The exocrine pancreas produces a large amount (1-2 L/day) of an aqueous secretion containing enzymes and electrolytes. A long-standing paradigm states that the aqueous portion is regulated separately from the enzyme-containing portion, and that the two secretions originate from separate cell types. This is called the two-component hypothesis. One component, the acinar cell, synthesizes and packages the enzymes in zymogen granules, which are discharged into the duct system via exocytosis (called regulated secretion), and the second component, the aqueous component, secreted by the duct cells, dilutes the enzymes with an alkaline solution and the mixture enters the duodenum. The first component, enzymes, is regulated predominately by cholecystokinin and acetylcholine at the acinar cell. The second component, the aqueous, by secretin stimulation of duct cells (in combination with other secretagogues). We propose a modification of this paradigm. In our hypothesis, the acinar cell contributes a substantial volume (equal to duct cells) to the aqueous secretion, and the relationship of the amount of water/electrolyte to the amount of enzyme is tightly regulated. This regulation takes the form of electrolytes (K+, Cl-, HCO3-) entering the zymogen granule and osmotically drawing in water, and causing the granules to swell, often more than doubling their volume. We suggest that this zymogen granule water is the primary secretion of the acinar cell during regulated secretion. At this point, the granule matrix, diluted with water, is discharged into the ductal system where further dilution with ductal secretions occurs. The volume of granule water discharged into the ductal tree by exocytosis can account for all the fluid initially secreted in response to a strong stimulus (neural or hormonal). These steps are well established in many cell types, including the exocrine pancreas. However, their relevance to pancreatic function and disorders have received little attention, in part, we believe, because it represents a major departure from the widely-accepted two-component paradigm, in that it implies that a major fraction of the aqueous component (acinar fluid) and enzyme component are NOT separately regulated, and do NOT originate from separate cell types. This hypothesis has not been tested, because fluid secretion from acinar cells has never been quantified, in contrast to duct fluid, which has been studied in vitro in isolated pancreatic ducts, and in vivo using a rat model in which the acinar cells are completely eliminated but duct cells remain intact and functional. We will use this model, the copper-deficient rat, to test the hypothesis that the hormone, cholecystokinin-58, stimulates a large amount water and protein from the acinar cell, but not from the duct cells, and that this CCK-58 stimulated fluid secretion (but not secretin-stimulated fluid) will be abolished in copper-deficient rats. CCK-58 is unique, because it is the only form in rat blood and the only form that strongly stimulates water and chloride from the pancreas. The results may be highly relevant to the pancreatic disorders pancreatitis and cystic fibrosis. ? ? Project narrative: The disorders of the exocrine pancreas, the most important organ for secreting the digestive enzymes, is subject to several disorders, such as cystic fibrosis and pancreatitis. Our study will test a new hypothesis on how the secretions are regulated that may suggest new treatments for these diseases ? ? ? ?
