An Overview of Gastric Mucosal Injury and Healing
World Small Animal Veterinary Association World Congress Proceedings, 2004
Colin F. Burrows, BVetMed, PhD, MRCVS, DACVIM
University of Florida, College of Veterinary Medicine
Gainesville, FL, USA

The canine and feline stomach suffers from a wide spectrum of primary and secondary disease. Most, if not all of these can cause vomiting and abdominal pain and are associated with some degree of damage to the gastric mucosa. The purpose of this paper is to review the mechanisms that facilitate or impair gastric mucosal protection in order to permit better understanding and treatment of gastric disease.

Why doesn't the stomach digest itself? Physicians, physiologists and many others have been puzzled by this question since René Antonoine Ferchault de Réamur, the 18th century man of many sciences, showed that juice secreted by the stomach could digest meat. One answer of course is that it sometimes does. Under some 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 was made of porcelain.

Gastric juice contains hydrochloric acid, one of the most corrosive acids known. At the concentration secreted by the gastric mucosa this acid is capable of dissolving zinc and is deadly to cells. Yet in the stomach it ordinarily acts only to perform the useful actions of killing ingested bacteria, softening fibrous foods and promoting pepsin formation. In the normal stomach this corrosive juice is prevented from contacting and damaging the stomach wall by a complex and interrelated series of physical and chemical processes that are only now beginning to be fully understood. Collectively these processes are called the gastric mucosal barrier and comprise the structural and functional protection of the stomach against its own secreted acid and pepsin as well as against the ravages of refluxed bile and pancreatic enzymes and ingested abrasive or toxic materials. There are five interrelated components: 1) the gastricepithelial cells; 2) gastric mucosal blood flow and local acid base balance; 3) gastric mucus; 4) mucosal prostaglandins and associated cytoprotection; and 5) the epithelial cell basement membrane.

The Gastric Epithelial Cells

The epithelial cells of the gastric mucosa form a formidable barrier against penetration by luminal contents, including hydrogen ions. The cells have very tight junctions, a lipid-rich, hydrophobic, acid-repelling mucosal surface, and secrete bicarbonate and mucus.

The gastric mucosa is routinely exposed to trauma, indeed, focal destruction of the mucosal barrier is a normal physiologic event, occurring for example, during intragastric digestion of a meal, after thermal, mechanical or osmolar damage and after ingestion of several different types of drug. Normally, however, the mucosa can repair or minimize this damage almost as soon as it occurs by a process of epithelial cell migration called restitution. This is a physiological event in which the epithelial cells at the mouth of the gastric glands adjacent to a damaged area flatten themselves and project finger like processes called lamellipodia. These extend over the underlying basal membrane and eventually fuse to form a new intact epithelial barrier.

Gastric Mucosal Blood Flow

The gastric mucosal blood supply has been called the mainstay of the gastric mucosal defense mechanisms that sustain a healthy gastric mucosa. Mucosal blood flow is achieved in a variety of ways, foremost of which is a unique vascular supply that maximizes mucosal oxygenation, bicarbonate delivery and buffering. Bicarbonate, a byproduct of acid production, is carried up to the mucosal surface by capillaries that surround each gastric gland. This bicarbonate escapes from the capillaries into the submucosa underneath the mucosa from where it is taken up by the epithelial cells and secreted into the surface mucus layer. The bicarbonate is trapped here and neutralizes any hydrogen ions that may diffuse into the mucus layer. As a result, the surface of the mucosa is maintained at a pH of about 7.2 while the pH of the lumen may be as low as 1.5. The bicarbonate-rich mucosal blood flow also maintains intramucosal acid base neutrality such that any hydrogen ions that may leak into the submucosa through a damaged epithelium are quickly neutralised. A decrease in mucosal blood flow however, will result in an increase in mucosal hydrogen ion concentration with subsequent tissue damage.

Mucus Secretion

Mucus neck cells produce the bulk of gastric mucus. This forms a viscid unstirred protective layer of varying thickness over the surface mucosa that traps secreted bicarbonate and lubricates the lining of the stomach. When damaged the epithelial cells themselves rupture and release copious quantities of protective mucus that forms a bicarbonate-rich protective mucus cap over the denuded area. Surrounding epithelial cells can migrate over the basal membrane and under this protective mucus cap.

Prostaglandin Secretion and Cytoprotection

Cytoprotection refers to the ability of certain substances to maintain tissue or cellular integrity in the face of mucosal damage. The term was originally coined to describe the ability of prostaglandins to reduce or eliminate hemorrhagic damage in mucosa exposed to injury. The term has been extended however, to describe a similar protective ability for a large number of endogenous and exogenously administered substances with anti-ulcerogenic effects. Cytoprotection is based upon the ability of these substances to inhibit acid secretion, stimulate mucus and bicarbonate secretion, and increase mucosal cell turnover and blood flow. Prostaglandins PGE2 and PGF2aare perhaps the best known examples of cytoprotectants. However, IL-1 and TNF released during inflammation increase mucosal blood flow and cytoprotection, as do exogenously administered sulfhydryl compounds such as acetylcysteine, glutathione and penicillamine. Epidermal growth factor which is found in saliva as well as in the gastric mucosa plays an important role in maintaining and stimulating mucosal cell turnover.

