2: 365–368, 1994.
11. Apte MV, Wilson JS, Lugea A, Pandol SJ. A starring role for stellate
cells in the pancreatic cancer microenvironment. Gastroenterology 144:
1210 –1219, 2013.
12. Ateyya H, Wagih HM, El-Sherbeeny NA. Effect of tiron on remote
organ injury in rats with severe acute pancreatitis induced by L-arginine.
Naunyn Schmiedebergs Arch Pharmacol 389: 873–885, 2016.
13. Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am
J Gastroenterol 101: 2379 –2400, 2006.
14. Bartholomew C. Acute scorpion pancreatitis in Trinidad. Br Med J 1:
666 –668, 1970.
15. Bernard C. Memoir on the pancreas and on the role of pancreatic juice
in digestive processes, particularly in the digestion of neutral fat. 1856.
Transl. Henderson J. Monogr Physiol Soc 42: 1–131, 1985.
16. Bertaccini G, De Caro G, Endean R, Erspamer V, Impicciatore M.
The action of caerulein on pancreatic secretion of the dog and biliary
secretion of the dog and the rat. Br J Pharmacol 37: 185–197, 1969.
17. Bi Y, Page SL, Williams JA. Rho and Rac promote acinar morpholog-
ical changes, actin reorganization, and amylase secretion. Am J Physiol
Gastrointest Liver Physiol 289: G561–G570, 2005.
Themes
G352 PANCREATITIS MODELS
18. Bi Y, Williams JA. Receptor biology and signal transduction in pancre-
atic acinar cells. Curr Opin Gastroenterol 20: 427–434, 2004.
19. Biczo G, Hegyi P, Berczi S, Dosa S, Hracsko Z, Varga IS, Ivanyi B,
Venglovecz V, Wittmann T, Takacs T, Rakonczay Z Jr. Inhibition of
arginase activity ameliorates L-arginine-induced acute pancreatitis in rats.
Pancreas 39: 868 –874, 2010.
20. Biczo G, Hegyi P, Dosa S, Shalbuyeva N, Berczi S, Sinervirta R,
Hracsko Z, Siska A, Kukor Z, Jarmay K, Venglovecz V, Varga IS,
Ivanyi B, Alhonen L, Wittmann T, Gukovskaya A, Takacs T, Ra-
konczay Z Jr. The crucial role of early mitochondrial injury in L-lysine-
induced acute pancreatitis. Antioxid Redox Signal 15: 2669 –2681, 2011.
21. Bilchik AJ, Zucker KA, Adrian TE, Modlin IM. Amelioration of
cholinergic-induced pancreatitis with a selective cholecystokinin recep-
tor antagonist. Arch Surg 125: 1546 –1549, 1990.
22. Boquist L. Morphologic effects of ethionine on the pancreas of the
Chinese hamster. A light and electron microscopic study of degenerative
changes. Acta Pathol Microbiol Scand 76: 91–105, 1969.
23. Chan YC, Leung PS. Acute pancreatitis: animal models and recent
advances in basic research. Pancreas 34: 1–14, 2007.
24. Cheever FS, Daniels JB, Hersey EF. A viral agent isolated from a case
of “non-paralytic poliomyelitis” and pathogenic for suckling mice: its
possible relation to the coxsackie group of viruses. J Exp Med 92:
153–167, 1950.
25. Clemens DL, Jerrells TR. Ethanol consumption potentiates viral pan-
creatitis and may inhibit pancreas regeneration: preliminary findings.
Alcohol 33: 183–189, 2004.
26. Criddle DN. The role of fat and alcohol in acute pancreatitis: a danger-
ous liaison. Pancreatology 15: S6 –S12, 2015.
27. Criddle DN, Raraty MG, Neoptolemos JP, Tepikin AV, Petersen
OH, Sutton R. Ethanol toxicity in pancreatic acinar cells: mediation by
nonoxidative fatty acid metabolites. Proc Natl Acad Sci USA 101:
10738 –10743, 2004.
28. Daniluk J, Liu Y, Deng D, Chu J, Huang H, Gaiser S, Cruz-
Monserrate Z, Wang H, Ji B, Logsdon CD. An NF-kappaB pathway-
mediated positive feedback loop amplifies Ras activity to pathological
levels in mice. J Clin Invest 122: 1519 –1528, 2012.
29. Dawra R, Sharif R, Phillips P, Dudeja V, Dhaulakhandi D, Saluja
AK. Development of a new mouse model of acute pancreatitis induced
by administration of L-arginine. Am J Physiol Gastrointest Liver Physiol
292: G1009 –G1018, 2007.
30. De Almeida AL, Grossman MI. Experimental production of pancreati-
tis with ethionine. Gastroenterology 20: 554 –577, 1952.
31. Delaney CP, McGeeney KF, Dervan P, Fitzpatrick JM. Pancreatic
atrophy: a new model using serial intra-peritoneal injections of L-argi-
nine. Scand J Gastroenterol 28: 1086 –1090, 1993.
32. Deng X, Wang L, Elm MS, Gabazadeh D, Diorio GJ, Eagon PK,
Whitcomb DC. Chronic alcohol consumption accelerates fibrosis in
response to cerulein-induced pancreatitis in rats. Am J Pathol 166:
93–106, 2005.
33. Dorigotti L, Glasser AH. Comparative effects of caerulein, pancreozy-
min and secretin on pancreatic blood flow. Experientia 24: 806 –807,
1968.
34. Dressel TD, Goodale RL Jr, Arneson MA, Borner JW. Pancreatitis as
a complication of anticholinesterase insecticide intoxication. Ann Surg
189: 199 –204, 1979.
