At maximal rates of H+ secretion, the parietal cell can drive the intraluminal pH of the stomach to 1 or less (i.e., [H+] > 100 mM) for long periods. The gastric epithelium must maintain an H+ concentration gradient of more than a million-fold because the intracellular pH of gastric epithelial cells is ~7.2 (i.e., [H+] ≅ 60 nM) and plasma pH is ~7.4 (i.e., [H+] ≅ 40 nM). Simultaneously, the plasma-to-lumen Na+ concentration ratio can approach ~30 because plasma [Na+] is 140 mM, whereas intragastric [Na+] can reach values as low as 5 mM, but only at high secretory rates (see Fig. 42-2). How is the stomach able to maintain these gradients? How is it that the epithelial cells are not destroyed by this acidity? Moreover, why do pepsins in the gastric lumen not digest the epithelial cells? The answer to all three questions is the so-called gastric diffusion barrier.
Although the nature of the gastric diffusion barrier had been controversial, it is now recognized that the diffusion barrier is both physiological and anatomical. Moreover, it is apparent that the diffusion barrier is characterized by at least three components: (1) relative impermeability to acid of the apical membrane and epithelial-cell tight junctions in the gastric glands, (2) a mucous gel layer varying in thickness between 50 and 200 µm overlying the surface epithelial cells, and (3) an -containing microclimate adjacent to the surface epithelial cells that maintains a relatively high local pH.
Vagal stimulation and irritation stimulate gastric mucous cells to secrete mucins
The mucous layer is largely composed of mucins, phospholipids, electrolytes, and water. Gastric mucins—MUC1, MUC5, and MUC6—are the high-molecular-weight glycoproteins (see p. 38) that contribute to the formation of a protective layer over the gastric mucosa. These mucins are oligomers (di-, tri-, and tetramers) and higher-order multimers of peptides joined by disulfide bonds. Each peptide chain is linked to long polysaccharides, which are often sulfated and are thus mutually repulsive. The ensuing high carbohydrate content is responsible for the viscosity of mucus, which explains, in large part, its protective role in gastric mucosal physiology.
Mucus is secreted by three different mucous cells: surface mucous cells (i.e., on the surface of the stomach), mucous neck cells (i.e., at the point where a gastric pit joins a gastric gland), and glandular mucous cells (i.e., in the gastric glands in the antrum). The type of mucus secreted by these cells differs; mucus that is synthesized and secreted in the glandular cells is a neutral glycoprotein, whereas the mucous cells on the surface and in the gastric pits secrete both neutral and acidic glycoproteins. Mucin forms a mucous gel layer in combination with phospholipids, electrolytes, and water. This mucous gel layer provides protection against injury from noxious luminal substances, including acid, pepsins, bile acids, and ethanol. Mucin also lubricates the gastric mucosa to minimize the abrasive effects of intraluminal food.
The mucous barrier is not static. Abrasions can remove pieces of mucus. When mucus comes in contact with a solution with a very low pH, the mucus precipitates and sloughs off. Thus, the mucous cells must constantly secrete mucus. Regulation of mucus secretion by gastric mucosal cells is less well understood than is regulation of the secretion of acid, pepsinogens, and other substances by gastric cells. The two primary stimuli for inducing mucus secretion are vagal stimulation and physical and chemical irritation of the gastric mucosa by ingested food. The current model of mucus secretion suggests that vagal stimulation induces the release of ACh, which leads to increases in [Ca2+]i and thus stimulates mucus secretion. Unlike for acid and pepsinogen secretion, cAMP does not appear to be a second messenger for mucus secretion.
Gastric surface cells secrete , stimulated by acetylcholine, acids, and prostaglandins
Surface epithelial cells both in the corpus and in the antrum of the stomach secrete . Despite the relatively low rate of secretion—in comparison with acid secretion— is extremely important as part of the gastric mucosal protective mechanism. The mucous gel layer provides an unstirred layer under which the secreted remains trapped and maintains a local pH of ~7.0 versus an intraluminal pH in the bulk phase of 1 to 3. As illustrated in Figure 42-13A, an electrogenic Na/HCO3 cotransporter (NBC) appears to mediate the uptake of across the basolateral membrane of surface epithelial cells. The electrogenic Cl-HCO3 exchanger SLC26A9 appears to mediate the exit of into the apical mucous layer.
