PANCREASPANCREAS

Dr. Zainab H.H.Dr. Zainab H.H.

Dept. of physiologyDept. of physiology

College of medicineCollege of medicine

Al-Nahrain UniversityAl-Nahrain University

Learning objectivesLearning objectives Describe the pancreatic secretionDescribe the pancreatic secretion Describe the function of cystic fibrosis Describe the function of cystic fibrosis

transmembrane conductance regulator transmembrane conductance regulator (CFTR)(CFTR)

Describe the regulatory mechanisms of Describe the regulatory mechanisms of pancreatic secretionpancreatic secretion

List the enzymatic components of List the enzymatic components of pancreatic secretionpancreatic secretion

PANCREASPANCREAS-is present outside GI but connected to it by a -is present outside GI but connected to it by a

duct. duct.

-has two components -has two components – Exocrine 90%: produces several digestive Exocrine 90%: produces several digestive

enzymesenzymes– ducts will secret an electrolyte solution that ducts will secret an electrolyte solution that

contain large amounts of water & contain large amounts of water & bicarbonate ionsbicarbonate ions

– Endocrine 2%: produces hormones such as Endocrine 2%: produces hormones such as insulininsulin

Composition of the pancreatic juice:Composition of the pancreatic juice:– The volume is 1-1.5 liter per day.The volume is 1-1.5 liter per day.– PH is 8PH is 8– It contains water and different electrolyte - It contains water and different electrolyte -

CATIONS (Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺)CATIONS (Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺)

- ANIONS (HCO3⁻, Cl⁻, SO4⁼, HPO4⁼)- ANIONS (HCO3⁻, Cl⁻, SO4⁼, HPO4⁼)

– neutralizing acid chyme emptied by stomachneutralizing acid chyme emptied by stomach

– organic constituents: different digestive organic constituents: different digestive enzymes for digestion of protein, fat and enzymes for digestion of protein, fat and CHO.CHO.

Acinar cellsAcinar cells ……. …….produce: produce: hydrolytic enzymes hydrolytic enzymes

aid in digestion of fats, proteins, carbohydrates, aid in digestion of fats, proteins, carbohydrates, and nucleic acidsand nucleic acids

secretagogues, secretagogues,

- In apical region of acinar cells In apical region of acinar cells - is secretory granulesis secretory granules- stimulate pancreatic enzyme secretion. stimulate pancreatic enzyme secretion. - causing an increase in cytosolic

Ca2+Concentration.- they arethey are : :

A-acetylcholine, secreted from vagal efferents,

B-cholecystokinin;

PANCREATIC DUCTPANCREATIC DUCT….…. Secretion: Secretion: Centroacinar and ductal cells produce the Centroacinar and ductal cells produce the initial initial

aqueous aqueous secretion, which is secretion, which is isotonicisotonic and contains Na, and contains Na, K , Cl, and HCO3K , Cl, and HCO3

This initial secretion is then modified by transport This initial secretion is then modified by transport processes in the ductal epithelial cells as follows: processes in the ductal epithelial cells as follows:

The The apical membrane apical membrane of of ductal cells contains a ductal cells contains a Cl Cl ––HCO3 exchangerHCO3 exchanger, and the , and the basolateral membrane basolateral membrane contains contains Na –K ATPase and an Na –H exchanger. Na –K ATPase and an Na –H exchanger.

In the presence of carbonic anhydrase, CO2 and H2O In the presence of carbonic anhydrase, CO2 and H2O combine in the cells to form H2CO3. H2CO3 dissociates combine in the cells to form H2CO3. H2CO3 dissociates into H and HCO3.into H and HCO3.

The HCO3 is secreted into pancreatic juice by the The HCO3 is secreted into pancreatic juice by the Cl-Cl-HCO3 HCO3 exchanger in the exchanger in the apical membrane. apical membrane.

The The HH is transported into the is transported into the bloodblood by the by the Na –H Na –H exchanger exchanger in the in the basolateral membrane.basolateral membrane.

The net result, or sum, of these transport The net result, or sum, of these transport processes is net secretion of HCO3 into pancreatic processes is net secretion of HCO3 into pancreatic ductal juice and net absorption of H ; absorption ductal juice and net absorption of H ; absorption of H causes of H causes acidification of pancreatic venous acidification of pancreatic venous blood blood

The Na and K concentrations are the same as The Na and K concentrations are the same as their concentrations in plasma, but the their concentrations in plasma, but the Cl Cl andand HCO3 HCO3 concentrations concentrations vary with pancreatic flow vary with pancreatic flow raterate..

