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BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION

GENERAL CONSIDERATIONS

The pancreas secretes 1500–3000 mL of isosmotic alkaline (pH >8) fluid per day containing ~20 enzymes. Pancreatic secretions provide the enzymes and bicarbonate needed to perform the major digestive activity of the gastrointestinal tract and provide an optimal pH for the function of these enzymes.

REGULATION OF PANCREATIC SECRETION

Secretions from the exocrine pancreas are highly regulated by neurohormonal systems in a phasic manner (cephalic, gastric, and intestinal phases). Gastric acid is the stimulus for the release of secretin from the duodenal mucosa (S cells), which stimulates the secretion of water and electrolytes from pancreatic ductal cells. Release of cholecystokinin (CCK) from the duodenal and proximal jejunal mucosa (Ito cells) is largely triggered by long-chain fatty acids, 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, particularly during the cephalic phase. Secretion evoked by secretin and CCK depends on the 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 affects the release of vasoactive intestinal peptide (VIP), a secretin agonist. Pancreatic exocrine secretion is also influenced by inhibitory neuropeptides including somatostatin, pancreatic polypeptide, peptide YY, neuropeptide Y, enkephalin, pancreastatin, calcitonin gene–related peptides, glucagon, and galanin. Pancreatic polypeptide and peptide YY may act primarily on nerves outside the pancreas, while somatostatin acts at multiple sites.

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 the duct lumen through the sodium bicarbonate cotransporter with depolarization caused by chloride efflux through the cystic fibrosis transmembrane conductance regulator (CFTR). Secretin and VIP bind at the basolateral surface and cause an increase in secondary messenger intracellular cyclic AMP and act on the apical surface of the ductal cells opening the CFTR, which promotes secretion. CCK, acting as a neuromodulator, markedly potentiates the stimulatory effects of secretin. Acetylcholine also plays an important role in ductal cell secretion. Intraluminal bicarbonate secreted from the ductal cells helps neutralize gastric acid, increases the solubility of fatty acids and bile acids, maintains an optimal pH for pancreatic and brush border enzymes, and prevents intestinal mucosal damage.

ENZYME SECRETION

The acinar cell is highly compartmentalized for the production and secretion of pancreatic enzymes. Proteins synthesized by the rough endoplasmic reticulum are processed in the Golgi and then targeted to the appropriate site: zymogen granules, lysosomes, or other cell compartments. The zymogen granules migrate to the ...

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