35. Duggan SN, Ni Chonchubhair HM, Lawal O, O’Connor DB, Conlon
KC. Chronic pancreatitis: a diagnostic dilemma. World J Gastroenterol
22: 2304 –2313, 2016.
36. Elmunzer BJ, Scheiman JM, Lehman GA, Chak A, Mosler P,
Higgins PD, Hayward RA, Romagnuolo J, Elta GH, Sherman S,
Waljee AK, Repaka A, Atkinson MR, Cote GA, Kwon RS, McHenry
L, Piraka CR, Wamsteker EJ, Watkins JL, Korsnes SJ, Schmidt SE,
Turner SM, Nicholson S, Fogel EL. A randomized trial of rectal
indomethacin to prevent post-ERCP pancreatitis. N Engl J Med 366:
1414 –1422, 2012.
37. Elsasser HP, Haake T, Grimmig M, Adler G, Kern HF. Repetitive
cerulein-induced pancreatitis and pancreatic fibrosis in the rat. Pancreas
7: 385–390, 1992.
38. Evander A, Lundquist I, Ihse I. Hormonal and cholinergic effects on
amylase and lysosomal enzyme activities in pancreatic tissue and ascites
of rats with acute experimental pancreatitis. J Surg Res 35: 168 –175,
1983.
39. Fan M, Wang X, Xu G, Yan Q, Huang W. Bile acid signaling and liver
regeneration. Biochim Biophys Acta 1849: 196 –200, 2015.
AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00372.2015 • www.ajpgi.org
Downloaded from journals.physiology.org/journal/ajpgi at Univ De Antioquia (200.024.017.012) on February 21, 2021.
40. Farber E, Popper H. Production of acute pancreatitis with ethionine and
its prevention by methionine. Proc Soc Exp Biol Med 74: 838 –840, 1950.
41. Foitzik T, Hotz HG, Eibl G, Buhr HJ. Experimental models of acute
pancreatitis: are they suitable for evaluating therapy? Int J Colorectal Dis
15: 127–135, 2000.
42. Fortunato F, Deng X, Gates LK, McClain CJ, Bimmler D, Graf R,
Whitcomb DC. Pancreatic response to endotoxin after chronic alcohol
exposure: switch from apoptosis to necrosis? Am J Physiol Gastrointest
Liver Physiol 290: G232–G241, 2006.
43. Foster JR. A review of animal models of nonneoplastic pancreatic
diseases. Toxicol Pathol 42: 243–259, 2014.
44. Frick TW, Dalo S, O’Leary JF, Runge W, Borner JW, Baraniewski
H, Dressel T, Shearen JG, Goodale RL. Effects of insecticide, diazi-
non, on pancreas of dog, cat and guinea pig. J Environ Pathol Toxicol
Oncol 7: 1–11, 1987.
45. Gaiser S, Daniluk J, Liu Y, Tsou L, Chu J, Lee W, Longnecker DS,
Logsdon CD, Ji B. Intracellular activation of trypsinogen in transgenic
mice induces acute but not chronic pancreatitis. Gut 60: 1379 –1388,
2011.
46. Gallagher S, Sankaran H, Williams JA. Mechanism of scorpion
toxin-induced enzyme secretion in rat pancreas. Gastroenterology 80:
970 –973, 1981.
47. Gautam D, Han SJ, Heard TS, Cui Y, Miller G, Bloodworth L, Wess
J. Cholinergic stimulation of amylase secretion from pancreatic acinar
cells studied with muscarinic acetylcholine receptor mutant mice. J
Pharmacol Exp Ther 313: 995–1002, 2005.
48. Gioiello A, Cerra B, Mostarda S, Guercini C, Pellicciari R, Macchi-
arulo A. Bile acid derivatives as ligands of the farnesoid x receptor:
molecular determinants for bile acid binding and receptor modulation.
Curr Top Med Chem 14: 2159 –2174, 2014.
49. Goldberg RC, Chaikoff IL, Dodge AH. Destruction of pancreatic
acinar tissue by DL-ethionine. Proc Soc Exp Biol Med 74: 869 –872,
1950.
50. Gomez-Perez Y, Gianotti M, Llado I, Proenza AM. Sex-dependent
effects of high-fat-diet feeding on rat pancreas oxidative stress. Pancreas
40: 682–688, 2011.
51. Gomez RM, Lascano EF, Berria MI. Murine acinar pancreatitis pre-
ceding necrotizing myocarditis after Coxsackievirus B3 inoculation. J
Med Virol 35: 71–75, 1991.
52. Goto M, Nakano I, Kimura T, Miyahara T, Kinjo M, Nawata H. New
chronic pancreatitis model with diabetes induced by cerulein plus stress
in rats. Dig Dis Sci 40: 2356 –2363, 1995.
53. Gress T, Muller-Pillasch F, Elsasser HP, Bachem M, Ferrara C,
Weidenbach H, Lerch M, Adler G. Enhancement of transforming
growth factor beta 1 expression in the rat pancreas during regeneration
from caerulein-induced pancreatitis. Eur J Clin Invest 24: 679 –685,
1994.
54. Griffith WH, Wade NJ. Choline metabolism. I. The occurrence and
prevention of hemorrhagic degeneration in young rats on a low choline
diet. Nutrition classics from The Journal of Biological Chemistry 131:
567–577, 1937. Nutr Rev 32: 112–114, 1974.
