The Gastric Mucosal Barrier: Why the Stomach does not Digest Itself

Ever since René Antoine Ferchault de Réamur, the 18th century man of many sciences, showed that juice secreted by the stomach could digest meat, philosophers, physiologists, and physicians alike have been puzzled by the question: why does the stomach not digest itself? One answer, of course, is that it sometimes does. Under certain circumstances, gastric juice can produce ulcers and even destroy most of the stomach lining. Normally, however, the stomach wall staunchly resists attack; as Claude Bernard observed, it behaves as if it were made of porcelain [1,2].

Gastric juice contains hydrochloric acid, one of the most corrosive acids known. At the concentration secreted by the parietal cells in the gastric mucosa, gastric acid is capable of dissolving zinc and is deadly to cells. Yet in the stomach, hydrochloric acid ordinarily acts only to perform the useful functions of killing ingested bacteria, softening fibrous foods, and promoting pepsin production [2]. The corrosive juice is prevented from attacking the stomach wall by a complex physicochemical barrier termed the gastric mucosal barrier (GMB). The GMB was first defined by Davenport as "that property of the gastric mucosa which impedes diffusion of acid from the lumen into the mucosa and impedes diffusion of sodium ions from the mucosal space into the lumen" [3,4]. The barrier cannot be defined on a strictly anatomic basis, but is rather a collection of interdependent physical and chemical processes that act in concert to protect the gastric mucosa against secreted acid and pepsin [5,6]. It is now generally agreed that the barrier has eight basic components: (1) epithelial cell tight junctions, (2) the ability of the gastric epithelial cells to change shape - a process called restitution, (3) mucosal bicarbonate (HCO3-) secretion, (4) the hydrophobic apical membrane of the gastric epithelial cells, (5) gastric mucosal blood flow and local acid-base balance, (6) gastric mucus production and secretion, (7) the protective and regulatory effect of mucosal prostaglandins, and (8) the basal lamina [7-9].

In the normal stomach the gastric mucosa is under a continuous state of physical and chemical siege. It is exposed daily, not only to the potential ravages of acid and pepsin, but also to a wide variety of potentially damaging agents that include certain foods, a range of temperatures, hyperosmolar and abrasive substances, chemical damage from refluxed bile and pancreatic juice, as well as to bacterial toxins and a variety of potentially damaging drugs [10]. Some damage is inevitable under these circumstances, yet the gastric mucosa normally retains its integrity even under these attacks. The balance between normal gastric mucosal physiologic damage and repair is a dynamic process involving a variety of complex mechanisms. Clinically, however, when this process breaks down, acute gastric mucosal injury results, often with the accompanying signs of acute gastric disease. If the process is severe or ongoing, progression to chronic gastric disease is the almost inevitable sequel.

Although the mechanisms of disruption of the gastric mucosal barrier can vary widely, the end result is the same, namely erosion of the gastric mucosa, which allows acid to diffuse back into the submucosa and to initiate an inflammatory response. Mucosal epithelial erosion, hemorrhage, gastritis, and overt ulceration may develop if the process remains unchecked. Barrier disruption occurs to some extent in virtually every type of gastric disease as well as under a variety of sometimes less well appreciated circumstances such as neurologic disease, stress, hypotension, sepsis, and protein-calorie malnutrition. An appreciation of the mechanisms of acid secretion as well as barrier disruption and repair, therefore, are important for most clinicians, as is an understanding of approaches that enhance the repair process.

Gastric Acid Secretion

The mammalian stomach is a specialized organ of the digestive tract that serves to store and process food for subsequent intestinal absorption. One of its features, considered to be the hallmark of gastric function, is its ability to secrete acid. In most species this is a continuous process that varies in intensity in response to a variety of exogenous and endogenous stimuli. In the dog, however, and possibly in the cat, animals that ancestrally, at least, can go for days without eating, acid secretion is more variable, with the distinct possibility that little or no basal acid secretion occurs in these species [11].

The gastric mucosa consists of a variety of cell types, predominantly mucus-filled tall columnar epithelial cells, which form a single protective layer. The secretory unit of the gastric mucosa is the gastric (or oxyntic) gland, of which the normal human stomach has been estimated to contain approximately one billion. These contain parietal (acid-producing and secreting) cells, chief (pepsinogen-producing and secreting) cells, mucous neck cells, and a variety of endocrine cells. Mucous neck cells are relatively few in number and are scattered among the parietal cells. Parietal cells are located mainly in the isthmus and neck region of the gland, whereas chief cells are located at its base (Fig. 29-1) [12]. Adjacent to the parietal cells are histamine-secreting enterochromaffin-like (ECL) cells and somatostatin-secreting "D cells". The surface epithelial cells have a lifespan of about three days and are replaced by division of cells just below the opening of the gastric glands. Immediately below the surface epithelial cell layer is a rich network of blood vessels, nerves, and lymphatics supported by a connective tissue matrix, which collectively form the submucosa.

