The Exocrine Pancreas Biology and Toxicology

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The Exocrine Pancreas Biology and Toxicology

• Richard H. Hinton
• School of Biomedical and Molecular Studies
• University of Surrey

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THE PANCREAS

• The pancreas forms from buds growing out from the
  primitive gut. In mammals it contains two
  distinct areas, the exocrine pancreas, producing
  digestive enzymes, and the endocrine pancreas
  (Islets of Langerhans), producing insulin etc.
  Both exocrine and endocrine cells have the same
  embryonic origen.We shall only consider the
  former.

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More anatomy

• The basic secretory unit of the pancreas is the
  acinus which is a small sack of epithelial cells
• The gross structure varies between species. It
  is spread diffusely through the me senteries in
  rabbits, is compact in hamsters, dogs and
  primates and intermediate in rats and mice.
  These differences are reflected in the
  connections between the pancreas and the gut. In
  species, like humans, with a compact pancreas
  there is a single extrapancreatic duct whereas in
  rats a large number of small ducts leave the
  pancreas and fuse with either the wall of the
  duodenum and jejunum or with the bile duct

• The old model of the pancreas envisaged the acini
  as hanging on the ducts like a bunch of grapes.
  The secretion of the pancreatic cells passes in
  to the lumen of the acinus and from there to
  ducts. In some sections of the pancreas duct
  cells are seen through the opening. These were
  known as centriacinar cells, but it is now known
  they are perfectly ordinary duct cells

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Pancreatic ducts
Intercalated ducts receive secretions from acini.
They have flattened cuboidal epithelium that
extends up into the lumen of the acinus to form
what are called centroacinar cells. Intralobular
ducts have a classical cuboidal epithelium and,
as the name implies, are seen within lobules.
They receive secretions from intercalated ducts.
Interlobular ducts are found between lobules,
within the connective tissue septae which also
carries branches of the pancreatic artery and
veuin. They vary considerably in size. The
smaller forms have a cuboidal epithelium, while a
columnar epithelium lines the larger ducts.
Intralobular ducts transmit secretions from
intralobular ducts to the major pancreatic duct.
The main pancreatic duct received secretion from
interlobular ducts and penetrates through the
wall of the duodenum. In some species, including
man, the pancreatic duct joins the bile duct
prior to entering the intestine. From
http//arbl.cvmbs.colostate.edu/hbooks/pathphys/di
gestion /pancreas/histo_exo.html
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Intra and extralobular ducts
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Is there any relation between the endocrine and
exocrine pancreas

• It has been suggested that some arterioles enter
  into capillaries in the islets and pass from
  there into the exocrine tissue before emptying
  into veins.
• It has been reported that the apparent activity
  of peri-insular acini is greater than that of the
  bulk of the pancreas.
• The pancreatic acinar cells have receptors for
  somatostatin which is made by the delta cells of
  the islets

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Cells of the exocrine pancreas

• The acinar cell is highly polarised . The
  nucleus lies towards the base of the cell and is
  surrounded by masses of rough endoplasmic
  reticulum in which mitochondria are embedded.
  Approximately half way down is a large golgi
  apparatus. On the apical side are large numbers
  of secretion granules.
• Drug metabolising enzymes including CYP1A1 and
  CYP2E1 are present and inducible
• Only microperoxisomes are present and these are
  not inducible.
• There is clearly vesicular traffic at the basal
  face of the cell. What is going on is obscure

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Acini and inter-acinar connective tissue
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• Pancreatic acinar cells in rats

And in guinea pigs
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Pancreatic ductular cells

• The pancreatic ductular cells are small rather
  anonymous cells with the marked interdigitation
  of the lateral surfaces seen in cells exposed on
  their apical surface to corrosive fluids. They
  secrete an alkali-rich fluid under the control of
  secretin
• Goblet cells are found along the larger ducts and
  secrete mucus

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Control of Pancreatic Secretion

• The major controller of pancreatic secretion is
  the hormone cholecystokinin(previously called
  pancreozymin). CCK is released from
  neuroendocrine cells in the duodenum in response
  to the presence of food in the intestine and
  causes discharge of secretion granules which, in
  turn, stimulates synthesis of new enzyme. Other
  gut hormones such as bombesin (GRP) may be
  involved
• Somatostatin inhibits synthesis and discharge of
  digestive enzymes from he pancreas
• Receptors for EGF are found on the acinar cell
  surface

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Nervous control of the pancreas

• The pancreas is innervated by branches of the
  vagus nerve. Nerve ending are found associated
  with acinar cells and gap junctions spread the
  signal, probably provided by the pyloric
  sphincter. This is believed to play a minor
  role, as compared to CCK, in stimulation of
  discharge from the pancreas
• Sympathetic fibers also innervate the pancreas,
  their role is not known

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Chemically-induced damage to the pancreas

• The pancreas is not a common target for chemical
  toxins.
• The model system for pancreatic damage is copper
  deficiency. The reason for this is not
  understood/ About 10 of chronic alcoholics will
  develop chronic acridities. In animals a
  choline-deficient diet combined with thiamine
  also produces damage
• Usually minor changes are found with a range of
  other compounds