55. Gukovskaya AS, Mouria M, Gukovsky I, Reyes CN, Kasho VN,
Faller LD, Pandol SJ. Ethanol metabolism and transcription factor
activation in pancreatic acinar cells in rats. Gastroenterology 122: 106 –
118, 2002.
56. Gukovskaya AS, Perkins P, Zaninovic V, Sandoval D, Rutherford R,
Fitzsimmons T, Pandol SJ, Poucell-Hatton S. Mechanisms of cell
death after pancreatic duct obstruction in the opossum and the rat.
Gastroenterology 110: 875–884, 1996.
57. Gukovsky I, Lugea A, Shahsahebi M, Cheng JH, Hong PP, Jung YJ,
Deng QG, French BA, Lungo W, French SW, Tsukamoto H, Pandol
SJ. A rat model reproducing key pathological responses of alcoholic
chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 294:
G68 –G79, 2008.
58. Gurda GT, Crozier SJ, Ji B, Ernst SA, Logsdon CD, Rothermel BA,
Williams JA. Regulator of calcineurin 1 controls growth plasticity of
adult pancreas. Gastroenterology 139: 609 –619, 619.e1–e6, 2010.
59. Hai Z, Jiang C, Zhang J, Wang L, Fang K. Relationship between
carbachol hyperstimulation-induced pancreatic acinar cellular injury and
trypsinogen or NF-kappaB activation in rats in vitro. J Huazhong Univ
Sci Technolog Med Sci 26: 34 –35, 58, 2006.
60. Harb JM, Burch GE. Spherical aggregates of coxsackie B4 virus
particles in mouse pancreas. Beitr Pathol 156: 122–127, 1975.

PANCREATITIS MODELS
61. Hardman J, Jamdar S, Shields C, McMahon R, Redmond HP,
Siriwardena AK. Intravenous selenium modulates L-arginine-induced
experimental acute pancreatitis. JOP 6: 431–437, 2005.
62. Hardman J, Shields C, Schofield D, McMahon R, Redmond HP,
Siriwardena AK. Intravenous antioxidant modulation of end-organ
damage in L-arginine-induced experimental acute pancreatitis. Pancrea-
tology 5: 380 –386, 2005.
63. Hartwig W, Werner J, Ryschich E, Mayer H, Schmidt J, Gebhard
MM, Herfarth C, Klar E. Cigarette smoke enhances ethanol-induced
pancreatic injury. Pancreas 21: 272–278, 2000.
64. Hietaranta AJ, Saluja AK, Bhagat L, Singh VP, Song AM, Steer ML.
Relationship between NF-kappaB and trypsinogen activation in rat pan-
creas after supramaximal caerulein stimulation. Biochem Biophys Res
Commun 280: 388 –395, 2001.
65. Hofmann AF, Small DM. Detergent properties of bile salts: correlation
with physiological function. Annu Rev Med 18: 333–376, 1967.
66. Huang H, Liu Y, Daniluk J, Gaiser S, Chu J, Wang H, Li ZS,
Logsdon CD, Ji B. Activation of nuclear factor-kappaB in acinar cells
increases the severity of pancreatitis in mice. Gastroenterology 144:
202–210, 2013.
67. Huang W, Booth DM, Cane MC, Chvanov M, Javed MA, Elliott VL,
Armstrong JA, Dingsdale H, Cash N, Li Y, Greenhalf W, Mukherjee
R, Kaphalia BS, Jaffar M, Petersen OH, Tepikin AV, Sutton R,
Criddle DN. Fatty acid ethyl ester synthase inhibition ameliorates
ethanol-induced Ca2⫹-dependent mitochondrial dysfunction and acute
pancreatitis. Gut 63: 1313–1324, 2014.
68. Hyun JJ, Lee HS. Experimental models of pancreatitis. Clin Endosc 47:
212–216, 2014.
69. Ida S, Ohmuraya M, Hirota M, Ozaki N, Hiramatsu S, Uehara H,
Takamori H, Araki K, Baba H, Yamamura K. Chronic pancreatitis in
mice by treatment with choline-deficient ethionine-supplemented diet.
Exp Anim 59: 421–429, 2010.
70. Jerrells TR, Chapman N, Clemens DL. Animal model of alcoholic
pancreatitis: role of viral infections. Pancreas 27: 301–304, 2003.
71. Ji B, Bi Y, Simeone D, Mortensen RM, Logsdon CD. Human pancre-
atic acinar cells lack functional responses to cholecystokinin and gastrin.
Gastroenterology 121: 1380 –1390, 2001.
72. Ji B, Kopin AS, Logsdon CD. Species differences between rat and
mouse CCKA receptors determine the divergent acinar cell response to
the cholecystokinin analog JMV-180. J Biol Chem 275: 19115–19120,
2000.
73. Ji B, Logsdon CD. Digesting new information about the role of trypsin
in pancreatitis. Gastroenterology 141: 1972–1975, 2011.
74. Ji B, Tsou L, Wang H, Gaiser S, Chang DZ, Daniluk J, Bi Y, Grote
T, Longnecker DS, Logsdon CD. Ras activity levels control the devel-
opment of pancreatic diseases. Gastroenterology 137: 1072–1082,
1082.e1– e6, 2009.
75. Jin S, Orabi AI, Le T, Javed TA, Sah S, Eisses JF, Bottino R,
Molkentin JD, Husain SZ. Exposure to radiocontrast agents induces
pancreatic inflammation by activation of nuclear factor-kappab, calcium
signaling, and calcineurin. Gastroenterology 149: 753–764.e11, 2015.
