The pancreas and major salivary glands are compound exocrine glands
The exocrine pancreas and major salivary glands are compound exocrine glands—specialized secretory organs that contain a branching ductular system through which they release their secretory products. The principal function of these exocrine glands is to aid in the digestion of food. The saliva produced by the salivary glands lubricates ingested food and initiates the digestion of starch. Pancreatic juice, rich in and digestive enzymes, neutralizes the acidic gastric contents that enter the small intestine and also completes the intraluminal digestion of ingested carbohydrate, protein, and fat. Each of these exocrine glands is under the control of neural and humoral signals that generate a sequential and coordinated secretory response to an ingested meal. We discuss the endocrine pancreas in Chapter 51.
Morphologically, the pancreas and salivary glands are divided into small but visible lobules, each of which represents a subdivision of the parenchyma and is drained by a single intralobular duct (Fig. 43-1A). Groups of lobules separated by connective tissue septa are drained by larger interlobular ducts. These interlobular ducts empty into a main duct that connects the entire gland to the lumen of the gastrointestinal tract.
FIGURE 43-1 Pancreatic acinus and duct morphology. A, The fundamental secretory unit is composed of an acinus and an intercalated duct. Intercalated ducts merge to form intralobular ducts, which in turn merge to form interlobular ducts, and then the main pancreatic duct. B, The acinar cell is specialized for protein secretion. Large condensing vacuoles are gradually reduced in size and form mature zymogen granules that store digestive enzymes in the apical region of the acinar cell. C, The duct cell is a cuboidal cell with abundant mitochondria. Small microvilli project from its apical membrane.
Within the lobules reside the microscopic structural and functional secretory units of the gland. Each secretory unit is composed of an acinus and a small intercalated duct. The acinus represents a cluster of 15 to 100 acinar cells that synthesize and secrete proteins into the lumen of the epithelial structure. In the pancreas, acinar cells secrete ~20 different digestive zymogens (inactive enzyme precursors) and enzymes. In the salivary glands, the principal acinar cell protein products are α-amylase, mucins, and proline-rich proteins. Acinar cells from both the pancreas and salivary glands also secrete an isotonic, plasma-like fluid that accompanies the secretory proteins. In all, the final acinar secretion is a protein-rich product known as the primary secretion.
Each acinar lumen is connected to the proximal end of an intercalated duct. Distally, the intercalated ducts fuse with other small ducts to form progressively larger ducts that ultimately coalesce to form the intralobular duct that drains the lobule. Although the ducts provide a conduit for the transport of secretory proteins, the epithelial cells lining the ducts also play an important role in modifying the fluid and electrolyte composition of the primary secretion. Thus, the final exocrine gland secretion represents the combined product of two distinct epithelial-cell populations, the acinar cell and the duct cell.
In addition to acini and ducts, exocrine glands contain a rich supply of nerves and blood vessels. Postganglionic parasympathetic and sympathetic fibers contribute to the autonomic regulation of secretion through the release of cholinergic, adrenergic, and peptide neurotransmitters that often bind to receptors on the acinar and duct cells. These efferent fibers also regulate blood flow. Both central and reflex pathways contribute to the neural regulation of exocrine secretion. The autonomic nerves also carry afferent pain fibers that are activated by glandular inflammation and trauma. The vasculature not only provides oxygen and nutrients for the gland but also carries the hormones that help to regulate secretion.
Acinar cells are specialized protein-synthesizing cells
Acinar cells—such as those in the pancreas (see Fig. 43-1B) and salivary glands (see Fig. 43-10, below)—are polarized epithelial cells that are specialized for the production and export of large quantities of protein. Thus, the acinar cell is equipped with extensive rough endoplasmic reticulum. However, the most characteristic feature of the acinar cell is the abundance of electron-dense secretory granules at the apical pole of the cell. These granules are storage pools of secretory proteins, and they are poised to release their contents after stimulation of the cell by neurohumoral agents. The secretory granules of pancreatic acinar cells contain the mixture of zymogens and enzymes required for digestion. The secretory granules of salivary acinar cells contain either α-amylase (in the parotid gland) or mucins (in the sublingual glands). Secretory granules in the pancreas appear uniform, whereas those in the salivary glands often exhibit focal nodules of condensation within the granules known as spherules.
The pancreatic acinar cell has served as an important model for elucidating protein synthesis and export via the secretory pathway (Fig. 43-2). Synthesis of secretory proteins (see pp. 34–35) begins with the cellular uptake of amino acids and their incorporation into nascent proteins in the rough endoplasmic reticulum (ER). Vesicular transport mechanisms then shuttle the newly synthesized proteins to the Golgi complex.
FIGURE 43-2 Movement of newly synthesized proteins through the secretory pathway. The four records in the graph show the time course of radiolabeled secretory proteins present in each compartment. (Data from Jamieson J, Palade G: J Cell Biol 34:597–615, 1967; and Jamieson J, Palade G: J Cell Biol 50:135–158, 1971.)
Within the Golgi complex, secretory proteins are segregated away from lysosomal enzymes. Most lysosomal enzymes require the mannose-6-phosphate receptor for sorting to the lysosome (see p. 40). However, the signals required to direct digestive enzymes into the secretory pathway remain unclear.
Secretory proteins exit the Golgi complex in condensing vacuoles or immature secretory granules. These large membrane-bound structures are acidic and maintain the lowest pH within the secretory pathway.