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Pancreatic cancer in humans

• Cancer of the exocrine pancreas is one of the
  top ten cancers in western countries. The
  tumour is symptom less until quite large.
  Treatment is palliative, attempt at cure would
  induce acute pancreatitis. the 5 year survival
  is less than 2
• The morphology may be ductular (most common),
  acinar or mixed
• Most tumours arise in the head of the gland and
  it has been suggested that reflux of bile may
  contribute

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Nutrition and human pancreatic carcinomas. DoH
report

• There is moderately consistent evidence that
  higher total and red meat consumption and high
  levels of coffee consumption are associated with
  increased risk of pancreatic cancer.
• The evidence for an association with total fat
  and fatty acid intakes is insufficient to draw
  conclusions
• There is moderately consistent evidence that
  higher intakes of fruit and vegetables, vitamin C
  and dietary fibre are associated with lower risk
  of pancreatic cancer but the evidence for intakes
  of b-carotene is inconsistent

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Experimental Pancreatic Carcinogenesis

• Cancer of the pancreas can be induced both by
  genotoxic and non-genotoxic agents
• The best studied genotoxic carcinogens are a very
  specific group of nitrosamines in hamsters but
  azaserine is also widely used as a model. There
  are major differences between species and the
  tumours vary in morphology - but morphology of
  large tumours can be very misleading

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Progression of changes

• The first sign in the pancreas of tumours are
  foci of altered cells. These may be basophilic
  or acidophilic. The latter are believed to be on
  the main path to carcinogenesis, the etiology of
  the first (found only with genotoxic agents is
  unknown)

Progression as with liver is though hyperplastic
nodules to adenomas, carcinomas in situ and
adenocarcinomas. Focus in focus type lesions
give evidence of progression
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Non-Genotoxic pancreatic carcinogens

• There are two proven groups
• 1) Trypsin inhibitors. The action of these is
  well characterised
• 2) Agents which cause peroxisome proliferation
  in the liver (only the most potent induce
  pancreatic cancer)
• 4) While sex hormones are not carcinogenic on
  their own there is a possible interaction with
  oestrogens as males get more spontaneous cancers
  than females and, following carcinogen treatment
  oestradiol and surgical castration reduce yield

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Cells added to the pancreas in response to a
chemical may removed on withdrawal
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Progression in Rats receiving raw soya flour

• 24-48h Increase in DNA synthesis
• 1-7 days Pancreatic hypertrophy
• 24 weeks Atypical cell foci and nodules in
  pancreas
• 60 weeks Acinar cell adenomas in 80-100 of
  animals
• 90 weeks Acinar cell carcinoma in 10 of animals
• The lesions are fully reversible - feed 24 weeks,
  rest 36 weeks all foci and nodules have
  disappeared

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CCK and pancreatic tumours

• The role of cholecystokinin is to ensure that
  there are sufficient digestive enzymes to handle
  the food intake. It achieves this by both
  increasing synthetic activity in the short term
  and causing pancreatic enlargement in the long
  term
• Feeding trypsin inhibitors can be shown to
  increase CCK secretion
• Adding a CCK inhibitor stops this increase
• This argues that anti-trypsins are working via CCK

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How do peroxisome proliferators work ?

• Not by via peroxisomes, these dont alter in the
  pancreas
• Peroxisomes proliferators appear able to mimic
  fatty acids both on allosteric sites and on
  receptors
• The neuro-endocrine cells which secrete CCK sense
  the products of digestion eg fatty acids
• Hence the peroxisome proliferator may fool the
  cells into believing there is fat in the gut
• There is also now direct evidence that CCK
  antagonists inhibit pancreatic hyperplasia caused
  by peroxisome proliferators

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Are humans rats?

• This can be shown directly, Infusion of CCK or
  treatment with agents which increase CCK promotes
  the tumour formation in azaserine-treated rats
• So does a high fat diet
• A high fat diet is sufficient to increase tumour
  incidence in rats. This was noted by the NIH
  when they compared the incidence of pancreatic
  tumours in rats where corn oil had been used as
  the vehicle and those in which other vehicles
  were used.

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Pancreatic Metaplasia

• This is most readily observed in recovery from
  copper depletion.
• Rats fed copper deficient diets develop severe
  acinar cell atrophy, islets and ducts are not
  affected within 4 weeks
• Further copper deficiency results in total
  collapse of the pancreatic framework and
  proliferation of oval cells. These stain neither
  for acinar cell nor ductular enzymes and appear
  to be a stem cell population
• If rats are now re-fed a normal diet there is
  some regeneration of the acinar cells but up to
  60 of the pancreas may be occupied by hepatocytes

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Continued

• Hepatocytes formed from ductular cells retain
  gamma-glutamyl trans-peptidase, a ductular enzyme
  The hepatocytes are perfectly formed including
  bile canaliculi. They also make liver specific
  proteins and, when the animals is treated with
  clofibrate peroxisomes proliferate only in the
  hepatocytes In-situ hybridisation early in the
  recovery phase shows that albumin mRNA is
  synthesised both in the oval cells and in some
  ductular cells. There thus appears to be both
  de-novo differentiation and trans-differentiation.
  

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And yet more

• Foci of hepatocytes are seen in the pancreas of
  rats treated with certain peroxisome
  proliferators even though there is no damage.
• Liver-enriched transcription factors of the HNF
  and other families are induced in the pancreatic
  hepaocytes except for HNF-3 which is associated
  with terminal differentiation
• Foci of cells resembling pancreatic acinar cells
  have been observed in the livers of PCB-treated
  rats