76. Johnson LR, Stening GF, Grossman MI. Effect of sulfation on the
gastrointestinal actions of caerulein. Gastroenterology 58: 208 –216,
1970.
77. Jupp J, Fine D, Johnson CD. The epidemiology and socioeconomic
impact of chronic pancreatitis. Best Pract Res Clin Gastroenterol 24:
219 –231, 2010.
78. Kahl S, Mayer JM. Update on experimental acute pancreatitis. Minerva
Gastroenterol Dietol 58: 355–363, 2012.
79. Kaiser AM, Saluja AK, Sengupta A, Saluja M, Steer ML. Relation-
ship between severity, necrosis, and apoptosis in five models of experi-
mental acute pancreatitis. Am J Physiol Cell Physiol 269: C1295–C1304,
1995.
80. Kambhampati S, Park W, Habtezion A. Pharmacologic therapy for
acute pancreatitis. World J Gastroenterol 20: 16868 –16880, 2014.
81. Kirkbride MB. The islands of Langerhans after ligation of the pancre-
atic ducts. J Exp Med 15: 101–105, 1912.
82. Kirkland JG, Godfrey CB, Garrett R, Kakar S, Yeh BM, Corvera
CU. Reversible surgical model of biliary inflammation and obstructive
jaundice in mice. J Surg Res 164: 221–227, 2010.
83. Kono H, Nakagami M, Rusyn I, Connor HD, Stefanovic B, Brenner
DA, Mason RP, Arteel GE, Thurman RG. Development of an animal
model of chronic alcohol-induced pancreatitis in the rat. Am J Physiol
Gastrointest Liver Physiol 280: G1178 –G1186, 2001.
AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00372.2015 • www.ajpgi.org
Downloaded from journals.physiology.org/journal/ajpgi at Univ De Antioquia (200.024.017.012) on February 21, 2021.
Themes
G353
84. Lampel M, Kern HF. Acute interstitial pancreatitis in the rat induced by
excessive doses of a pancreatic secretagogue. Virchows Arch A Pathol
Anat Histol 373: 97–117, 1977.
85. Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet 386:
85–96, 2015.
86. Lansdown AB. Pathological changes in the pancreas of mice following
infection with Coxsackie B viruses. Br J Exp Pathol 57: 331–338, 1976.
87. Laukkarinen JM, Van Acker GJ, Weiss ER, Steer ML, Perides G. A
mouse model of acute biliary pancreatitis induced by retrograde pancre-
atic duct infusion of Na-taurocholate. Gut 56: 1590 –1598, 2007.
88. Le Page SL, Bi Y, Williams JA. CCK-A receptor activates RhoA
through G alpha 12/13 in NIH3T3 cells. Am J Physiol Cell Physiol 285:
C1197–C1206, 2003.
89. Le T, Eisses JF, Lemon KL, Ozolek JA, Pociask DA, Orabi AI,
Husain SZ. Intraductal infusion of taurocholate followed by distal
common bile duct ligation leads to a severe necrotic model of pancreatitis
in mice. Pancreas 44: 493–499, 2015.
90. Lee AT, Xu Z, Pothula SP, Patel MB, Pirola RC, Wilson JS, Apte
MV. Alcohol and cigarette smoke components activate human pancreatic
stellate cells: implications for the progression of chronic pancreatitis.
Alcohol Clin Exp Res 39: 2123–2133, 2015.
91. Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis.
Gastroenterology 144: 1180 –1193, 2013.
92. Lerch MM, Saluja AK, Dawra R, Ramarao P, Saluja M, Steer ML.
Acute necrotizing pancreatitis in the opossum: earliest morphological
changes involve acinar cells. Gastroenterology 103: 205–213, 1992.
93. Lerch MM, Saluja AK, Runzi M, Dawra R, Steer ML. Luminal
endocytosis and intracellular targeting by acinar cells during early biliary
pancreatitis in the opossum. J Clin Invest 95: 2222–2231, 1995.
94. Li J, Guo M, Hu B, Liu R, Wang R, Tang C. Does chronic ethanol
intake cause chronic pancreatitis?: evidence and mechanism. Pancreas
37: 189 –195, 2008.
95. Li Y, Owyang C. Vagal afferent pathway mediates physiological action
of cholecystokinin on pancreatic enzyme secretion. J Clin Invest 92:
418 –424, 1993.
96. Lieber CS, DeCarli LM. Alcoholic liver injury: experimental models in
rats and baboons. Adv Exp Med Biol 59: 379 –393, 1975.
97. Logsdon CD, Ji B. Ras activity in acinar cells links chronic pancreatitis
and pancreatic cancer. Clin Gastroenterol Hepatol 7: S40 –S43, 2009.
98. Logsdon CD, Ji B. The role of protein synthesis and digestive enzymes
in acinar cell injury. Nat Rev Gastroenterol Hepatol 10: 362–370, 2013.
99. Lombardi AV. A factor analysis of morphogenetic fields in the human
dentition. Am J Phys Anthropol 42: 99 –104, 1975.
100. Lombardi B, Estes LW, Longnecker DS. Acute hemorrhagic pancre-
atitis (massive necrosis) with fat necrosis induced in mice by DL-
ethionine fed with a choline-deficient diet. Am J Pathol 79: 465–480,
1975.
101. Lombardi B, Rao NK. Acute hemorrhagic pancreatic necrosis in mice.
Influence of the age and sex of the animals and of dietary ethionine,
choline, methionine, and adenine sulfate. Am J Pathol 81: 87–100, 1975.
