When enzymes secreted by pancreatic acinar cells are activated before they reach their intended site in the small intestinal lumen, it can result in pancreatitis. The pancreatic juice contains various trypsin inhibitors to prevent premature activation, as trypsin activates other pro-forms of enzymes in the juice. Additionally, trypsin can be degraded by other trypsin molecules as a secondary defense mechanism. However, some individuals may develop hereditary pancreatitis spontaneously, even in the absence of known risk factors. This can occur due to a mutation in trypsin that makes it resistant to degradation or mutations in trypsin inhibitors that render them inactive. If the other defenses are breached and trypsin becomes active prematurely, it leads to a cycle of enzyme activation and bouts of pancreatitis.

In the postprandial period, the pancreatic ductular cells play a role in the flow and composition of pancreatic juice. The ducts of the pancreas act as the effector arm of a pH regulatory system. The lobules of acinar and ductal parenchyma contribute to the secretion of water and extralobular HCO3 in response to the absorption of Cl˜ by the ductal system. The location of important transport processes involved in the elaboration of pancreatic juice is shown in Figure 30.2. Acinar fluid, which is isotonic and resembles plasma in its concentrations of Na+, K+, Cl−, and HCO3−, is stimulated primarily by CCK for secretion. Secretin, another hormone, stimulates the secretion of water and electrolytes from the extralobular ducts. The secretion stimulated by secretin is richer in HCO3− than the acinar secretion due to Cl−/HCO3− exchange.

The ductular cells are responsible for the secretion of bicarbonate into the ductular lumen, with water following to maintain osmotic equilibrium via the paracellular route. Secretin stimulates epithelial cells at the cellular level, leading to the secretion of bicarbonate. This is achieved by increasing cyclic adenosine monophosphate (cAMP) levels in the ductular cells, which opens cystic fibrosis transmembrane conductance regulator (CFTR). This regulatory function is essential to restore pH neutrality in response to luminal acid in the small intestine and relies on specialized endocrine cells called S cells. When the luminal pH drops below approximately 4.5, S cells release secretin in response to the increase in [H+]. This regulatory loop forms a self-limited system, as the secretion of bicarbonate by secretin leads to an increase in pH in the small intestinal lumen and terminates the signal for secretin release from S cells. The pH-sensing mechanism is not limited to the pancreas but also present in other epithelia, such as biliary ductules and the duodenal epithelium, capable of secreting bicarbonate.
Pancreatitis canresultwhenenzymessecretedbypancreaticacinarcellsbecomeproteolyticallyactivatedbeforetheyhavereachedtheirappropriatesiteofactioninthesmallintestinallumen.Indeed,pancreaticjuicecontainsavarietyoftrypsininhibitorstoreducetheriskofprematureactivation,becausetrypsinistheactivatorofotherpro-formsofenzymessecretedinpancreaticjuice.Asecondlevelofprotectionliesinthefactthattrypsincanbedegradedbyothertrypsinmolecules.Despitethesedefenses,someindividualsaresusceptibletohereditarypancreatitisthatoccursspontaneouslyintheabsenceofknownriskfactors.Insomeofthesepatientsthereisamutationintrypsinthatrendersitresistanttodegradationbyothertrypsinmolecules.Othersharbormutationsintrypsininhibitors,renderingtheinhibitorsinactive.Inanyevent,ifotherdefenseshavebeenbreachedandtrypsinbecomesactiveprematurely,aviciouscycleofenzymeactivationensuesandboutsofpancreatitisfollow.
Characteristics and Control of Ductular Secretion
In this section we consider how the pancreatic ductular cells contribute to the flow and composition of pancreatic juice in the postprandial period. The ducts of the pancreas can be considered the effector arm of a pH regulatory
Lobules of acinar and ductal parenchyma
Secretion of H2O and –
Extralobular HCO3 in response to ductal system absorption of Cl˜ Cl˜
Direction of fluid movement •Fig. 30.2 Locationsofimportanttransportprocessesinvolvedintheelaborationofpancreaticjuice.AcinarfluidisisotonicandresemblesplasmainitsconcentrationsofNa+ ,K+ ,Cl− ,andHCO3− .SecretionofacinarfluidandtheproteinsitcontainsisstimulatedprimarilybyCCK.Thehormonesecretinstimulatessecretionofwaterandelectrolytesfromthecellsthatlinetheextralobularducts.Thesecretin-stimulatedsecretionisricherinHCO3− thantheacinarsecretionbecauseofCl−/HCO3− exchange.(AdaptedfromSwansonCH,SolomonAK.J Gen Physiol 1973;62:407.) system designed to respond to luminal acid in the small intestine and secrete just enough bicarbonate to restore pH to neutrality (
Fig. 30.3 ). This regulatory function also requires mechanisms to sense luminal pH and convey this information to the pancreas as well as other epithelia (e.g., biliary ductules and the duodenal epithelium itself) capable of secreting bicarbonate. The pH-sensing mechanism is embodied in specialized endocrine cells known as S cells, localized within the small intestinal epithelium. When luminal pH falls below approximately 4.5, S cells are triggered to release secretin in response to the increase in [H+]. The components of this regulatory loop constitute a self-limited system. Thus as secretin evokes secretion of bicarbonate, pH in the small intestinal lumen will rise and the signal for release of secretin from S cells will be terminated.
At the cellular level, secretin stimulates epithelial cells to secrete bicarbonate into the ductular lumen, with water following via the paracellular route to maintain osmotic equilibrium. Secretin increases cyclic adenosine monophosphate (cAMP) in the ductular cells and thereby opens cystic fibrosis transmembrane conductance regulator (CFTR) • BOX 30.1 Products of Pancreatic Acinar Cells