Figure 29.1. Diagram of tubular gastric (oxyntic) gland in the body of the mammalian stomach. (From I to S: Functional gastric morphology. In: Physiology of the Gastrointestinal Tract, 2nd ed. Johnson LR (ed). Philadelphia: Lippincott Williams & Wilkins, 1987, with permission.)

The stomach secretes hydrogen ions, sodium, chloride, pepsinogen, lipase, and varying quantities of mucus into its lumen. Hydrogen ions are secreted into the lumen of the gastric gland in exchange for potassium by an energy-dependent exchange enzyme in the mucosal surface of the parietal cell called the hydrogen potassium-adenosine triphosphatase (H+K+ -ATPase) pump (Fig. 29-2) [13]. During acid secretion, the H+K+ -ATPase secretes H+ ions into the lumen of the gland in exchange for K+ ions, which have previously moved out of the cell down their concentration gradient. Simultaneously, chloride ions move from the cell into the lumen down an electrochemical gradient. Water moves out of the cell in response to the subsequent osmotic gradient, to form hydrochloric acid. This acid then flows from the glands through pores in the overlying mucus, which acts to prevent back-diffusion of acid from the lumen [14].

Figure 29.2. Non-secreting parietal cell. The cytoplasm is replete with tubulovesicular membranes, which contain H+K+-ATPase. B.Acid-secreting parietal cell. The tubulovesicular membrane has fused with the apical plasma membrane to form a secretory canalicular membrane with numerous microvilli. H+K+-ATPase is inserted into the membrane so that the cell can secrete acid. (From the BSAVA Manual of Canine and Feline Gastroenterology. Thomas DA, Simpson JW, Hall EJ (eds)., 1996, with permission.)

Acid secretion can be stimulated by the binding of acetylcholine or histamine to specific receptors in the serosal membrane of the parietal cell. Gastrin, another important stimulus of acid secretion, is believed to bind to receptors on the ECL cells and to stimulate them to release histamine (Fig. 29-3). It can, however, also stimulate the parietal cell directly via CCK-B(2) receptor. When gastrin, acetylcholine, or histamine bind with the cell, a variety of second messengers are stimulated that increase intracellular cyclic AMP (gastrin and histamine) or calcium (acetylcholine) concentration. These in turn stimulate acid secretion.

Figure 29.3. Current concept of the role of the enterochromaffin-like (ECL) cell, gastrin- (G) and somatostatin-secreting (D) cells in the peripheral regulation of acid secretion by parietal cells. Nervous stimulation from the CNS causes release of acetylcholine from the myenteric plexus. This binds with a muscarinic M3 receptor on the parietal cell, which results in an increase in intracellular calcium concentration. Calcium in turn stimulates insertion of H+K+-ATPase into the canaliculi membrane. Release of histamine is brought about by either gastrin or acetylcholine binding to receptors on the ECL cell. Histamine binds with H2 receptors on the parietal cell, which increases intracellular cAMP. This activates H+K+H+K+-ATPase in the membrane. Gastrin also probably reacts directly with the parietal cell in the dog. Somatostatin released from D cells in the gastric mucosa inhibits both histamine and gastrin release. (From the BSAVA Manual of Canine and Feline Gastroenterology. Thomas DA, Simpson JW, Hall EJ (eds)., 1996, with permission.)

Gastric acid secretion is divided into four phases: basal, cephalic, gastric, and intestinal. The basal state, as has been mentioned, may be minimal in carnivores although it can be augmented by sepsis [15) and possibly by a variety of other stressful events. The cephalic phase of gastric secretion is activated by the thought (in man), sight, and smell of food via vagal impulses conducted from the brain to muscarinic receptors in the gastric mucosa. During the gastric phase of secretion, which accounts for 40 to 50% of the response to a meal, acid secretion is stimulated by both chemical and physical factors that include gastric distention and ingested protein. Amino acids in the duodenum are mainly responsible for initiation of the intestinal phase, primarily through stimulation of gastrin release.

After a meal, acid secretion is modulated by a negative feedback mechanism in which antral acidification inhibits further release of gastrin, possibly via the inhibitory effect of somatostatin [12]. The relative importance of and exact relationship between histamine, gastrin, and acetylcholine receptors in the stimulation of acid secretion is unclear. The two main activating receptors on the parietal cell are a histamine (H2) receptor and a muscarinic (M3) receptor. It is believed that the activity of the M3 receptor is regulated by acetylcholine released from nerve fibers, whereas activity of the H2 receptor depends on histamine released locally from the ECL cell. Release of histamine from the ECL cell results from the binding of either gastrin or acetylcholine to receptors in the ECL cell wall [16].