102. Lugea A, Gong J, Nguyen J, Nieto J, French SW, Pandol SJ.
Cholinergic mediation of alcohol-induced experimental pancreatitis. Al-
cohol Clin Exp Res 34: 1768 –1781, 2010.
103. Lugea A, Tischler D, Nguyen J, Gong J, Gukovsky I, French SW,
Gorelick FS, Pandol SJ. Adaptive unfolded protein response attenuates
alcohol-induced pancreatic damage. Gastroenterology 140: 987–997,
2011.
104. Machado JC, da Silveira Filho JF. [Induction of acute hemorrhagic
pancreatitis in dogs by scorpion venom from T serrulatus]. Mem Inst
Butantan 40 – 41: 1–9, 1976.
105. Majumder S, Chari ST. Chronic pancreatitis. Lancet 387: 1957–1966,
2016.
106. Maki T, Kakizaki G, Sato T, Saito Y, Onuma T. Experimental study
on alcoholic pancreatitis. Tohoku J Exp Med 92: 415–421, 1967.
107. Maleth J, Balazs A, Pallagi P, Balla Z, Kui B, Katona M, Judak L,
Nemeth I, Kemeny LV, Rakonczay Z Jr, Venglovecz V, Foldesi I,
Peto Z, Somoracz A, Borka K, Perdomo D, Lukacs GL, Gray MA,
Monterisi S, Zaccolo M, Sendler M, Mayerle J, Kuhn JP, Lerch MM,
Sahin-Toth M, Hegyi P. Alcohol disrupts levels and function of the
cystic fibrosis transmembrane conductance regulator to promote devel-
opment of pancreatitis. Gastroenterology 148: 427–439.e16, 2015.
108. Malfertheiner P, Schutte K. Smoking—a trigger for chronic inflamma-
tion and cancer development in the pancreas. Am J Gastroenterol 101:
160 –162, 2006.
Themes
G354 PANCREATITIS MODELS
109. Masamune A, Kikuta K, Watanabe T, Satoh K, Satoh A, Shimose-
gawa T. Pancreatic stellate cells express Toll-like receptors. J Gastro-
enterol 43: 352–362, 2008.
110. Mizunuma T, Kawamura S, Kishino Y. Effects of injecting excess
arginine on rat pancreas. J Nutr 114: 467–471, 1984.
111. Mooren F, Hlouschek V, Finkes T, Turi S, Weber IA, Singh J,
Domschke W, Schnekenburger J, Kruger B, Lerch MM. Early
changes in pancreatic acinar cell calcium signaling after pancreatic duct
obstruction. J Biol Chem 278: 9361–9369, 2003.
111a.Mouret J. Contribution a l’étude des cellules glandulaires (pancreas). J
Anat Physiol 31: 221–236, 1895.
112. Muili KA, Wang D, Orabi AI, Sarwar S, Luo Y, Javed TA, Eisses JF,
Mahmood SM, Jin S, Singh VP, Ananthanaravanan M, Perides G,
Williams JA, Molkentin JD, Husain SZ. Bile acids induce pancreatic
acinar cell injury and pancreatitis by activating calcineurin. J Biol Chem
288: 570 –580, 2013.
113. Muller S, Kaiser H, Kruger B, Fitzner B, Lange F, Bock CN, Nizze
H, Ibrahim SM, Fuellen G, Wolkenhauer O, Jaster R. Age-dependent
effects of UCP2 deficiency on experimental acute pancreatitis in mice.
PLoS One 9: e94494, 2014.
114. Murayama KM, Barent BL, Gruber M, Brooks A, Eliason S, Brunt
EM, Smith GS. Characterization of a novel model of pancreatic fibrosis
and acinar atrophy. J Gastrointest Surg 3: 418 –425, 1999.
115. Murtaugh LC, Keefe MD. Regeneration and repair of the exocrine
pancreas. Annu Rev Physiol 77: 229 –249, 2015.
116. Neuschwander-Tetri BA, Bridle KR, Wells LD, Marcu M, Ramm
GA. Repetitive acute pancreatic injury in the mouse induces procollagen
alpha1 (I) expression colocalized to pancreatic stellate cells. Lab Invest
80: 143–150, 2000.
117. Neuschwander-Tetri BA, Burton FR, Presti ME, Britton RS, Janney
CG, Garvin PR, Brunt EM, Galvin NJ, Poulos JE. Repetitive self-
limited acute pancreatitis induces pancreatic fibrogenesis in the mouse.
Dig Dis Sci 45: 665–674, 2000.
118. Nevalainen TJ, Aho HJ. Standards of morphological evaluation and
histological grading in experimental acute pancreatitis. Eur Surg Res 24,
Suppl 1: 14 –23, 1992.
119. Niederau C, Ferrell LD, Grendell JH. Caerulein-induced acute necro-
tizing pancreatitis in mice: protective effects of proglumide, benzotript,
and secretin. Gastroenterology 88: 1192–1204, 1985.
120. Niederau C, Luthen R, Niederau MC, Grendell JH, Ferrell LD.
Acute experimental hemorrhagic-necrotizing pancreatitis induced by
feeding a choline-deficient, ethionine-supplemented diet. Methodology
and standards. Eur Surg Res 24, Suppl 1: 40 –54, 1992.
121. Ohashi S, Nishio A, Nakamura H, Asada M, Tamaki H, Kawasaki K,
Fukui T, Yodoi J, Chiba T. Overexpression of redox-active protein
thioredoxin-1 prevents development of chronic pancreatitis in mice.
Antioxid Redox Signal 8: 1835–1845, 2006.