The Basal Membrane

This, the last defensive barrier is important for the process of restitution. The basal membrane is permeable to fluid and electrolytes and when disrupted allows an inrush of hydrogen ions and proteases from the gastric lumen. These invoke an inflammatory response and mark the changeover from physiologic to pathologic (i.e., inflammatory) repair of the mucosa.

BARRIER DISRUPTION

Pathologic and inflammatory barrier disruption occurs in virtually every type of gastric disease as well as in a variety of less well appreciated circumstances such as stress, brain and spinal cord injury, hypotension, hypoadrenocorticism, sepsis, uremia, liver disease, hypoproteinemia and protein-calorie malnutrition (Table 1). Most instances of barrier disruption associated with this diverse group of disorders can be attributed to a decrease in gastric mucosal blood flow, except for the hypoproteinemic or cachectic patient in which decreased cell turnover also plays a role.

Table 1. Disorders associated with a disrupted mucosal barrier

 Gastric Disease

 Hypoadrenocorticism

 Liver disease

 Acidosis

 Sepsis (esp. peritonitis)

 Shock (septic > hypovolemic > traumatic)

 "Stress"

 Protein-calorie malnutrition

 Hypoproteinemia

 Enteritis (with vomiting)

 Uremia

 Hypoxemia

 NSAID therapy

 CNS and spinal cord injury

In humans and some other species, infection with the Gram negative gastric bacteria Helicobacter is associated with gastric and duodenal injury. Mucosal damage from infection with H. pylori in humans is associated with the cytotoxic effects of a number of bacterial metabolites including ammonia, endotoxin, and a variety of inflammatory peptides. The organism also inhibits somatostatin secretion allowing an increase in acid secretion. Strangely, these properties do not appear to be present in the Helicobacter species (e.g., H. felis, H. bizzozeroni) that infect the dog and cat. Gastric structure and function for example, are no different between infected and uninfected dogs. The exact role of Helicobacter infection, if any, in the genesis of gastric lesions in the dog and cat therefore remains to be elucidated.

Virtually every critically ill patient has some degree of gastric mucosal damage that is evidenced by gastric erosions or ulceration with associated hemorrhage. This sometimes "hidden" injury very often prolongs patient morbidity, and if unappreciated or untreated may progress to a serious or life-threatening condition. An appreciation of the processes of barrier disruption and repair, together with an understanding of current methods for facilitating or enhancing the repair process are therefore important for most clinicians.

THE RESPONSE TO INJURY

A break in the gastric mucosal barrier allows hydrogen ions and pepsin to diffuse into the mucosa from the lumen and sodium ions to diffuse in the opposite direction. Back-diffusion of acid and pepsin into the tissues stimulates further acid and pepsin secretion, decreases mucosal blood flow and decreases gastric motility. The acid also damages connective tissue and submucosal capillaries to cause focal mucosal hemorrhage and microulceration. If sufficiently severe and prolonged overt gastric ulceration may occur.

Mucosal integrity, however, is rapidly reestablished if the inciting cause is removed or if appropriate and prompt treatment is given. Of concern to the clinician are factors that may delay or impair epithelial cell restitution and the repair process, such as hypoxia, sepsis or concomitant drug therapy. Corticosteroids for example, decrease gastric epithelial cell renewal and while relatively harmless in the healthy animal may delay repair or exacerbate mucosal injury in the sick one. It should be noted however that methyl prednisolone sodium succinate at a dose of 30mg/kg/day for two days induced gastric hemorrhage in 100% of healthy normal dogs and that the synthetic prostaglandin misoprostol did not prevent the hemorrhage. Nonsteroidal anti-inflammatory drugs (NSAIDs) are another group of compounds that exacerbate underlying disease and delay repair, primarily through their inhibition of cyclooxygenase and a decrease in mucosal prostaglandin concentration. Recent attention has focused on the fact that there are two types of cyclooxygenase (cyclooxygenase 1 and 2 or COX-1 and COX-2). COX-1 is constitutively expressed in most cells and tissues, notably platelets, endothelial cells, stomach and kidney. COX-1 plays a key role in the synthesis of prostaglandins responsible for mucosal cytoprotection. COX-2 on the other hand is typically undetectable in normal tissue but is induced in inflammatory conditions by cytokines or lipopolysaccharides. NSAIDs exert their antiinflammatory effect through the inhibition of COX-2 whereas many of their adverse effects are due primarily to the inhibition of COX-1. Several COX-2 specific antiinflammatory drugs have recently been introduced and purportedly reduce inflammation while sparing the gastric mucosa. Aspirin inhibits both cyclooxygenases but in addition, when the intragastric pH is less than 4.0, it undergoes a change in lipid permeability and is absorbed directly into the gastric epithelial cell where it disrupts cellular function. The drug is also purported to facilitate bile reflux in the dog. The canine stomach is particularly sensitive to NSAIDs and none of these drugs should be considered "safe" in this species.