Acetylcholine and histamine are also the major stimuli for pepsinogen secretion by chief cells, although secretin also stimulates its release. Pepsinogen is always secreted in parallel with acid and is converted to pepsin, its active form, by acid at a pH of about 1.5 as well as by previously converted pepsin. Stimulation of mucus secretion from the mucus neck cells also appears to be under the control of acetylcholine. This mucus is more viscid than mucus released by rupture of the surface epithelial cells. An acid-stable lipase is released from the chief cells and mucous-producing cells that is responsible for the digestion of up to 30% of dietary fat [17,18].

Hydrogen ion secretion is accompanied by the passive secretion of chloride from the parietal cell and by the production of an equivalent amount of HCO3-. This is secreted from the base of the cell into the interstitium from where it is picked up by mucosal capillary vessels and carried to the systemic circulation.

Gastric secretion is inhibited by a low intraluminal pH, which inhibits gastrin secretion [16]. Secretion is also inhibited by hydrochloric acid, fatty acids, and hyperosmolar solutions contacting receptors in the duodenal mucosa. These negative feedback mechanisms ensure that acid secretion is proportional to need. Somatostatin secreted from D cells, adjacent to the parietal cells, is one of the principal inhibitors of acid secretion. D cells are also found in the gastric mucosa adjacent to the ECL cells where secreted somatostatin inhibits gastrin release (Fig. 29-3). Prostaglandins, which are secreted by a variety of mucosal cells, also exert a tonic inhibitory effect on acid secretion by decreasing cyclic AMP production in the parietal cell [16].

Components of the Barrier

Gastric Epithelial Cell Tight Junction

The stomach is lined by a layer of columnar epithelial cells, which form very tight junctions with each other and constitute the main anatomic portion of the gastric mucosal barrier [19]. These cells, however, are not completely impervious to luminal H+ nor to diffusion of tissue Na+. Small quantities of Na+ and H+ normally diffuse in both directions across the mucosa, with any H+ that diffuses into the mucosa being neutralized by tissue buffers. Gastric mucosal cells are formed by division from mucus neck cells and have a lifespan of about 3 days, after which time they are sloughed into the lumen and replaced by lateral migration of younger cells from the neck of the oxyntic gland [8]. Mucus neck cells are located in the neck and isthmus region of gastric glands (Fig. 29-1). Cells in the mucosal proliferative zone in the isthmus are responsible for the constant replacement of gastric epithelium in both health and disease [20].

Restitution

Studies of the mechanisms of gastric repair after mucosal damage by such substances as alcohol, salicylates, and bile salts revealed that, in areas of relatively superficial cell disruption not extending deep into the mucosa, much of the damage is repaired within minutes. This is accomplished by a process called restitution, which occurs by migration of still viable epithelial cells from areas adjacent to or just beneath the injured surface cells [13]. After the necrotic surface cells exfoliate, the viable mucus cells in the upper gastric pits immediately flatten, extend finger-like projections called lamellipodia, and migrate across the exposed basal lamina to restore an intact cell layer over shallow defects (Fig. 29-4). However, deeper lesions or ulcers require new cells to fill in the defect. The process of restitution occurs within minutes of injury and before the appearance of an extensive inflammatory response or cell proliferation [9,19). The response is evoked, at lease in part, in response to hyperemia invoked by a capsaicin-sensitive emergency neural response system [21]. If gastric acid remains in contact with the mucosa, damage is ongoing, the basal lamina is destroyed along with the mucosa, and the substratum necessary for restitution is removed. This can result in persistent macroscopic lesions that may bleed, invoke a classic inflammatory response, and become clinically significant.

Figure 29.4. Low-power scanning electron micrograph of ethanol-disrupted rat gastric epithelium with much of the interpit basal lamina exposed. Many mucus cells from the gastric pits (GP) have lamellipodia (arrows) extending onto the basal lamina (x 1500). (From Lacy ER, Ito S: Rapid epithelial restitution of the rat gastric mucosa after ethanol injury. Lab Invest 51:573-583, 1984 with permission from Lippincott Williams & Wilkins. - PubMed - )

The shed surface cells are believed to play an important role in protecting the mucosa from further injury and to facilitate the process of re-epithelialization [22]. When traumatized, the apical plasma membrane of the shed cells ruptures, spilling mucoid contents and contributing to a gelatinous mass that contains mucus, cellular debris, necrotic tissue, and trapped alkaline exudate from damaged capillaries. It is believed that this layer may provide a protective microenvironment for reconstitution [23]. Each of these responses to superficial injury, namely formation of a protective mucoid layer, flow of alkaline mucosal fluid that may act to dilute luminal noxious agents, and rapid restitution of superficial epithelial cells appears to help prevent the formation of deeper hemorrhagic lesions and subsequent pathology [23]. Indeed, factors that facilitate or impair these early mucosal defense mechanisms are now believed to be of far greater importance in the development and repair of gastric damage than is the integrity of the classic gastric mucosal barrier itself [23]

Bicarbonate Secretion

Under normal circumstances HCO3-, produced as a by-product of H+ secretion, is present in abundance in the gastric mucosa. Some of this HCO3- is taken up by mucosal cells by means of a prostaglandin-dependent pump mechanism in exchange for chloride. The HCO3- is transported across the cell and secreted with mucus into the lumen. At one time it was believed that secreted HCO3- was trapped in the surface mucus where it neutralized H+ back-diffusing from the lumen [24-26]. Until recently, epithelial HCO3- secretion was accepted as the most important defense mechanism against acid [26]. This theory has been called into question by more recent work that shows the surface pH is kept constant at a pH of about 4 by dual secretion of HCO3- and acid as needed into a surface unstirred layer [27]. In the mouse at least, pH control at the protective surface pH gradient is regulated by cyclooxygenase-1 (COX-1) [28].