Cl− is Cl− is recycledrecycled by by Cl− channel Cl− channel from cell to lumen from cell to lumen via: via: cystic fibrosis transmembrane conductance cystic fibrosis transmembrane conductance regulator (CFTR) regulator (CFTR)

■ ■ Na+ Na+ secretion secretion ::is secreted into duct lumen following HCO3 − secretion; is secreted into duct lumen following HCO3 − secretion;

water :water : follows by follows by osmosisosmosis produce fluid secretion.produce fluid secretion.

Which of the following is true about the Which of the following is true about the secretion from the exocrine pancreas?secretion from the exocrine pancreas?

(A) It has a higher Cl– concentration than(A) It has a higher Cl– concentration than

does plasmadoes plasma

(B) It is stimulated by the presence of (B) It is stimulated by the presence of HCO3HCO3

– – in the duodenumin the duodenum

(C) Pancreatic HCO3(C) Pancreatic HCO3– secretion is increased – secretion is increased byby

gastringastrin

(D) Pancreatic enzyme secretion is (D) Pancreatic enzyme secretion is increased by cholecystokinin (CCK)increased by cholecystokinin (CCK)

(E) It is hypotonic(E) It is hypotonic

Effect of Flow Rate on Effect of Flow Rate on CompositionCompositionof Pancreatic Juiceof Pancreatic Juice At the highest pancreatic flow rates (more At the highest pancreatic flow rates (more

than 30 mL/min), the HCO3 concentration than 30 mL/min), the HCO3 concentration of pancreatic juice is highest (and much of pancreatic juice is highest (and much higher than plasma HCO3), and the Cl higher than plasma HCO3), and the Cl concentration is lowest. concentration is lowest.

At the lowest flow rates, HCO3 is lowest At the lowest flow rates, HCO3 is lowest and Cland Cl

is highestis highest The Na and K concentrations in pancreatic The Na and K concentrations in pancreatic

juice juice remain constantremain constant..

Regulation of Pancreatic Regulation of Pancreatic SecretionSecretion

Pancreatic secretion has two functions: Pancreatic secretion has two functions:

(1) to secrete the enzymes necessary for (1) to secrete the enzymes necessary for digestion of carbohydrates, proteins, and digestion of carbohydrates, proteins, and lipids; the enzymatic portion of lipids; the enzymatic portion of pancreatic secretion performs these pancreatic secretion performs these digestive functions; digestive functions;

(2) to neutralize H in the chyme delivered (2) to neutralize H in the chyme delivered to the duodenum from the stomachto the duodenum from the stomach

The enzymatic and aqueous portions are The enzymatic and aqueous portions are regulated separately:regulated separately:

The aqueous secretion is stimulated by The aqueous secretion is stimulated by the arrival of H in the duodenum,the arrival of H in the duodenum,

The enzymatic secretion is stimulated by The enzymatic secretion is stimulated by products of digestion (small peptides, products of digestion (small peptides, amino acids, and fatty acids).amino acids, and fatty acids).

REGULATION OF PANCREATIC REGULATION OF PANCREATIC SECRETIONSECRETION::

1.1. Nervous by vagus. Nervous by vagus. 2.2. Hormonal Hormonal

a- Cholecystokinin-pancreozymin CCK.a- Cholecystokinin-pancreozymin CCK.b- Secretin.b- Secretin.

PHASES OF PANCREATIC SECRETION:PHASES OF PANCREATIC SECRETION:1.1. Cephalic and Gastric phase: Cephalic and Gastric phase: -acetylcholine released by vagal nerve. -acetylcholine released by vagal nerve. -secretion is rich in enzymes and poor in -secretion is rich in enzymes and poor in waterwater & &

bicarbonate.bicarbonate.-accounts for -accounts for 20%20% of total secretion of of total secretion of

pancreatic enzymes after a meal.pancreatic enzymes after a meal.2. The intestinal phase is the most important 2. The intestinal phase is the most important

phase and accounts for approximately phase and accounts for approximately 80%80% of the pancreatic secretionof the pancreatic secretion

Acinar cells (enzymatic secretion) have :Acinar cells (enzymatic secretion) have :

1.1. receptors for CCK (receptors for CCK (CCK-A receptorsCCK-A receptors))

2.2.muscarinic receptors muscarinic receptors for ACh. for ACh. During the intestinal phase, During the intestinal phase, CCKCCK is the is the

most most important stimulantimportant stimulant for the for the enzymatic secretion. enzymatic secretion.

The The I cells I cells of intestinal mucosa are of intestinal mucosa are stimulated to stimulated to secrete CCK secrete CCK by the by the presence of presence of amino acids, small peptides, amino acids, small peptides, and fatty acidsand fatty acids in the intestinal lumen. in the intestinal lumen.

ACh ACh stimulates enzyme secretion and stimulates enzyme secretion and potentiatespotentiates the action of the action of CCKCCK by by vagovagal reflexesvagovagal reflexes

Ductal cells Ductal cells (aqueous secretion of Na+, HCO3-, and H2O). (aqueous secretion of Na+, HCO3-, and H2O).

have receptors for:have receptors for:

CCK, ACh, and secretin. CCK, ACh, and secretin.