FIGURE 42-13 Diffusion barrier in the surface of the gastric mucosa. A, The mucus secreted by the surface cells acts as a diffusion barrier for H+ and traps a relatively alkaline solution of . This titrates any H+ that diffuses into the gel layer from the stomach lumen. The alkaline layer also inactivates any pepsin that penetrates into the mucus. B, If H+ penetrates into the gastric epithelium, it damages mast cells, which release histamine and other agents, setting up an inflammatory response. If the insult is mild, the ensuing increase in blood flow can promote the secretion of both mucus and . If the insult is more severe, the inflammatory response leads to a decrease in blood flow and thus to cell injury.
Similar to the situation for mucus secretion, relatively limited information is available about the regulation of secretion. The present model suggests that vagal stimulation mediated by ACh leads to an increase in [Ca2+]i, which, in turn, stimulates secretion. Sham feeding is a potent stimulus for secretion via this pathway. A second powerful stimulus for gastric secretion is intraluminal acid. The mechanism of stimulation by acid appears to be secondary to both activation of neural reflexes and local production of PGE2. Finally, evidence suggests that a humoral factor may also be involved in the induction of secretion by acid.
Mucus protects the gastric surface epithelium by trapping an -rich fluid near the apical border of these cells
Mucous cells on the surface of the stomach, as well as in the gastric pits and neck portions of the gastric glands, secrete both and mucus. Why is this barrier so effective? First, the secreted mucus forms a mucous gel layer that is relatively impermeable to the diffusion of H+ from the gastric lumen to the surface cells. Second, beneath this layer of mucus is a microclimate that contains fluid with a high pH and high , the result of secretion by gastric surface epithelial cells (see Fig. 42-13A). Thus, this neutralizes most acid that diffuses through the mucous layer. Mucosal integrity, including that of the mucosal diffusion barrier, is also maintained by PGE2, which—as discussed in the previous section—stimulates mucosal secretion.
Deep inside the gastric gland, where no obvious mucous layer protects the parietal, chief, and ECL cells, the impermeability of the cells' apical barrier appears to exclude H+ even at pH values as low as 1. The paradox of how HCl secreted by the parietal cells emerges from the gland and into the gastric lumen may be explained by a process known as viscous fingering. Because the liquid emerging from the gastric gland is both extremely acidic and presumably under pressure, it can tunnel through the mucous layer covering the opening of the gastric gland onto the surface of the stomach. However, this stream of acid apparently does not spread laterally, but rather rises to the surface as a “finger” and thus does not neutralize the in the microenvironment between the surface epithelial cells and the mucus.
The mucous gel layer and the trapped alkaline solution protect the surface cells not only from H+ but also from pepsin. The mucus per se acts as a pepsin-diffusion barrier. The relative alkalinity of the trapped inactivates any pepsin that penetrates the mucus. Recall that pepsin is reversibly inactivated at pH values greater than ~3.5 and is irreversibly inactivated by pH values greater than ~7.2. Thus, the mucus/ layer plays an important role in preventing autodigestion of the gastric mucosa (Box 42-2).
Breakdown of the Gastric Barrier
The integrity of the gastric epithelial barrier can be conveniently judged by maintenance of a high lumen-negative transepithelial potential difference (PD) of approximately –60 mV. Several agents that cause mucosal injury, including mucosal ulceration, can alter the mucosal diffusion barrier. Salicylates, bile acids, and ethanol all impair the mucosal diffusion barrier and result in H+ (acid) back-diffusion, an increase in intraluminal [Na+], a fall in PD, and mucosal damage (see Fig. 42-13B). Three decades ago, Davenport proposed an attractive model to explain how H+, after having breached the mucosal diffusion barrier, produces injury to the gastric mucosa. Although several details of this original model have been modified during the ensuing years, it is still believed that entry of acid into the mucosa damages mast cells, which release histamine and other mediators of inflammation. The histamine and other agents cause local vasodilation that increases blood flow. If the damage is not too severe, this response allows the surface cells to maintain their production of mucus and . However, if the injury is more severe, inflammatory cells release a host of agents—including platelet-activating factor, leukotrienes, endothelins, thromboxanes, and oxidants—that reduce blood flow (ischemia) and result in tissue injury, including capillary damage.