122. Ohshio G, Saluja A, Steer ML. Effects of short-term pancreatic duct
obstruction in rats. Gastroenterology 100: 196 –202, 1991.
123. Orabi AI, Shah AU, Muili K, Luo Y, Mahmood SM, Ahmad A, Reed
A, Husain SZ. Ethanol enhances carbachol-induced protease activation
and accelerates Ca2⫹ waves in isolated rat pancreatic acini. J Biol Chem
286: 14090 –14097, 2011.
124. Owyang C, Logsdon CD. New insights into neurohormonal regulation
of pancreatic secretion. Gastroenterology 127: 957–969, 2004.
125. Pandol SJ, Lugea A, Mareninova OA, Smoot D, Gorelick FS, Guk-
ovskaya AS, Gukovsky I. Investigating the pathobiology of alcoholic
pancreatitis. Alcohol Clin Exp Res 35: 830 –837, 2011.
126. Pandol SJ, Periskic S, Gukovsky I, Zaninovic V, Jung Y, Zong Y,
Solomon TE, Gukovskaya AS, Tsukamoto H. Ethanol diet increases
the sensitivity of rats to pancreatitis induced by cholecystokinin octapep-
tide. Gastroenterology 117: 706 –716, 1999.
127. Pandol SJ, Saluja AK, Imrie CW, Banks PA. Acute pancreatitis: bench
to the bedside. Gastroenterology 132: 1127–1151, 2007.
128. Parenti DM, Steinberg W, Kang P. Infectious causes of acute pancre-
atitis. Pancreas 13: 356 –371, 1996.
129. Peery AF, Dellon ES, Lund J, Crockett SD, McGowan CE, Bulsie-
wicz WJ, Gangarosa LM, Thiny MT, Stizenberg K, Morgan DR,
Ringel Y, Kim HP, Dibonaventura MD, Carroll CF, Allen JK, Cook
SF, Sandler RS, Kappelman MD, Shaheen NJ. Burden of gastrointes-
tinal disease in the United States: 2012 update. Gastroenterology 143:
1179 –1187.e1– e3, 2012.
AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00372.2015 • www.ajpgi.org
Downloaded from journals.physiology.org/journal/ajpgi at Univ De Antioquia (200.024.017.012) on February 21, 2021.
130. Perides G, Laukkarinen JM, Vassileva G, Steer ML. Biliary acute
pancreatitis in mice is mediated by the G-protein-coupled cell surface
bile acid receptor Gpbar1. Gastroenterology 138: 715–725, 2010.
131. Perides G, Tao X, West N, Sharma A, Steer ML. A mouse model of
ethanol dependent pancreatic fibrosis. Gut 54: 1461–1467, 2005.
132. Perides G, van Acker GJ, Laukkarinen JM, Steer ML. Experimental
acute biliary pancreatitis induced by retrograde infusion of bile acids into
the mouse pancreatic duct. Nat Protoc 5: 335–341, 2010.
133. Philip B, Roland CL, Daniluk J, Liu Y, Chatterjee D, Gomez SB, Ji
B, Huang H, Wang H, Fleming JB, Logsdon CD, Cruz-Monserrate
Z. A high-fat diet activates oncogenic Kras and COX2 to induce
development of pancreatic ductal adenocarcinoma in mice. Gastroenter-
ology 145: 1449 –1458, 2013.
134. Ponnappa BC, Marciniak R, Schneider T, Hoek JB, Rubin E. Ethanol
consumption and susceptibility of the pancreas to cerulein-induced pan-
creatitis. Pancreas 14: 150 –157, 1997.
135. Popper HL, Necheles H, Russell KC. Transition of pancreatic edema
into pancreatic necrosis. Surg Gynecol Obstet 87: 79 –82, 1948.
136. Rakonczay Z Jr, Hegyi P, Dosa S, Ivanyi B, Jarmay K, Biczo G,
Hracsko Z, Varga IS, Karg E, Kaszaki J, Varro A, Lonovics J, Boros
I, Gukovsky I, Gukovskaya AS, Pandol SJ, Takacs T. A new severe
acute necrotizing pancreatitis model induced by L-ornithine in rats. Crit
Care Med 36: 2117–2127, 2008.
137. Rao KN, Eagon PK, Okamura K, Van Thiel DH, Gavaler JS, Kelly
RH, Lombardi B. Acute hemorrhagic pancreatic necrosis in mice.
Induction in male mice treated with estradiol. Am J Pathol 109: 8 –14,
1982.
138. Rao KN, Tuma J, Lombardi B. Acute hemorrhagic pancreatic necrosis
in mice. Intraparenchymal activation of zymogens, and other enzyme
changes in pancreas and serum. Gastroenterology 70: 720 –726, 1976.
139. Robertson JS. The pancreatic lesion in adult mice, infected with a strain
of pleurodynia virus. I. Electron microscopical observations. Aust J Exp
Biol Med Sci 32: 393–409, 1954.
140. Romac JM, Shahid RA, Choi SS, Karaca GF, Westphalen CB, Wang
TC, Liddle RA. Pancreatic secretory trypsin inhibitor I reduces the
severity of chronic pancreatitis in mice overexpressing interleukin-1␤ in
the pancreas. Am J Physiol Gastrointest Liver Physiol 302: G535–G541,
2012.
141. Sah RP, Dudeja V, Dawra RK, Saluja AK. Cerulein-induced chronic
pancreatitis does not require intra-acinar activation of trypsinogen in
mice. Gastroenterology 144: 1076 –1085.e2, 2013.