Secretin, which is secreted by the S cells of the duodenum, is Secretin, which is secreted by the S cells of the duodenum, is the major stimulant of the aqueous HCO3 -rich secretion.the major stimulant of the aqueous HCO3 -rich secretion.

Secretin is secreted in response to H in the lumen of the Secretin is secreted in response to H in the lumen of the intestine, which signals the arrival of acidic chyme from the intestine, which signals the arrival of acidic chyme from the stomach. stomach.

To ensure that pancreatic lipases will be active (since they To ensure that pancreatic lipases will be active (since they are inactivated at low pH), the acidic chyme requires rapid are inactivated at low pH), the acidic chyme requires rapid neutralization by the HCO3 -containing pancreatic juice. neutralization by the HCO3 -containing pancreatic juice.

The effects of secretin are The effects of secretin are potentiatedpotentiated by both CCK and ACh by both CCK and ACh

Secretion of which of the following Secretion of which of the following substances is inhibited by low pH?substances is inhibited by low pH?

(A) Secretin(A) Secretin

(B) Gastrin(B) Gastrin

(C) Cholecystokinin (CCK)(C) Cholecystokinin (CCK)

(D) Vasoactive intestinal peptide (VIP)(D) Vasoactive intestinal peptide (VIP)

(E) Gastric inhibitory peptide (GIP)(E) Gastric inhibitory peptide (GIP)

Enzymatic component of pancreatic secretion Enzymatic component of pancreatic secretion (acinar cells).(acinar cells).

Protein digesting enzymes:Protein digesting enzymes:

1. Trypsin. 1. Trypsin.

2. Chymotrypsin. 2. Chymotrypsin.

3. Elastase. 3. Elastase.

4. Carboxypeptidase.4. Carboxypeptidase.

are secreted from pancreas in an inactive form:are secreted from pancreas in an inactive form:1.1. trypsinogen, trypsinogen,

2.2. chymotrypsinogen, chymotrypsinogen,

3.3. proelastase, & proelastase, &

4.4. Procarboxypeptidase.Procarboxypeptidase.

– activated after secreted into intestinal tract activated after secreted into intestinal tract (not in pancreas).(not in pancreas).

Trypsinogen :Trypsinogen : is activated by an enzyme called is activated by an enzyme called enterokinaseenterokinase or or

enteropeptidase enteropeptidase secreted by intestinal mucosa when chyme comes in secreted by intestinal mucosa when chyme comes in

contact with mucosa. .contact with mucosa. . Enterokinase Enterokinase :convert inactive trypsinogen into :convert inactive trypsinogen into

Trypsin.Trypsin. trypsin trypsin can activate: trypsinogen …into ………trypsincan activate: trypsinogen …into ………trypsin. .

once trypsin is formed :once trypsin is formed :

it cause autocatalytic chain reaction by which moreit cause autocatalytic chain reaction by which more

trypsinogen is activated into ……..trypsin.trypsinogen is activated into ……..trypsin.

also activate: also activate: chymotrypsinogen ……into ……..chymotrypsin, chymotrypsinogen ……into ……..chymotrypsin, procarboxypeptidase ..into ….carboxypeptidase, procarboxypeptidase ..into ….carboxypeptidase, proelastase proelastase ……………..……………..into ………elastaseinto ………elastase..

Trypsin and chymotrypsin Trypsin and chymotrypsin will digest whole or partially digested protein into will digest whole or partially digested protein into peptidepeptide level. level.

Carboxypeptidase :Carboxypeptidase :will digest will digest peptidespeptides into into amino acidsamino acids. .

Enzymes for the digestion of nucleic acids:Enzymes for the digestion of nucleic acids:1.1. Ribonuclease: which acts on RNA.Ribonuclease: which acts on RNA.

2.2. Deoxyribonuclease: which acts on DNA.Deoxyribonuclease: which acts on DNA.

Enzymes for digestion of carbohydrates:Enzymes for digestion of carbohydrates:α-amylase: α-amylase:

similar to that of salivary secretion. similar to that of salivary secretion.

It splits starches and glycogen into disaccharides such as maltose and It splits starches and glycogen into disaccharides such as maltose and isomaltose.isomaltose.

Fat splitting enzymesFat splitting enzymes

Fat splitting enzymes:Fat splitting enzymes:1.1. Lipase.Lipase.

2.2. Procolipase (colipase): Procolipase (colipase):

secreted as procolipse (inactive form) secreted as procolipse (inactive form)

activated into active form by trypsin. activated into active form by trypsin.