Gastric Epithelial Cell Membrane

The luminal surface of gastric epithelial cells contains a layer of surface-active phospholipids that confers a degree of hydrophobicity to the cell surface [29]. Phosphatidyl-cholines are present in high concentrations in the luminal membrane of gastric mucosal cells and are oriented so that the hydrophobic end of the molecule is at the exterior surface. These hydrophobic molecules are believed to render the cell resistant to any acid that permeates the mucus layer. When the lipid layer is damaged however, the route is opened for acid to permeate into the cell and begin destruction.

A number of lipid-soluble non ionized substances can easily disrupt the membrane and penetrate the epithelial cells to initiate gastric mucosal damage. Bile salts, for example, have been shown to disrupt the mucosal barrier and initiate cell damage [30], whereas lipid-soluble bile acids are taken up directly into the cell to cause mucosal injury from within the cell [31]. Reflux of bile into the stomach is a normal physiologic event in most species; however, it is usually quickly cleared so that no lasting damage is done to the gastric mucosa [32]. If normal clearance mechanisms fail, prolonged contact ensures membrane damage and development of gastritis [33]. Part of the damage caused by refluxed intestinal content is also caused by lysolecithin, a potent membrane-toxic phospholipid formed by the action of pancreatic phospholipase on biliary lecithin in the duodenal lumen [34]. Prolonged reflux of upper intestinal content causes extensive mucosal damage and chronic gastritis.35 In endotoxemia, exposure of the stomach to bile causes macroscopic injury to the gastric mucosa [36,37].

Aspirin has long been recognized as a substance that disrupts the mucosal barrier and causes extensive mucosal damage [38]. In humans, for example, ingestion of a single aspirin tablet results in the loss of between 0.5 and 2.0 ml of blood [39]. In some susceptible individuals much larger blood volumes may be lost and severe mucosal lesions may develop. The same situation can occur in the dog [40]. The mechanisms of aspirin damage are complex, but the most important is through a pH-dependent effect on mucosal hydrophobicity. At a pH of less than 3.5 to 4.0, acid is in its lipid-soluble form and disrupts the cell membrane. At a higher pH, aspirin is lipid-insoluble and little or no direct damage is done [41]. Another important effect is the inhibitory effect of aspirin and other NSAIDs on cyclooxygenase (see further on).

Gastric Mucosal Blood Flow and Local Acid-Base Balance

An adequate mucosal blood flow is critical for barrier integrity. If mucosal blood flow is decreased, gastric mucosal erosions and hemorrhage almost inevitably develop [42]. It was once thought that mucosal damage developed because of tissue hypoxia, but microanatomic and physiologic studies have shown that delivery of HCO3- to the mucosa and the prevention of local acidosis are much more important.

Anatomic studies have shown that the gastric arteries supply an arterial network in the submucosa from which arterioles penetrate the muscularis mucosae to supply the mucosal capillaries with blood (Fig. 29-5). These capillaries run both in between and parallel to the oxyntic glands and are interconnected by short capillaries parallel with the mucosal surface. These capillaries form short loops around the mouth of the gastric gland before joining the collecting veins, which penetrate the muscularis mucosae vertically to form an extensive network of veins at the submucosal level [7]. Bicarbonate, produced as a by-product of H+ synthesis in the parietal cells, escapes to be picked up by the vertically flowing capillaries, which are especially fenestrated at the mucosal surface to facilitate HCO3- flux. A small proportion of HCO3- escapes while the rest is carried to the systemic circulation (Fig. 29-6) [43,44].

Figure 29.5. Three-dimensional view in the blood supply to the gastric mucosa. (From Miederer SE: The gastric mucosal barrier. Hepato-gastroenterology 33:88-91, 1986, with permission of IASG.)

Figure 29.6. Schematic diagram of the vascular organization in oxyntic mucosa (right) and the proposed mechanism for vascular transport of bicarbonate toward the surface mucus cells from deeper within the mucosa (inset left). (From Gannon B, et al. Mucosal microvascular architecture of the fundus and body of the human stomach. Gastroenterology 86:866-875, 1984, with permission of WB Saunders). - PubMed -  

The epithelial cell membrane is not totally impervious to H+ ions, which diffuse through the intact gastric mucosa in relatively small amounts. Mucosal HCO3-, however, normally neutralizes this acid to maintain a normal tissue acid-base balance. If the barrier is damaged, H+ diffusion increases and HCO3- buffers are reduced [9]. When tissue buffers are exhausted, the tissues become acidotic and submucosal damage develops.

