Signalopathies - Pancreatitis

Question 1

What is Pancreatitis?

Answer 1

= disease of the pancreas

= in which the proteases needed for digestion of food in gut are inappropriately activated inside the cell

= end up digesting the pancreas itself

Question 2

What is Acute Pancreatitis?

Answer 2

= initially caused by gallstones / alcohol

= 100 cases per 100,000

= symptoms: agonising pain, extensive pancreatic necrosis, multiple organ failure, prolonged hospitalisation

= 5% mortality rate

= causes severe disease in 20% of patients

Question 3

What is Chronic Pancreatitis?

Answer 3

= due to repeat attacks of acute pancreatitis

= linked to heavy alcohol consumption and smoking

= 50 cases per 100,000

= gives rise to pancreatic cancer
(3-4% patients survive beyond 5 years)

Question 4

What are Zymogens?

Answer 4

= inactive enzyme precursors (pro-enzymes)

= synthesised in pancreatic acinar cells (in ER)

= stored in membrane-bound granules (zymogen granules)

Pancreatitis
= follows the activation of trypsin (from zymogen trypsinogen) within acinar cells

Question 5

How does Ca2+ signalling work in pancreatic acinar cells?

Answer 5

= calcium released from intracellular stores in response to signal / stimulus

= can occur through activation of various receptors, including GPCRs and ion channels

= once released, binds to activate intracellular protein e.g. calmodulin and protein kinase C = activate downstream signalling pathway

CCK stimulates oscillations in Ca2+ conc. in apical region

Question 6

What happens when the pancreas is behaving normally?

Answer 6

1. Oscillations in cytoplasmic Ca2+ conc.
   = triggered by pM concentrations of CCK
   = then triggers fusion of zymogen granules with acinar cell plasma mebrane
2. Release of inactive trypsin into pancreatic duct

(3. Replenishment of Ca2+ stores)

4. Activation of trypsin by intestinal enteropeptidase enzyme
5. Protein digestion

CCK hyperstimulation
= stimulates sustained global increases in cytoplasmic calcium conc.

hyperstimulation-induced increases in Ca2+ also produces:
= fatty acids (palmitoleic acid - POA)
= and bile salts (taurolithocholic acid surface - TLC-S)
(as well as CCK)

Question 7

What happens when the pancreas misbehaves?

Answer 7

1. Sustained global increase in cytoplasmic Ca2+ conc
   = triggered by hyperstimulation
   (e.g. nM conc. of CCK, POA, TLC-S)
   = then trigger trypsin activation in zymogen granules within acinar cells
2. Digestion and destruction of ZG membrane, misshaped looking vacuoles
3. Digestion of acinar cells and surrounding tissues