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Physiology of duct cell secretion 7 Min Goo Lee and Shmuel Muallem
cells are in contact with centroacinar cells, which have several Introduction ductal characteristics and are regarded as the terminal cells of the ductal tree. The contents of the acini empty into the inter- calated, intralobular, and finally the interlobular ducts (Fig. The pancreas secretes digestive enzymes and a fluid rich in 7.2). In humans, the interlobular ducts join to form the main HCO and poor in Cl . The digestive enzymes are synthesized 3 pancreatic duct, which shares a duodenal opening with the and secreted by the acinar cells, which also secrete a small vol- common bile duct at the ampulla of Vater. However, in rodents ume of an isotonic NaCl-rich fluid. The pancreatic duct secretes a number of interlobular ducts open directly into the common the bulk of the HCO -rich fluid [1,2]. While exocytotic enzyme 3 pancreaticobiliary duct without forming a main duct. secretion by acinar cells has been studied extensively [3], the In the human pancreas, the intercalated and the small molecular mechanism of fluid secretion by the duct is only intralobular ducts are the major sites of HCO secretion. In the partially understood [1]. This is despite the fact that we now 3 mouse and rat, the interlobular duct secretes the bulk of the know that impaired ductal secretion leads to destruction of the fluid and HCO [11]. The HCO -secreting portion of these pancreas, as occurs in cystic fibrosis [4,5], and may contribute 3 3 ducts is lined by the principal cells, which share common char- to other diseases of the pancreas including alcohol-associated acteristics. They contain a relatively small amount of rough chronic pancreatitis [6]. Hence beside its intrinsic interest, endoplasmic reticulum, Golgi complexes, and secretory vesicles, understanding the mechanisms of pancreatic ductal fluid and but are rich in mitochondria in order to satisfy the energy electrolyte secretion has an immediate link to a better under- requirements of active HCO secretion. The luminal (apical) standing of common pancreatic diseases. 3 membrane of the principal cell possesses microvilli. The lateral The ductal tree provides a structural framework for acinar membranes are interdigitated and linked by tight and adherent and endocrine tissues, secretes fluid that acts as a vehicle for junctions and by desmosomes. In the larger ducts the principal the transport of digestive enzymes, and secretes HCO that 3 cells become columnar and the duct contains goblet cells, which neutralizes gastric acid and provides an optimum pH environ- are specialized in secreting mucins. ment for digestive enzymes in the duodenum [2,7]. An over- looked function of HCO3 secretion is that HCO3 is a chaotropic ion that is important for the solubilization of Composition of pancreatic juice macromolecules in order to prevent the aggregation of digestive enzymes and mucins. This chapter focuses on the molecular The human pancreas secretes 1–2 L of pancreatic juice per day in mechanisms of fluid and HCO3 secretion and their regulation response to physiologic stimuli, mainly secretin and vagal output. and attempts to explain how the duct secretes HCO3 at a con- The pancreatic juice is a clear, alkaline, isotonic fluid. The human centration more than five times higher than that found in pancreatic duct can secrete a fluid containing 120–140 mmol/L plasma. HCO3 [12]; however, in the rat the HCO3 concentration is about 70 mmol/L [13]. The HCO3 content in the juice increases with increased flow rate. Peak HCO3 content is reached at Structure of the ductal tree 30–50% of maximal flow. The reciprocal Cl absorption and HCO secretion results in isotonic osmolality at all flow rates The pancreas develops from the ventral and dorsal surfaces of 3 (Fig. 7.3) [13–15]. The cation composition of the juice is nearly the primitive foregut, and the two parts later fuse to form a com- constant (140 mmol/L Na and 10–15 mmol/L K ) regardless of plex endocrine–exocrine organ. Acinar and islet cells are derived flow rate. Human pancreatic juice also contains 1–2 mmol/L from the ductal bud, which has stem cell-like properties. Even Ca2 and a small amount of Mg2 , Zn2 , PO3 , and SO2 . after completion of morphogenesis, duct cells retain some prolif- 4 4 erative capacity in order to generate new duct and islet cells [8]. In humans and most other mammals, duct cells comprise Regulation of pancreatic secretion about 10% of the number of cells and 5% of the total mass of the pancreatic gland [9]. The duct endings are connected to a The principle involved in the control of pancreatic fluid and elec- group of acinar cells to form the acini (Fig. 7.1). The acinar trolyte secretion is that of the common neurohumoral control
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PHYSIOLOGY OF DUCT CELL SECRETION
(a) (b)
A
D
D A
Figure 7.1 (a) Scanning electron microscopic view of rat pancreatic lobules. Arrows indicate a long intercalated duct. (b) Scanning electron microscopic view of rat pancreatic ducts after removal of most acini by ultrasonic vibration. Arrows indicate intercalated ducts. (From ref. 10 with permission.)
Acinar cell Pancreatic enzymes 160 Na
HCO3
120
Centroacinar cell 80 Water Duct cell NaHCO3
40
Ion concentration (mmol/L) CI Intercalated duct K 04 8 121620 Interlobular duct Intralobular duct Pancreatic secretion rate (µL/g/min)
Figure 7.2 Schematic diagram of the pancreatic exocrine system. The Figure 7.3 Composition of pancreatic juice at different flow rates endings of the terminal duct are connected to a group of acinar cells in the cat in response to secretin stimulation. The reciprocal Cl to form an acinus. The contents of the acini empty into intercalated absorption and HCO3 secretion results in juice with isotonic ducts, intralobular ducts and, in turn, small and large interlobular osmolality regardless of flow rate. (From ref. 16 with permission.) ducts. The pancreatic duct secretes the bulk of the fluid in the pancreatic juice that is rich in HCO3 .
of gastrointestinal secretion as proposed over 100 years ago human. When informative, data obtained with genetically [17,18], and includes vagal and secretin stimulation. However, manipulated mice are also discussed. Additional information recent findings indicate that the regulation of pancreatic secre- can be found in references 7 and 15. tion is more complex, with numerous stimulatory and inhibitory inputs [19]. Another consideration when studying pancreatic Interdigestive secretion secretion is the highly species-specific pattern of secretion. In this chapter, we emphasize the physiology of the human pan- In dogs and possibly in humans, interdigestive (resting) pancre- creas, and list information obtained with the guinea-pig atic HCO3 and digestive enzyme secretion is less than 2% pancreas, the secretion of which most resembles that of the and 10% of the maximum, respectively [20]. Ductal HCO3
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CHAPTER 7