In that it carries HCO3- to the mucosa to maintain normal tissue acid-base balance, gastric mucosal blood flow is critical to the prevention of gastric lesions. Systemic acid-base balance is also important in that with acidosis less HCO3- is available for mucosal protection. This is one of the reasons advanced for the development of gastric lesions in critically ill or hypotensive individuals. It has been shown, for example, that intravenous sodium HCO3- not only prevents the decreases in gastric intramural pH induced by hemorrhagic shock but also prevents mucosal ulceration.45 Plasma HCO3- concentration also plays a key role in mucosal resistance to ulceration in experimentally induced canine gastric dilatation [46]. It has also been observed that the absolute amount of H+ that diffuses into the tissue from the luminal solution is less important in causing ulceration than the ability of the tissue to dispose of influxing H+ by neutralization with mucosal HCO3- [47].

Gastric mucosal blood flow is regulated by constriction and dilation of submucosal arterioles. Smooth muscle in these arterioles constricts to inhibit mucosal blood flow under a variety of conditions, including hypotension, stress, and sepsis as well as in response to a variety of vasoconstricting drugs [48,49]. Prostaglandins, beta-adrenergic agents, and gastrin all increase mucosal blood flow and, thereby, reduce gastric mucosal damage. This is one of the mechanisms by which prostaglandins are thought to exert cytoprotection (see further on) [50].

Gastric Mucus and Mucus Secretion

The gastric mucosa is covered by a variable layer of mucus between 5 and 200 μm thick that is believed to play a multifactorial role in mucosal defense. Composed of various mucopolysaccharides, glycoproteins, and water, mucus is secreted by the mucus neck cells in the parietal glands and by the gastric epithelial cells themselves. Mucus occurs in two physical forms: water soluble and water insoluble. The water insoluble form is produced by the mucus neck cells and consists of a thin layer of stable gel that firmly adheres to the gastric mucosal surface. Adherent mucus is impermeable to large proteins and thus protects the mucosa against peptic proteolysis. Water-soluble mucus comes from the surface epithelial cells, is less viscous, and acts as a lubricant to prevent mechanical damage to the mucosa. The adherent insoluble mucus provides a stable unstirred layer that traps secreted HCO3- to cause an alkaline interface between the surface and the lumen. Microelectrode studies showed a pH gradient within the mucus gel that varied somewhat among species and experimental conditions. The gradient peaks around 6.6 to 7.0 near the apical membrane [9]. More recent work has shown that this gradient may be only a part-time defender of the gastric epithelium, however, present only when the luminal pH is 3 or below [51,52]. The ability of mucus to form a pH gradient by trapping HCO3- at the epithelial cell surface (Fig. 29-7) provides a mechanism that is believed to reduce acid diffusion into the mucosa by neutralization with concomitant production of carbon dioxide and water [53].

Figure 29.7. Gastric mucus pH gradient. (From Turnberg LA: Gastric mucus, bicarbonate and pH gradients in mucosal protection. Clin Invest Med 10:178-180, 1987.) - PubMed -  

The neural emergency response system enhances mucus production after gastric injury. Mucus flows copiously out of the gastric glands and spreads over the mucosal surface to form a protective cap over the damaged area and restituting cells beneath [21]. Much of the mucus cap, however, comes from mucus in the disintegrating damaged epithelial cells themselves. Viscous mucus produced by the mucus neck cells in the upper regions of the gastric glands forms strands of thicker mucus that hold the cap in place. This facilitation of repair, by holding a HCO3- -rich cap over damaged areas while epithelial integrity is reestablished, is believed to be one of the most important functions of gastric mucus [54].

Various agents such as E-type prostaglandins, calcium, and glucagon stimulate both gastric mucus and HCO3- secretion, whereas compounds such as NSAIDs and bile salts decrease them.

Prostaglandins and Cytoprotection

Prostaglandins are found in high concentrations in the gastric mucosa and gastric juice and have been shown to protect the gastric and duodenal mucosa against injury, a function that has been termed cytoprotection [54]. Prostaglandins are found in a variety of cells in the gastric mucosa including mast cells, macrophages, and endothelial cells and are synthesized locally from arachidonic acid via the action of cyclooxygenase. Since Vane in 1971 showed that acetylsalicylic acid inhibits the cyclooxygenase system and thus the synthesis of prostaglandins, and hypothesized that this explained not only the therapeutic effects of acetylsalicylic acid but also its gastric side effects, there has been a tremendous amount of interest in the effect of prostaglandins on the stomach [55]. Prostaglandins promote mucosal defense through a variety of actions (Table 29-1), most important of which are the inhibition of acid output, augmentation of HCO3- and mucus secretion, and regulation of mucosal blood flow [56,57]. The wide range of effects of prostaglandins listed in Table 29-1 demonstrates their overall importance in gastric mucosal protection. Their synthesis can also be stimulated by a variety of mild irritants, with subsequent protection against more severe damage [56]. A deficiency of prostaglandins can result in a mucosa that looks and functions normally but that is more susceptible to injury [56].