142. Sah RP, Garg P, Saluja AK. Pathogenic mechanisms of acute pancre-
atitis. Curr Opin Gastroenterol 28: 507–515, 2012.
143. Saluja AK, Dudeja V. Relevance of animal models of pancreatic cancer
and pancreatitis to human disease. Gastroenterology 144: 1194 –1198,
2013.
144. Sarles H, Lebreuil G, Tasso F, Figarella C, Clemente F, Devaux MA,
Fagonde B, Payan H. A comparison of alcoholic pancreatitis in rat and
man. Gut 12: 377–388, 1971.
145. Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Mandavilli
U, Knoefel WT, Warshaw AL. A better model of acute pancreatitis for
evaluating therapy. Ann Surg 215: 44 –56, 1992.
146. Sendler M, Beyer G, Mahajan UM, Kauschke V, Maertin S, Schur-
mann C, Homuth G, Volker U, Volzke H, Halangk W, Wartmann T,
Weiss FU, Hegyi P, Lerch MM, Mayerle J. Complement component 5
mediates development of fibrosis, via activation of stellate cells, in 2
mouse models of chronic pancreatitis. Gastroenterology 149: 765–
776.e10, 2015.
147. Senninger N, Moody FG, Coelho JC, Van Buren DH. The role of
biliary obstruction in the pathogenesis of acute pancreatitis in the opos-
sum. Surgery 99: 688 –693, 1986.
148. Shaheen NJ, Hansen RA, Morgan DR, Gangarosa LM, Ringel Y,
Thiny MT, Russo MW, Sandler RS. The burden of gastrointestinal and
liver diseases, 2006. Am J Gastroenterol 101: 2128 –2138, 2006.
149. Singh S, Bhardwaj U, Verma SK, Bhalla A, Gill K. Hyperamylasemia
and acute pancreatitis following anticholinesterase poisoning. Hum Exp
Toxicol 26: 467–471, 2007.
150. Stumpf F, Algul H, Thoeringer CK, Schmid RM, Wolf E, Schneider
MR, Dahlhoff M. Metamizol relieves pain without interfering with
cerulein-induced acute pancreatitis in mice. Pancreas 45: 572–578, 2016.
151. Takacs T, Czako L, Jarmay K, Farkas G Jr, Mandi Y, Lonovics J.
Cytokine level changes in L-arginine-induced acute pancreatitis in rat.
Acta Physiol Hung 84: 147–156, 1996.

PANCREATITIS MODELS
152. Takacs T, Czako L, Morschl E, Laszlo F, Tiszlavicz L, Rakonczay Z
Jr, Lonovics J. The role of nitric oxide in edema formation in L-arginine-
induced acute pancreatitis. Pancreas 25: 277–282, 2002.
153. Takacs T, Farkas G Jr, Czako L, Jarmay K, Mandi Y, Lonovics J.
Time-course changes in serum cytokine levels in two experimental acute
pancreatitis models in rats. Res Exp Med (Berl) 196: 153–161, 1996.
154. Tani S, Itoh H, Okabayashi Y, Nakamura T, Fujii M, Fujisawa T,
Koide M, Otsuki M. New model of acute necrotizing pancreatitis
induced by excessive doses of arginine in rats. Dig Dis Sci 35: 367–374,
1990.
155. Tardini A, Anversa P, Bordi C, Bertaccini G, Impicciatore M.
Ultrastructural and biochemical changes after marked caerulein stimula-
tion of the exocrine pancreas in the dog. Am J Pathol 62: 35–56, 1971.
156. Terry TR, Grant DA, Hermon-Taylor J. Intraduct enterokinase is
lethal in rats with experimental bile-salt pancreatitis. Br J Surg 74:
40 –43, 1987.
157. Thrower EC, Gorelick FS, Husain SZ. Molecular and cellular mech-
anisms of pancreatic injury. Curr Opin Gastroenterol 26: 484 –489,
2010.
158. Treiber M, Neuhofer P, Anetsberger E, Einwachter H, Lesina M,
Rickmann M, Liang S, Kehl T, Nakhai H, Schmid RM, Algul H.
Myeloid, but not pancreatic, RelA/p65 is required for fibrosis in a mouse
model of chronic pancreatitis. Gastroenterology 141: 1473–1485,
1485.e1– e7, 2011.
159. Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: an update. J
Clin Gastroenterol 39: 709 –716, 2005.
160. Tsukamoto H, Towner SJ, Yu GS, French SW. Potentiation of
ethanol-induced pancreatic injury by dietary fat. Induction of chronic
pancreatitis by alcohol in rats. Am J Pathol 131: 246 –257, 1988.
161. Vaquero E, Molero X, Tian X, Salas A, Malagelada JR. Myofibroblast
proliferation, fibrosis, and defective pancreatic repair induced by cyclo-
sporin in rats. Gut 45: 269 –277, 1999.
162. Volzke H, Baumeister SE, Alte D, Hoffmann W, Schwahn C, Simon
P, John U, Lerch MM. Independent risk factors for gallstone formation
in a region with high cholelithiasis prevalence. Digestion 71: 97–105,
2005.
163. Vonlaufen A, Phillips PA, Xu Z, Zhang X, Yang L, Pirola RC,
Wilson JS, Apte MV. Withdrawal of alcohol promotes regression while
continued alcohol intake promotes persistence of LPS-induced pancreatic
injury in alcohol-fed rats. Gut 60: 238 –246, 2011.
164. Vonlaufen A, Xu Z, Daniel B, Kumar RK, Pirola R, Wilson J, Apte
MV. Bacterial endotoxin: a trigger factor for alcoholic pancreatitis?
