The Exocrine Pancreas Biology and Toxicology

							The Exocrine Pancreas – Biology
       and Toxicology

            Richard H. Hinton
School of Biomedical and Molecular Studies
           University of Surrey
            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.
                            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
               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 veu=in. 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/digestion
/pancreas/histo_exo.html
Intra and extralobular ducts
 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
      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
Acini and inter-acinar connective
              tissue
             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
 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
 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
• The pancreas is not a            Chemically-
  common target for
  chemical toxins.              induced damage to
• The model system for
  pancreatic damage is             the pancreas
  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
    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
    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
       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
      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     Progression as with liver is
  path to carcinogenesis, the    though hyperplastic nodules
  etiology of the first (found   to adenomas, carcinomas in
  only with genotoxic agents     situ and adenocarcinomas.
  is unknown)                    “Focus in focus” type
                                 lesions give evidence of
                                 progression
       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
Cells added to the pancreas in
 response to a chemical may
   removed on withdrawal
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
    CCK and
                   • The role of cholecystokinin is to
pancreatic tumours   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
             How do “peroxisome
             proliferators” work ?
• Not by via peroxisomes, these don’t 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
            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.
          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
Hepatocytes” formed from ductular       Continued
  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.
                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