Given the wide range of beneficial effects of prostaglandins, it is no wonder that exogenous stimulation by the synthetic prostaglandin misoprostol offers some protection against NSAID-induced mucosal damage. Various other compounds have also been shown to exert a protective effect, at least in part, through stimulation of endogenous prostaglandin synthesis. These include sucralfate, arachidonic and linoleic acids, cimetidine, bismuth, and possibly, aluminum-containing antacids [8,56]. The hormone gastrin and salivary epidermal growth factor also have cytoprotective effects through a trophic effect on the gastric mucosa [58]. Even milk, the oldest ulcer remedy, has been shown to contain large quantities of PGE2 and to protect against stress ulcers in rats [59].

Basal Membrane

Destruction of the surface epithelial cells leaves the basement membrane exposed. This is permeable to alkaline proteinaceous tissue fluid, which exudes as part of the repair process. The basal membrane is the final barrier, however, and is essential as a surface for the spread of epithelial lamellipodia and associated reconstitution. Its destruction, which is heralded by the appearance of red blood cells on the mucosal surface, leaves the path open for erosion and ulcer formation and invokes the inflammatory process [7].

The Response to Injury and Gastric Disease

One of the basic tenets of gastric pathophysiology has long been that a break in the gastric mucosal barrier results in increased gastric mucosal permeability to hydrogen ions and loss of sodium ions into the lumen. Back-diffusion of acid into the mucosa has a variety of consequences, including the stimulation of parietal and chief cells to secrete more acid and pepsinogen [23]. This acid diffuses across the broken barrier, repeating the cycle and exhausting intracellular and tissue buffers. Nerve endings are stimulated, invoking the neural emergency response system, which induces local smooth muscle contraction, and in humans at least, is associated with pain [21]. The decrease in mucosal pH also stimulates mucosal mast cells to release histamine and initiate an inflammatory response. This histamine stimulates the parietal cells to secrete even more acid and dilates precapillary sphincters, which increase mucosal blood flow through a prostaglandin-mediated response. Histamine is also believed to increase capillary permeability and to allow plasma protein and fluid to escape into the interstitium to cause local edema. Rapid diffusion of acid into the mucosa can break down capillary walls and trigger hemorrhage (Fig. 29-8). Events so far can be considered a virtually normal physiologic event because tiny superficial hemorrhages are sometimes seen during digestion of a meal. These, however, are transient and are quickly repaired. The same processes also occur in disease, but if the insult is non-physiologic, if it is widespread or ongoing, then the normal repair processes are inadequate, and gastritis, possibly with gastric hemorrhage and the signs of gastric disease, develops.

Figure 29.8. The normal gastric mucosal barrier (left) and the broken gastric mucosal barrier (right). The normal stomach is prevented from autodigestion by a variety of physical and chemical defense mechanisms. Acid production in the parietal cells results in concomitant production of bicarbonate. The acid diffuses out of the cell into the mucosa where it is picked up by the uniquely arranged capillaries that flow beside each gastric gland and carry the acid to the surface. The acid then diffuses out of the vessels into the mucosa and the surface epithelial cells. It diffuses from the epithelial cells into the lumen where it is trapped in surface mucus secreted by mucus neck cells. Acid that diffuses back into the mucosa is thus neutralized by the bicarbonate. The biocarbonate maintains the surface of the cells at a pH of about 7 in contrast to the pH in the lumen, which can be as low as 2.5. The epithelial cells also contain a high proportion of hydrophobic phospholipids in the apical surfaces that also acts to repel acid. The cells have tight junctions that prevent intracellular acid flow. The mucosal blood flow also maintains good tissue oxygenation and local acid-base balance. Mucosal blood flow is under the influence of prostaglandins, particularly PGE2, which is produced by a variety of mucosal cell types. When the mucosa is damaged, mucosal cells rupture and release mucus that forms a protective cap. This cap protects undamaged cells at the periphery of the lesion that change shape and cover the lesion by growing over the basement membrane, a process called restitution. Acid in the mucosa overwhelms local buffering capacities and causes cell death and the release of histamine from mucosal mast cells. Histamine augments acid secretion from parietal cells and causes constriction of smooth muscles in blood vessel walls that diminishes mucosal blood flow and exacerbates tissue damage. Mucosal blood flow can also be disturbed by stress-induced submucosal vasoconstriction. This process also removes tissue buffer capacity and disrupts the barrier. (From Burrows CF: Vomiting and regurgitation in the dog. Viewpoints in Veterinary Medicine, 1990, with permission of ALPO Pet Center, ALPO Petfoods Inc., Pennsylvania.)