Prostaglandins play a central role in maintaining mucosal integrity. For example, prostaglandins prevent or reverse mucosal injury secondary to salicylates, bile, and ethanol. This protective effect of prostaglandins is the result of several actions, including their ability to inhibit acid secretion, stimulate both and mucus secretion, increase mucosal blood flow, and modify the local inflammatory response induced by acid.
Acid entry into the duodenum induces S cells to release secretin, triggering the pancreas and duodenum to secrete
The overall process of regulating gastric acid secretion involves not only stimulation and inhibition of acid secretion (as discussed above), but also neutralization of the gastric acid that passes from the stomach into the duodenum. The amount of secreted gastric acid is reflected by a fall in intragastric pH. We have already seen that this fall in pH serves as the signal to antral D cells to release somatostatin and thus to inhibit further acid secretion, a classic negative-feedback process. Similarly, low pH in the duodenum serves as a signal for the secretion of alkali to neutralize gastric acid in the duodenum.
The key factor in this neutralization process is secretin, the same secretin that inhibits gastric acid secretion and promotes pepsinogen secretion by chief cells. A low duodenal pH, with a threshold of 4.5, triggers the release of secretin from S cells in the duodenum. However, the S cells are probably not pH sensitive themselves but, instead, may respond to a signal from other cells that are pH sensitive. Secretin stimulates the secretion of fluid and by the pancreas (see pp. 886–887), thus leading to intraduodenal neutralization of the acid load from the stomach. Maximal secretion is a function of the amount of acid entering the duodenum, as well as the length of duodenum exposed to acid. Thus, high rates of gastric acid secretion trigger the release of large amounts of secretin, which greatly stimulates pancreatic secretion; the increased , in turn, neutralizes the increased duodenal acid load.
In addition to pancreatic secretion, the duodenal acid load resulting from gastric acid secretion is partially neutralized by duodenal secretion. This duodenal secretion occurs in the proximal—but not the distal—part of the duodenum under the influence of prostaglandins. Attention has been focused on duodenal epithelial cells (villus or crypt cells) as the cellular source of secretion, but the possibility that duodenal originates, at least in part, from duodenal submucosal Brunner's glands has not been excluded. The mechanism of duodenal secretion is similar to that in the pancreatic duct (see Fig. 43-6), and involves both Cl-HCO3 exchange and cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. Patients with duodenal ulcer disease tend to have both increased gastric acid secretion and reduced duodenal secretion (Box 42-3). Thus, the increased acid load in the duodenum is only partially neutralized, so the duodenal mucosa has increased exposure to a low-pH solution.
During the past decade, our understanding of the etiology of duodenal and gastric ulcers has radically changed. Abundant evidence now indicates that most peptic ulcers are an infectious disease that in most (but not all) cases is caused by Helicobacter pylori, a gram-negative bacillus that colonizes the antral mucosa. Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for ~20% of ulcers. Although almost all ulcers that are not associated with NSAID use are secondary to H. pylori infection, many, if not most, individuals with evidence of H. pylori infection do not have peptic ulcer disease. The factors responsible for H. pylori–induced inflammation or ulceration are not known. However, the increase in gastric acid secretion that is present in most patients with duodenal ulcers may occur because H. pylori–induced antral inflammation inhibits the release of somatostatin by antral D cells. Because somatostatin normally inhibits gastrin release by antral G cells, the result would be increased gastrin release and thus increased gastric acid secretion. Indeed, as noted in Table 42-1, serum gastrin levels are modestly elevated in patients with duodenal ulcers.
Inhibition of acid secretion heals, but does not cure, H. pylori–induced peptic ulcers. However, antibiotic therapy that eradicates H. pylori cures peptic ulcer disease. For their pioneering work on H. pylori, Barry J. Marshall and J. Robin Warren shared the 2005 Nobel Prize in Physiology or Medicine. N42-5.
Barry J. Marshall and J. Robin Warren
For more information about Barry J. Marshall and J. Robin Warren and the work that led to their Nobel Prize, visit http://www.nobelprize.org/nobel_prizes/medicine/laureates/2005/ (accessed September 2014).