Colipase Colipase is a protein that binds to surface of is a protein that binds to surface of

fat droplet fat droplet displacing emulsifying agents and displacing emulsifying agents and

anchoring lipase to droplet,.anchoring lipase to droplet,.

lipase :lipase : not act on fat droplets covered by not act on fat droplets covered by

emulsifying agents without colipaseemulsifying agents without colipase..

3-Phospholipase A2 3-Phospholipase A2 – secreted as inactive form (prophospholipase A2) & secreted as inactive form (prophospholipase A2) &

activated by trypsin into phospholipase A2,activated by trypsin into phospholipase A2,– phospholipase A2 acts phospholipase A2 acts on lecithinon lecithin

In acute pancreatitis In acute pancreatitis prophospholipase A2 is activated inside pancreas prophospholipase A2 is activated inside pancreas and cause partial digestion of lecithin into and cause partial digestion of lecithin into lysolecithinlysolecithin and a fatty acid. and a fatty acid. Lysolecithin causes damage of pancreatic tissue.Lysolecithin causes damage of pancreatic tissue.

4-Trypsin inhibitor: 4-Trypsin inhibitor: is secreted by cells that secrete proteolytic is secreted by cells that secrete proteolytic

enzymes enzymes It surrounds the enzyme granules and prevents It surrounds the enzyme granules and prevents

itsitsactivation both inside acini or the ducts of activation both inside acini or the ducts of

pancreaspancreas. .

Why Pancreas does not digest itself

1- enzymes are secreted in an inactive form.

2- Trypsin inhibitor.

3- Flow (no stagnation). amount of enzyme secreted will flow.

DEFICIENCY OF PANCREATIC ENZYMESDEFICIENCY OF PANCREATIC ENZYMES::

Caused by chronic pancreatitis or damage to Caused by chronic pancreatitis or damage to pancreas. pancreas.

– fat digestion:fat digestion:

It affects It affects mainlymainly– Protein digestion Protein digestion

Will be affected Will be affected

protein loss will be protein loss will be significant. significant. – carbohydrates digestion carbohydrates digestion

is little affected.is little affected.

deficiency of deficiency of lipaselipase::

result in deficiency in digestion of fat lead to result in deficiency in digestion of fat lead to steatorrhoeasteatorrhoea..

(stool bulky, pale, greasy and of bad odour and (stool bulky, pale, greasy and of bad odour and floats on water). floats on water).

SECRETIN: SECRETIN: -is secreted by the S cells of the duodenum-is secreted by the S cells of the duodenum

-it-it’’s secreted when chyme enters intestine. s secreted when chyme enters intestine.

-important factor that causes release of -important factor that causes release of secretin is:secretin is:

ACID → hydrochloric acid → causes release of ACID → hydrochloric acid → causes release of secretin → absorbed by blood → to pancreas.secretin → absorbed by blood → to pancreas.

- The secretion is a - The secretion is a waterywatery, , alkaline juicealkaline juice poorpoor in in enzymes and chlorideenzymes and chloride..

Importance of secretin mechanism:Importance of secretin mechanism: 1.1. neutralize the acid in the duodenum.neutralize the acid in the duodenum.

2. bicarbonate ions will provide a suitable PH 2. bicarbonate ions will provide a suitable PH for the action of the pancreatic enzymes.for the action of the pancreatic enzymes.

3. provide the fluid medium to wash out 3. provide the fluid medium to wash out enzymes that are secreted into acini.enzymes that are secreted into acini.

CHOLECYSTOKININ-PANCREOZYMIN (CCK):CHOLECYSTOKININ-PANCREOZYMIN (CCK):-released from mucosa of upper s. intestine (I cells) in -released from mucosa of upper s. intestine (I cells) in

response to fat and partial byproducts of protein response to fat and partial byproducts of protein digestion. digestion.

– CCK when released will be absorbed by the blood CCK when released will be absorbed by the blood and then will go to pancreas to cause secretion of and then will go to pancreas to cause secretion of pancreatic juice pancreatic juice

--rich in enzymesrich in enzymes but but poorpoor in in water and bicarbonate. water and bicarbonate.

--similarsimilar to vagal stimulation to vagal stimulation butbut not blocked by not blocked by atropine.atropine.

-accounts for about -accounts for about 70-80%70-80% of total secretion of of total secretion of pancreatic digestive enzymes after a meal. pancreatic digestive enzymes after a meal.

Cholecystokinin (CCK) inhibitsCholecystokinin (CCK) inhibits

(A) gastric emptying(A) gastric emptying

(B) pancreatic HCO3(B) pancreatic HCO3– secretion– secretion

(C) pancreatic enzyme secretion(C) pancreatic enzyme secretion

(D) contraction of the gallbladder(D) contraction of the gallbladder

(E) relaxation of the sphincter of Oddi(E) relaxation of the sphincter of Oddi