The gastric mucosal barrier is disrupted in virtually all types of gastric disease (Table 29-2) as well as in a variety of other and perhaps less well appreciated situations (Table 29-3). Of concern in the development of overt gastric disease in this latter group are factors that may delay or impair either epithelial cell restitution or the repair process. Corticosteroids have been shown to delay epithelial cell renewal and, in high doses, to cause mucosal damage [60-62].

Gastric mucosal injury is well documented in a variety of clinical situations in humans. It occurs for example, during severe stress, hypotension, sepsis, and uremia, as well as with severe burns, intracranial lesions, and bile reflux. It also occurs after ingestion of certain agents such as alcohol, aspirin, or other NSAIDs [8,48]. Superficial erosions or ulcerations that develop in individuals who are victims of shock, trauma, burns, or sepsis, and especially, peritonitis are called stress ulcers (Table 29-4) [10]. These are located primarily in the fundic mucosa and are superimposed on a background of erosive gastritis. It has been estimated that approximately 5% of patients who are the victims of shock, trauma, burns, and sepsis have major gastrointestinal hemorrhage during the course of their illness. Risk factors for gastric hemorrhage include hypotension, continued sepsis, jaundice, renal disease, and hypoxia [63-65]. Specific mechanisms for barrier disruption and inhibition of the normal restitution and repair processes in these patients are unclear, but it is believed that mucosal ischemia with subsequent local acidosis is most important [10].

Gastric mucosal injury and ulceration under such circumstances are less well documented in veterinary medicine, although clinical impression and anecdotal reports suggest that they may be much more widespread than is generally realized. Gastric hemorrhage occurred in 90% of dogs undergoing spinal surgery combined with administration of methylprednisolone sodium succinate [66]. In the dog, ulcers have been associated with peritonitis and liver disease [67], with protein-calorie malnutrition [68], and gastric erosions and hemorrhage with hypoadrenocorticism [69]. Gastroscopy in animals with such diverse conditions as peritonitis, hypoxia, pneumonia, chronic vomiting, systemic mastocytosis, liver disease, pyometra, feline infectious peritonitis, carcinomatosis, pancreatitis, and antral mucosal hypertrophy has revealed the presence of often severe and yet clinically unsuspected erosive gastritis with hemorrhage or frank ulceration (Burrows, unpublished observations).

Aspirin and other NSAIDs are notorious for the damage they cause to the mucosal barrier. This damage is achieved in a variety of ways, including damaging the mucosal cell membrane and enhancing mucosal cell permeability; inhibiting active mucosal ion transport; producing changes in mucosal blood flow; decreasing mucus production; and inhibiting prostaglandin synthesis [70]. Of all of these, the impact on prostaglandin synthesis through the inhibition of COX may be the most important. After Vane [55] showed that NSAIDs inhibited COX, the next great step in our understanding came in the early 1990s with the demonstration that COX had two isoforms: COX-1, which was constitutively expressed; and COX-2, which was inducible [71]. COX-2 is rapidly up-regulated at inflammatory sites and is responsible for the formation of pro-inflammatory prostanoids. COX-1 is responsible for the production of physiologically relevant prostanoids such as those in the stomach and platelets. Pharmacology defined the selectivity of existing NSAIDs on these COX enzymes and played a key role in producing a new generation of COX-2-selective drugs. These drugs would, it was hoped, have much reduced toxic side effects, particularly on the stomach [71]. COX-2, however, also has a physiologic role, being involved, for example, in the maintenance of fluid balance by the kidney. The COX-1 and -2 models, however, did not fully explain the antipyretic and analgesic effects and non-anti-inflammatory effects of acetaminophen. This might be explained by a variant of COX-2 now named COX-3 [72,73]. The proposed pathways are shown in Fig. 29-9. Different NSAIDs have different effects on the gastric mucosa but are most severe when the drugs are administered orally. Parenteral NSAIDs also have an effect, however. Much of the local effect perhaps can be attributed to the action of some NSAIDs, especially aspirin, in the acid milieu of the stomach to damage the hydrophobic lipid layer [41], whereas the systemic effect is a result of the inhibition of COX.

Although all NSAIDs cause gastric mucosal damage, there is a wide interspecies susceptibility to specific drugs that may be associated with varying susceptibility of COX to different NSAIDs and to different metabolic pathways (Table 29-5). Aspirin, flunixine, and phenylbutazone for example, seem relatively well tolerated in the dog, although aspirin at a dose needed to obtain analgesic blood levels still causes gastric hemorrhage [74]. Wide individual susceptibility also exists. Flunixine, for example, appears to be relatively well tolerated over the short term in most dogs but caused severe ulceration after only 2 days of treatment in an apparently susceptible patient (Burrows, unpublished observations). These drugs, therefore, should always be used with caution because we currently have no means of identifying susceptible individuals. Other NSAIDs should never be used in veterinary medicine. Indomethacin and naproxen for example, cause severe, often fatal gastric and duodenal ulceration and hemorrhage in the dog [75-78].

