Physiology of Duct Cell Secretion 7 Min Goo Lee and Shmuel Muallem
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9781405146647_4_007.qxd 1/30/08 11:34 AM Page 78 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 HCOϪ and poor in ClϪ. 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 HCOϪ-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 HCOϪ 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 HCOϪ [11]. The HCOϪ-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 HCOϪ 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 HCOϪ 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- Ϫ Ϫ 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 Ϫ mechanisms of fluid and HCO3 secretion and their regulation response to physiologic stimuli, mainly secretin and vagal output. Ϫ 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 Ϫ Ϫ plasma. HCO3 [12]; however, in the rat the HCO3 concentration is Ϫ about 70 mmol/L [13]. The HCO3 content in the juice increases Ϫ with increased flow rate. Peak HCO3 content is reached at Structure of the ductal tree Ϫ 30–50% of maximal flow. The reciprocal Cl absorption and HCOϪ 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 Naϩ and 10–15 mmol/L Kϩ) 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 Ca2ϩ and a small amount of Mg2ϩ, Zn2ϩ, PO3Ϫ, and SO2Ϫ. 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 78 9781405146647_4_007.qxd 1/30/08 11:34 AM Page 79 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 ClϪ to form an acinus. The contents of the acini empty into intercalated Ϫ 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 Ϫ 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- Ϫ creas, and list information obtained with the guinea-pig atic HCO3 and digestive enzyme secretion is less than 2% Ϫ pancreas, the secretion of which most resembles that of the and 10% of the maximum, respectively [20]. Ductal HCO3 79 9781405146647_4_007.qxd 1/30/08 11:34 AM Page 80 CHAPTER 7 Ϫ salvage mechanisms contribute to the low basal HCO3 output its secretion. Cells in the islets of Langerhan release insulin, [21]. During the interdigestive period, transient bursts of secre- somatostatin, and several other peptide hormones that affect tion occur every 1–2 hours. This coincides with the cyclical ductal and acinar secretion. These agents are present at rela- motor activity of the upper gastrointestinal tract (interdigestive tively high concentration and reach their target through the migrating motor complex, IMMC). Gastric and biliary secre- insuloacinar portal system [29]. Other agonists, including tion, and blood levels of motilin and pancreatic polypeptide (PP), purines, prostaglandins, and activated trypsin, are released by also increase along with the IMMC. The IMMC is generated by either acinar or duct cells and regulate ductal function in circulating motilin and by cholinergic stimulation [22]. The pre- numerous physiologic and pathologic states. Receptors for cise physiologic significance of the IMMC is uncertain. these agonists (autacoids, paracrine) are expressed in both the luminal and the basolateral membranes of the duct. Both the extrinsic and the intrinsic nervous systems partici- Response to a meal pate in the neuronal control of pancreatic secretion. Nerve Ϫ Pancreatic HCO3 and enzyme secretion are increased in fibers travel through the lamina propria of the intercalated, response to a meal. Control of pancreatic secretion is divided interlobular, and main ducts. The nerve terminals are located into the cephalic, gastric, and intestinal phases. Secretion by in close proximity to the duct basal membrane [30]. In this acinar cells is controlled by the cephalic and gastric inputs. manner the neurotransmitters diffuse only a short distance, For example, sham feeding with visual, olfactory, and gusta- retain a high concentration at their effector sites, and produce tory stimuli increases enzyme secretion by up to 50% of max- a relatively rapid response. Some agonists, such as ATP, are imum in humans [23]. Gastric distension with a balloon also released by both neuron and the pancreatic acinar and duct increases enzyme output [24]. However, both stimuli have lit- cells and activate the same class of receptors [31]. Ϫ tle effect on ductal HCO3 and fluid secretion. The intestinal phase is the most important phase for meal- Endocrine and paracrine control of ductal secretion induced pancreatic secretion and commences with the passage of chyme into the proximal duodenum. Secretin, secreted by Secretin cells in the upper duodenum, and an enteropancreatic vago- The entry of acidic chyme into the duodenum evokes the release vagal reflex are the two principal mechanisms that induce ductal Ϫ of secretin from neuroendocrine cells in the duodenal mucosa.