FACILITATION OF MUCOSAL REPAIR

The most important concept in dealing with the disrupted mucosal barrier is to recognize that disruption is widespread and that it can occur in such a wide variety of diseases (Table 1). Barrier disruption occurs routinely for example in hypoadrenocorticism, peritonitis, pyometra, pneumonia, liver disease, hypoproteinemia, severe trauma, uremia and in most if not all primary gastric diseases. The most important remedy in all these disorders is to treat the underlying disease. All other actions are of secondary, but nevertheless still considerable importance.

Drug therapy, however, remains the mainstay of treatment. These fall into two main groups 1) antisecretory drugs and 2) cytoprotectants that are usually combined to achieve an optimum effect (Table 2).

Table 2. Drugs that augment the mucosal barrier

Antisecretory

Cytoprotectants

Cimetidine 5mg/kg q8h

Misoprostol 3-4μg/kg q12h

Ranitidine 2mg/kg q12h

Sucralfate 0.25-1.0g/patient q8-12h

Famotidine 1mg/kg q24h

Aluminum ions to effect

Omeprazole 0.7mg/kg q24h

Bismuth subsalts to effect

Antisecretory Drugs

A variety of compounds have been used to reduce acid secretion but most widely used are the H2 receptor antagonists such as cimetidine, ranitidine and famotidine.

Cimetidine interferes with the cytochrome p450 system in the liver and can influence the action of some drugs (e.g., ketoconazole, theophylline, propranolol, quinidine and metronidazole) and the absorption or effect of others (e.g., metoclopramide and sucralfate). Cimetidine, however, is ineffective against aspirin-induced mucosal injury in dogs. Ranitidine binds much more strongly to the H2 receptor on the parietal cell and therefore requires a lower frequency of administration as well as indirectly increasing gastric motility. Cimetidine also has additional protective effects on the mucosal barrier (increased cell turnover, mucus production, mucosal blood flow, bicarbonate secretion and cellular integrity). Famotidine inhibits stress-induced decreases in gastric mucosal blood flow and has the benefit of once daily dosage which makes it attractive to many clients. The prophylactic use of H2 receptor antagonists should therefore be routine in critically ill patients.

Omeprazole, is another very effective antisecretory drug. Cimetidine, famotidine and ranitidine block only histamine-induced acid secretion but omeprazole blocks all acid secretion by inhibiting H+K+ATP'ase at the luminal surface of the parietal cell. While a major portion of the therapeutic efficacy of omeprazole involves inhibition of gastric acid secretion, some of its cytoprotective properties are probably associated with its action on the mucosal vasculature. Oral omeprazole for example, maintains mucosal blood flow in the face of mucosal damage and decreases mucosal production of the vasoconstrictor phospholipid platelet activating factor (PAF).

Cytoprotective Drugs

These include synthetic prostaglandins, sucralfate, antacids containing aluminum, and the bismuth sub-salts. Sucralfate is a complex polymer of sucrose with multiple substitutions of sulfate and aluminum salts. At a pH <4.0 it undergoes a change in chemical configuration, developing a positive charge which binds electrochemically with the negative charge in serum protein to form a protective layer over ulcerated areas which protects the mucosa against further injury by acid, pepsin and bile salts. The drug also stimulates the synthesis and release of prostaglandins, epidermal growth factor and nitric oxide as well as augmenting other aspects of the mucosal barrier such as gastric mucosal blood flow, bicarbonate secretion and mucus production. Sucralfate also stimulates angiogenesis in injured gastric mucosa.

The bismuth subsalts and aluminum containing antacids at doses less than those required to neutralize acid also exert beneficial effects on the mucosal barrier through augmented prostaglandin synthesis.

CONCLUSION

Gastric mucosal damage and repair are ongoing processes in the normal stomach with repair, primarily through epithelial cell restitution, rapidly restoring the ravages of normal wear and tear. The repair process however, may be impaired in gastric disease as well as in a variety of other diseases that weaken gastric defenses. If unrecognized and untreated this will increase patient morbidity with the likelihood of overt ulceration. Treatment with H2 receptor antagonists and cytoprotective drugs is critical to patient well being.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Colin F. Burrows, BVetMed, PhD, MRCVS, DACVIM
University of Florida, College of Veterinary Medicine
Gainesville, FL


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