Facilitation of Barrier Repair

One of the basic tenets of medicine is that, in order to diagnose a disease, one has first to suspect it. The purpose of this chapter is to alert the reader to the possibility that gastric mucosal disease may be present not only in a variety of gastric diseases (Table 29-2) but also in a wide range of other disorders (Table 29-3). Recognition and appropriate treatment of barrier disruption may well reduce patient morbidity and mortality.

In dealing with the broken barrier, one first has to identify and, if possible, treat the underlying disease. All other actions are of secondary but nevertheless still considerable importance. Much of the mucosal damage comes from secreted acid, and one of the most important therapeutic approaches is to reduce acid output. This can be accomplished, at least to some extent, by dietary manipulation and, more importantly, by antisecretory drugs. Mucosal repair is also facilitated by a variety of cytoprotectants that protect the damaged mucosa from further acid damage.

As in most species, food is a potent stimulus to gastric secretion in the dog and cat. Since these species have little or no basal acid output, however, mucosal repair in many acute diseases may be facilitated by withholding food for 24 to 48 hours. Afterward, avoiding high-protein meals and providing frequent feedings in small quantities to reduce acid output may also be useful. This constitutes only supportive care, however, and most patients require additional antisecretory or cytoprotective drug therapy.

Antisecretory Drugs

The old maxim "no acid no ulcer" [79] is as true today as it ever was. A variety of substances can be used to reduce acid output but most widely used are the H2 receptor antagonists and proton pump inhibitors (PPIs). Cimetidine, famotidine, and ranitidine are most widely used H2 receptor antagonists in veterinary medicine. These drugs combine with the histamine receptors on parietal cells to inhibit histamine-stimulated secretion. They inhibit not only the acid secretory response to histamine, but also the response to cholinergic agents, gastrin, food, and vagal stimulation [12]. Their use should perhaps be routine as prophylaxis against mucosal injury in critically ill or stressed patients (Table 29-3 and Table 29-4). Cimetidine is ineffective against aspirin-induced mucosal injury in the dog [80], probably because in partly reducing acid synthesis, cimetidine also reduces HCO3- production and subsequent mucosal buffering [70]. Famotidine at a twice-daily dose appears to be the most effective drug in this class at reducing gastric acid secretion in the dog [81].

The PPIs (e.g., omeprazole, pantoprazole, lansasoprole, esomeprazole) block the Na+H+-ATPase in the parietal cell in its secretory state. They are the most effective of the available drug classes in blocking acid secretion and are indicated in a spectrum of severe gastric diseases [82]. One study has shown that pantoprazole and omeprazole are effective in reducing acid secretion in dogs. Twice-daily dosing of omeprazole was the only regimen tested, however, that approached the potential therapeutic efficacy for acid-related disease when assessed by criteria used for human patients [81]. Omeprazole given once daily lessened aspirin-induced gastritis in the dog [83]. No data have been published for cats.

Cytoprotectants

Cytoprotection is defined as protection against gastric mucosal injury by a mechanism other than inhibition or neutralization of acid secretion [84]. Cytoprotective drugs include the synthetic prostaglandins, sucralfate, aluminum-containing antacids, bismuth compounds, and carbenoxolone (Table 29-5). It is possible that cimetidine also exerts some of its protective effect through this mechanism. In general, cytoprotective drugs promote the mechanisms responsible for maintaining a normal barrier, including increased mucus and HCO3-secretion, increased mucosal blood flow, promotion of apical cell restitution, phospholipid synthesis, and maintenance of vascular permeability to HCO3-.

Misoprostol and sucralfate are the most widely used cytoprotectants. Misoprostol, a synthetic prostaglandin that is effective when given orally, reduces the gastric mucosal side effects of NSAIDs. Sucralfate is a complex polymer of sucrose with multiple substitutions of aluminum sulfate. At a pH of less than 4.0 in the stomach, this compound undergoes a change in chemical configuration, develops a positive change, and binds electrochemically with negatively charged proteins leaking from the damaged mucosa [85]. In so doing, it forms a protective barrier over the damaged mucosa. The drug appears to be most useful in veterinary patients with gastric mucosal disease and was shown to be effective in lessening aspirin-induced gastritis [83]. It binds cimetidine, however, and the two drugs should not be given orally at the same time. Cimetidine, sucralfate, and misoprostol were ineffective in prophylaxis of gastrointestinal bleeding in dogs undergoing spinal surgery after having received methylprednisolone sodium succinate [66]. Omeprazole or pantoprazole may be more effective in these patients.

In conclusion, it should be appreciated that barrier disruption can occur under a wide variety of disease conditions. It should be considered as a complicating factor in most, if not all, critically ill patients. Mucosal protection therefore should be a routine part of therapy in such patients.