The pancreas secretes 1500−3000 mL of isosmotic alkaline (pH >8) fluid per day containing about 20 enzymes. The pancreatic secretions provide the enzymes needed to effect the major digestive activity of the gastrointestinal tract and provide an optimal pH for the function of these enzymes.
Regulation of Pancreatic Secretion
The exocrine pancreas is influenced by intimately interacting hormonal and neural systems. Gastric acid is the stimulus for the release of secretin from the duodenum, which stimulates the secretion of water and electrolytes from pancreatic ductal cells. Release of cholecystokinin (CCK) from the duodenum and proximal jejunum is largely triggered by long-chain fatty acids, certain essential amino acids (tryptophan, phenylalanine, valine, methionine), and gastric acid itself. CCK evokes an enzyme-rich secretion from acinar cells in the pancreas. The parasympathetic nervous system (via the vagus nerve) exerts significant control over pancreatic secretion. Secretion evoked by secretin and CCK depends on permissive roles of vagal afferent and efferent pathways. This is particularly true for enzyme secretion, whereas water and bicarbonate secretions are heavily dependent on the hormonal effects of secretin and to a lesser extent CCK. Also, vagal stimulation effects the release of vasoactive intestinal peptide (VIP), a secretin agonist.
Pancreatic exocrine secretion is influenced by inhibitory neuropeptides such as somatostatin, pancreatic polypeptide, peptide YY, neuropeptide Y, enkephalin, pancreastatin, calcitonin gene−related peptides, glucagon, and galanin. Although pancreatic polypeptide and peptide YY may act primarily on nerves outside the pancreas, somatostatin acts at multiple sites. Nitric oxide (NO) is also an important neurotransmitter. The mechanism of action of these various factors has not been fully defined.
Water and Electrolyte Secretion
Bicarbonate is the ion of primary physiologic importance within pancreatic secretion. The ductal cells secrete bicarbonate predominantly derived from plasma (93%) more than from intracellular metabolism (7%). Bicarbonate enters through the sodium bicarbonate cotransporter with depolarization caused by chloride efflux through the cystic fibrosis transmembrane conductance regulator (CFTR). Secretin and VIP, both of which increase intracellular cyclic AMP, act on the ductal cells opening the CFTR in promoting secretion. CCK, acting as a neuromodulator, markedly potentiates the stimulatory effects of secretin. Acetylcholine also plays an important role in ductal cell secretion. Bicarbonate helps neutralize gastric acid and creates the appropriate pH for the activity of pancreatic enzymes and bile salts.
The acinar cell is highly compartmentalized and is concerned with the secretion of pancreatic enzymes. Proteins synthesized by the rough endoplasmic reticulum are processed in the Golgi and then targeted to the appropriate site, whether that be zymogen granules, lysosomes, or other cell compartments. The pancreas secretes amylolytic, lipolytic, and proteolytic enzymes. Amylolytic enzymes such as amylase, hydrolyze starch to oligosaccharides and to the disaccharide maltose. The lipolytic enzymes include lipase, phospholipase A2, and cholesterol esterase. Bile salts inhibit lipase in isolation, but colipase, another constituent of pancreatic secretion, binds to lipase and prevents this inhibition. Bile salts activate phospholipase A and cholesterol esterase. Proteolytic enzymes include endopeptidases (trypsin, chymotrypsin), which act on internal peptide bonds of proteins and polypeptides; exopeptidases (carboxypeptidases, aminopeptidases), which act on the free carboxyl- and amino-terminal ends of peptides, respectively; and elastase. The proteolytic enzymes are secreted as inactive precursors and packaged as zymogens. Ribonucleases (deoxyribonucleases, ribonuclease) are also secreted. Enterokinase, an enzyme found in the duodenal mucosa, cleaves the lysine-isoleucine bond of trypsinogen to form trypsin. Trypsin then activates the other proteolytic zymogens and phospholipase A2 in a cascade phenomenon. All pancreatic enzymes have pH optima in the alkaline range. The nervous system initiates pancreatic enzyme secretion. The neurologic stimulation is cholinergic, involving extrinsic innervation by the vagus nerve and subsequent innervation by intrapancreatic cholinergic nerves. The stimulatory neurotransmitters are acetylcholine and gastrin-releasing peptides. These neurotransmitters activate calcium-dependent second messenger systems, resulting in the release of zymogen granules. VIP is present in intrapancreatic nerves and potentiates the effect of acetylcholine. In contrast to other species, there are no CCK receptors on acinar cells in humans. CCK in physiologic concentrations stimulates pancreatic secretion by stimulating afferent vagal and intrapancreatic nerves.
Autoprotection of the Pancreas
Autodigestion of the pancreas is prevented by the packaging of pancreatic proteases in precursor form and by the synthesis of protease inhibitor [i.e., pancreatic secretory trypsin inhibitor (PSTI) or SPINK1], which can bind and inactivate about 20% of trypsin activity. Mesotrypsin, chymotrypsin c, and enzyme y can also lyse and inactivate trypsin. These protease inhibitors are found in the acinar cell, the pancreatic secretions, and the α1- and α2-globulin fractions of plasma. In addition, low calcium concentration within the cytosol of acinar cells in the normal pancreas promotes the destruction of spontaneously activated trypsin. Loss of any of these protective mechanisms leads to zymogen activation, autodigestion, and acute pancreatitis.
Insulin appears to be needed locally for secretin and CCK to promote exocrine secretion; thus, it acts in a permissive role for these two hormones.
Enteropancreatic Axis and Feedback Inhibition
Pancreatic enzyme secretion is controlled, at least in part, by a negative feedback mechanism induced by the presence of active serine proteases in the duodenum. To illustrate, perfusion of the duodenal lumen with phenylalanine causes a prompt result in increased plasma CCK levels as well as increased secretion of chymotrypsin and other pancreatic enzymes. However, simultaneous perfusion with trypsin blunts both responses. Conversely, perfusion of the duodenal lumen with protease inhibitors actually leads to enzyme hypersecretion. The available evidence supports the concept that the duodenum contains a peptide called CCK-releasing factor (CCK-RF) that is involved in stimulating CCK release. It appears that serine proteases inhibit pancreatic secretion by inactivating a CCK-releasing peptide in the lumen of the small intestine. Thus, the ...