GIT - acute pancreatisis and cancer Flashcards
What are the exocrine functions of pancreas?
Secrete pancreatic juices and enzymes into duct system
Which cells perform exocrine function of pancreas?
Pancreatic Acinar cell - 80% mass
Duct cells!
What are the endocrine functions of the pancreas?
Secrete Insulin and glucagon
and satiety hormone too (ghrelin, somarostatin
Why are digestive enzymes stored in secretory granules?
To ensure they don’t become prematurely activate. They are stored in inactive form (zymogen)
What is a secretagogue?
Molecule that promotes cell to secrete hormone, neurotransmitter
What secretagogue stimulate PAC? What is their effect?
Ach for exocytosis of zymogen granules
CCK helps with pancreatic fluid secretion into duct
How do chloride channels act in PAC?
Calcium rise activates chloride channel on apical membrane allowing chloride to enter cell
On luminal side chloride aids paracellular transport or water and sodium due to its negative charge so fluid is secreted
What is function of duct cells ?
Secrete pancreatic juices and also secrete bicarbonate to control pH and neutralise the juices
Which hormone stimulate duct cell to secrete bicarbonate?
Secretin produced from S-cells in duodenum
Able to bind to GPCR receptor and leads to CFTR channel luminal side activation so bicarbonate released into luman
how can a rise in cytosolic calcium be buffered in PACs?
the mitochondria which can surround the granules in the cell is able to uptake calcium (temp) via the VDAC and mitch uniporter channel
what does the digestive juice secreted by PAC contain?
NaCl
water
digestive enzymes
bicarbonate
how can the PACs influence the duct cells?
PACs secrete chloride into lumen allowing HC03- secretion in duct cells
PAC secrete ATP, activating purinergic receptors on duct cell channels = stimulate ductal fluid + HC03- secretion
how can duct cells influence PAC?
if the luminal pH (controlled by duct cell) is dysregulated then a prolonged acidic environment would destroy PAC
(Seen in cystic fibrosis)
how do PAC and pancreatic B-cells differ?
in function - secrete pancreatic juices or hormones
in cell type - non excitable or excitable
how can insulin production be affected during acute pancreatitis?
during AP, PAC can rupture releasing trypsin
trypsin acts on B-cells and blocks insulin production
what are the 3 main causes of AP?
alcohol metabolites (POAEE)
bile acids
medicines like aspariganases (childhood Lymphoblastic leukemia)
but others like genetics, having hypercalcaemia
despite no cure for AP, how do some people recover?
need evidence for nfkb
the pancreas is able to REGENERATE!
also acinar-ductal metaplasia and remodelling of acinar cell genes to look like duct cell
so they don’t produce secretory enzymes and remain protected
what is the molecular end result of AP?
calcium overload leads to mitch dysfunction and loss of ATP production = necrosis
calcium overload activates digestive enzymes and the secretory granules burst open = autodigestion and inflammation
what is the key action of calmodulin?
calcium sensitive sensor and becomes activated when calcium binds to its EF hands
able to then downregulate activity of IP3R and RyR
why are SOCE channels a preferable target than IP3R in treating AP?
they are on cell membrane surface so drug doesn’t need to be permeable to pass the lipid bilayer
name 2 ways alcohol can be metabolised?
non-oxidative and oxidative routes
how can ox. alcohol metabolism lead to AP?
acetate is a product and can accumulate in mitch
this means mitch can’t function so no buffer for excess cytosolic calcium
how can non ox. alcohol metabolism lead to AP?
conversion of alcohol to FA-Ethyl-Esters which can deplete ER stores and affect ATP synthesis too
what is particularly dangerous about the alcohol metabolite POAEE?
POAEE can activate trypsinogen in granules very quickly
how can bile lead to AP?
bile can enter cell through various transporters and accumulate and block SERCA activity = Ca2+ excess
bile also activates GPCR on PAC -> deplete ER store
what cells make up 2% of pancreatic mass?
pancreatic stellate cells and immune cells which are organised very tightly together
both non-excitable cells
what are pancreatic stellate cells?
quiescent fibroblasts which help maitain structure and store lipid and vit A
in pathology contribute to wound healing, inflammation and eventual fibrosis
how are stellate cells implicated in cancer?
stellate cells form over 50% of tumoural stroma and support tumour progression
why are ACE inhibitors dangerous in patients with or at risk of AP?
ACEi lower BP by inhibit BK degrade
during AP, PAC ruptures and release kallikreins which activate bradykinin production (a natural BP lowering peptide) and BK plasma level rise
so v. low BP can lead to pacreatic odema
how do stellate cells produce calcium transients?
>what molecule
bradykinin binds to type 2 BK receptor on stellate cells and activate calcium signalling and release ECM, cytokine and GF
so stellate cells become active
how can stellate cell activation lead to AP?
biphasic response where IP3R opens and large Ca+ spike occcurs and then 2nd smaller spike as SOCE occurs
how can pancreatic cancer be initiated?
> molecularly
activated stellate cells secrete periostin which stimulates cell adhesion and cancer cell growth
what molecules do stellate cells secrete when stimulated/activated by Bradykini?
nitric oxide and prostaglandins which are pro-i molecules
how do PAC and stellate cells communicate with each other?
thought that the nitric oxide gas can diffuse to PAC