Evidence from a novel, physiologically relevant animal model. Gastro-
enterology 133: 1293–1303, 2007.
165. Vuorinen T, Kallajoki M, Hyypia T, Vainionpaa R. Coxsackievirus
B3-induced acute pancreatitis: analysis of histopathological and viral
parameters in a mouse model. Br J Exp Pathol 70: 395–403, 1989.
166. Wachstein M, Meisel E. Equal effectiveness of L and D-ethionine in
producing tissue damage in rats and mice. Proc Soc Exp Biol Med 82:
70 –72, 1953.
167. Walker NI. Ultrastructure of the rat pancreas after experimental duct
ligation. I. The role of apoptosis and intraepithelial macrophages in
acinar cell deletion. Am J Pathol 126: 439 –451, 1987.
168. Watanabe S, Abe K, Anbo Y, Katoh H. Changes in the mouse exocrine
pancreas after pancreatic duct ligation: a qualitative and quantitative
histological study. Arch Histol Cytol 58: 365–374, 1995.
AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00372.2015 • www.ajpgi.org
Downloaded from journals.physiology.org/journal/ajpgi at Univ De Antioquia (200.024.017.012) on February 21, 2021.
Themes
G355
169. Weaver C, Bishop AE, Polak JM. Pancreatic changes elicited by
chronic administration of excess L-arginine. Exp Mol Pathol 60: 71–87,
1994.
170. Wen L, Voronina S, Javed MA, Awais M, Szatmary P, Latawiec D,
Chvanov M, Collier D, Huang W, Barrett J, Begg M, Stauderman K,
Roos J, Grigoryev S, Ramos S, Rogers E, Whitten J, Velicelebi G,
Dunn M, Tepikin AV, Criddle DN, Sutton R. Inhibitors of ORAI1
prevent cytosolic calcium-associated injury of human pancreatic acinar
cells and acute pancreatitis in 3 mouse models. Gastroenterology 149:
481–492.e7, 2015.
171. Whitcomb DC. Mechanisms of disease: advances in understanding the
mechanisms leading to chronic pancreatitis. Nat Clin Pract Gastroen-
terol Hepatol 1: 46 –52, 2004.
172. Willemer S, Elsasser HP, Adler G. Hormone-induced pancreatitis. Eur
Surg Res 24, Suppl 1: 29 –39, 1992.
173. Williams JA, Krawitz B, Hou Y. Caerulein. In: Pancreapedia: Exo-
crine Pancreas Knowledge Base. doi: 10.3998/panc.2014.15, 2014.
174. Williams JA, Korc M, Dormer RL. Action of secretagogues on a new
preparation of functionally intact, isolated pancreatic acini. Am J Physiol
Endocrinol Metab Gastrointest Physiol 235: E517–E524, 1978.
175. Williams JA, Sans MD, Tashiro M, Schafer C, Bragado MJ, Dab-
rowski A. Cholecystokinin activates a variety of intracellular signal
transduction mechanisms in rodent pancreatic acinar cells. Pharmacol
Toxicol 91: 297–303, 2002.
176. Wittel UA, Wiech T, Chakraborty S, Boss B, Lauch R, Batra SK,
Hopt UT. Taurocholate-induced pancreatitis: a model of severe necro-
tizing pancreatitis in mice. Pancreas 36: e9 –e21, 2008.
177. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancre-
atic cancer. Gastroenterology 144: 1252–1261, 2013.
178. Yadav D, Timmons L, Benson JT, Dierkhising RA, Chari ST.
Incidence, prevalence, and survival of chronic pancreatitis: a population-
based study. Am J Gastroenterol 106: 2192–2199, 2011.
179. Yadav D, Whitcomb DC. The role of alcohol and smoking in pancre-
atitis. Nat Rev Gastroenterol Hepatol 7: 131–145, 2010.
180. Yamaguchi T, Kihara Y, Taguchi M, Nagashio Y, Tashiro M,
Nakamura H, Otsuki M. Persistent destruction of the basement mem-
brane of the pancreatic duct contributes to progressive acinar atrophy in
rats with experimentally induced pancreatitis. Pancreas 31: 365–372,
2005.
181. Zambirinis CP, Pushalkar S, Saxena D, Miller G. Pancreatic cancer,
inflammation, and microbiome. Cancer J 20: 195–202, 2014.
182. Zhang J, Rouse RL. Histopathology and pathogenesis of caerulein-,
duct ligation-, and arginine-induced acute pancreatitis in Sprague-Daw-
ley rats and C57BL6 mice. Histol Histopathol 29: 1135–1152, 2014.
183. Zhao HF, Ito T, Gibo J, Kawabe K, Oono T, Kaku T, Arita Y, Zhao
QW, Usui M, Egashira K, Nawata H. Anti-monocyte chemoattractant
protein 1 gene therapy attenuates experimental chronic pancreatitis in-
duced by dibutyltin dichloride in rats. Gut 54: 1759 –1767, 2005.
184. Zhao JB, Liao DH, Nissen TD. Animal models of pancreatitis: can it be
translated to human pain study? World J Gastroenterol 19: 7222–7230,
2013.
185. Zheng H, Chen D, Zhang J, Tian Y. Involvement of M3 cholinergic
receptor signal transduction pathway in regulation of the expression of
chemokine MOB-1, MCP-1 genes in pancreatic acinar cells. J Huazhong
Univ Sci Technolog Med Sci 24: 140 –143, 157, 2004.