Maturation of the condensing vacuole to a secretory or zymogen granule is marked by condensation of the proteins within the vacuole and pinching off of membrane vesicles. The diameter of a secretory (zymogen) granule is about two thirds that of a condensing vacuole, and its content is more electron dense. Secretory proteins are stored in zymogen granules that are located in the apical region of the acinar cell. The bottom portion of Figure 43-2 shows the results of a pulse-chase experiment that follows the cellular itinerary of radiolabeled amino acids as they move sequentially through the four major compartments of the secretory pathway.
Exocytosis, the process by which secretory granules release their contents, is a complex series of events that involves the movement of the granules to the apical membrane, fusion of these granules with the membrane, and release of their contents into the acinar lumen. Secretion is triggered by stimulation of cell-surface receptors by either hormones or neurotransmitters (neurohumoral stimulation). At the onset of secretion, the surface area of the apical plasma membrane transiently increases as much as 30-fold. Thereafter, activation of an apical endocytic pathway leads to retrieval of the secretory granule membrane for recycling and a decrease in the area of the apical plasma membrane back to its resting value. Thus, during the steady state of secretion, secretory granule membrane is simultaneously delivered to and retrieved from the apical membrane.
Before the exocytotic event, vacuolar-type H pumps (see pp. 118–119) in the vesicle membrane use the energy of ATP hydrolysis to transport H+ from the cytosol to the lumen of the vesicle. This transport process sets up both a chemical gradient for H+ (inside acid) and an electrical gradient (inside positive) across the vesicle membrane. Cl− channels in the vesicle membrane can then allow Cl− to flow into the vesicle lumen, in parallel with the H+, so that the overall process is HCl movement from cytosol to vesicle lumen. Water follows by osmosis. The above “secretion” of minute amounts of Cl− into the secretory vesicle may contribute to the hydration of proteins within the granule before vesicle fusion. Furthermore, exocytosis of the vesicle contents may lead to a transient acidification of the acinar lumen and may modulate adjacent epithelial cells.
The cytoskeleton of the acinar cell plays an important role in the regulation of exocytosis. A component of the actin network appears to be required for delivery of the secretory granules to the apical region of the cell. A second actin network, located immediately below the apical membrane, acts as a barrier that blocks fusion of the granules with the apical plasma membrane. On stimulation, this second network reorganizes and then releases the blockade to permit the secretory granules to approach the apical plasma membrane. Fusion of the granules with the plasma membrane probably requires the interaction of SNAREs on secretory granules and the apical plasma membrane, as well as various other factors (see p. 37). After fusion, the granule contents enter the acinar lumen and move down the ducts into the gastrointestinal tract.
Duct cells are epithelial cells specialized for fluid and electrolyte transport
Pancreatic and salivary duct cells are polarized epithelial cells specialized for the transport of electrolytes across distinct apical and basolateral membrane domains. Duct epithelial cells contain specific membrane transporters and an abundance of mitochondria to provide energy for active transport, and they exhibit varying degrees of basolateral membrane infolding that increases the membrane surface area of pancreatic duct cells (see Fig. 43-1C) and salivary duct cells (see Fig. 43-10C). Although some duct cells contain prominent cytoplasmic vesicles, the synthetic machinery (i.e., ER and Golgi complex) of the duct cell is, in general, much less developed than that of the acinar cell.
Duct cells exhibit a considerable degree of morphological heterogeneity along the length of the ductal tree. At the junction between acinar and duct cells, and protruding into the pancreatic lumen, are small cuboidal epithelial cells known as centroacinar cells. These cells express very high levels of carbonic anhydrase (see p. 630) and presumably play a role in secretion. The epithelial cells of the most proximal (intercalated) duct are squamous or low cuboidal, have an abundance of mitochondria, and tend to lack cytoplasmic vesicles. These features suggest that the primary function of these cells is fluid and electrolyte transport. Progressing distally, the cells become more cuboidal columnar and contain more cytoplasmic vesicles and granules. These features suggest that these cells are capable of both transport of fluid and electrolytes and secretion of proteins. Functional studies indicate that the types of solute transport proteins within duct cells differ depending on the cell's location in the ductal tree.
Ion transport in duct cells is regulated by neurohumoral stimuli that act through specific receptors located on the basolateral membrane. As is the case for cells elsewhere in the body, duct cells can increase transcellular electrolyte movement either by activating individual transport proteins or by increasing the number of transport proteins in the plasma membrane.
Goblet cells contribute to mucin production in exocrine glands
In addition to acinar and duct cells, exocrine glands contain varying numbers of goblet cells. These cells secrete high-molecular-weight glycoproteins known as mucins (see p. 874). When hydrated, mucins form mucus. Mucus has several important functions, including lubrication, hydration, and mechanical protection of surface epithelial cells. Mucins also play an important immunological role by binding to pathogens and interacting with immune-competent cells. These properties may help to prevent infections. In the pancreas, mucin-secreting goblet cells are primarily found among the epithelial cells that line the large distal ducts. They can account for as many as 25% of the epithelial cells in the distal main pancreatic duct of some species. In the salivary gland, goblet cells are also seen in the large distal ducts, although in less abundance than in the pancreas. However, in many salivary glands, mucin is also secreted by acinar cells.