Pancreatic Stellate Cells and Chronic

Raffaele Pezzilli
Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi Hospital.
Bologna, Italy
Chronic pancreatitis is a disease often
characterized by recurrent episodes of
abdominal pain accompanied by progressive
pancreatic exocrine and endocrine
insufficiency [1] and it sometimes requires
jaundice, duodenal stenosis, left-sided portal
hypertension, pseudocyst and mass formation,
and pancreatic carcinoma may occur as
complications of chronic pancreatitis. The
disease is frequently the result of chronic
alcohol abuse, even if other factors such as
genetic alterations, autoimmune disorders,
and obstructive disease of the biliary tract and
the pancreas may cause the disease [2].
Medical therapy is the treatment of choice for
most patients and it is based on substitutive
therapy for either exocrine or endocrine
insufficiency and on analgesics for pain
control. In the presence of intractable pain,
surgical management is the main option [3]
even if, in recent years, other therapeutic
options such as endoscopic therapy [4],
thoracoscopic splanchnicectomy [5], and
extracorporeal shockwave lithotripsy have
been applied in clinical practice [6].
From a pathological point of view, chronic
pancreatitis is characterized by irregular
sclerosis with destruction and loss of the
exocrine parenchyma, and complete
replacement of acinar, ductal and endocrine
tissue by fibrotic tissue. It has recently been
reported that acute alcoholic pancreatitis
develops in a pancreas already affected by
chronic pancreatitis [7].
In 1982, Watari et al. [8] reported the
presence of vitamin A-containing cells in the
vitamin A-fed rat pancreas. These were later
described and characterized as stellate cells in
the rat and the human pancreas [9, 10].
Pancreatic stellate cells are morphologically
similar to hepatic stellate cells. They bear
long cytoplasmic processes and are situated
close to the pancreatic acini. In the quiescent
state, these cells contain lipid droplets, store
vitamin A and express markers such as
desmin, glial fibrillary acidic protein, neural
cell adhesion molecule and neurotrophin
nerve growth factor just as hepatic stellate
cells do. Pancreatic stellate cells contain the
enzyme alcohol dehydrogenase [11] and,
when activated, they assume a myofibroblast-
like phenotype [12]. Activated pancreatic
stellate cells are characterized by the
disappearance of fat globules and the
expression of alpha-smooth muscle actin.
These cells have proliferative and migratory
[13, 14, 15] functions and they also synthesize
and secrete extracellular fibrous tissue matrix
proteins, matrix metalloproteinases and their
inhibitors [16]; it has also been demonstrated
that pancreatic stellate cells have phagocytic
activity [17]. Thus, the ability of pancreatic
stellate cells to synthesize as well as to
degrade extracellular matrix proteins suggests
their role in maintaining a normal pancreatic
architecture which can shift towards
fibrogenesis if the balance is altered. Ethanol,
acetaldehyde and oxidant stress are capable of
activating activate pancreatic stellate cells via

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JOP. Journal of the Pancreas - - Vol. 8, No. 2 - March 2007. [ISSN 1590-8577]
three mitogen-activated protein kinase
pathways [18], namely extracellular signal
kinase, p38 kinase and c-jun amino terminal
kinase [19, 20, 21], and ethanol and
acetaldehyde are also capable of activating
phosphatidylinositol 3-kinase and protein
kinase C [22]. On the other hand, extracellular
signal kinase activation occurs via a signal
transduction pathway which involves G-
protein Ras and serine threonine protein
kinase Raf-1 [23, 24]. The Ras superfamily G
modification involving isoprenylation, a
process which requires intermediate
substrates of cholesterol biosynthesis [25, 26]
which is regulated by HMG CoA reductase
[27]. The paracrine pro-fibrogenic effect of
TGF-beta on pancreatic stellate cells is
mediated via smad while the autocrine effect
is mediated through the extracellular signal
kinase pathway [28]; furthermore, the role of
receptor-gamma seems to be involved in the
activation of pancreatic stellate cells [29,30].
The major part of the studies published on
pancreatic stellate cells have been carried out
in experimental animals; thus, the study of
Suda et al. seems of particular interest
because it was performed on humans [31].
These authors investigated the distribution of
activated pancreatic stellate cells or
myofibroblasts using immunohistochemistry
and a computer-counting device in relation to
fibrogenesis in 24 patients with clinically
diagnosed chronic alcoholic pancreatitis. In
all cases, fibrosis was patchily distributed in
the perilobular or interlobular, areas
accompanied by a cirrhosis-like appearance; it
had extended into the intralobular area in
advanced cases. Seven patients had a massive
or confluent loss of exocrine tissue, resulting
in extensive interlobular fibrosis; the more
extensive the interlobular fibrosis, the smaller
the lobules. Immunoreactivity to alpha-
smooth muscle actin, a myofibroblast marker,
was found mostly in the same areas of the
fibrosis, mainly the interlobular, and less
often the periacinar, areas; the average
percentage area of perilobular myofibroblasts
was significantly higher than that of
periacinar myofibroblasts in 20 randomly
selected lobules; fibrosis also immunostained
positive for collagen types I and III. In
conclusion, this study carried out on humans,
further supports the hypothesis that the
fibrotic alterations in chronic alcoholic
pancreatitis are not due to recurrent episodes
of necrotizing pancreatitis but the disease is
due to a chronic stimulation of alcohol on
pancreatic stellate cells which play an
important role in pancreatic fibrogenesis.
Keywords Fibrosis; Pancreatitis, Alcoholic;
Pancreatitis, Chronic
Raffaele Pezzilli
Department of Digestive Diseases and
Internal Medicine
Sant’Orsola-Malpighi Hospital
Via Massarenti, 9
40138 Bologna
Phone: +39-051.636.4148
Fax: +39-051.636.4148
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