Mechanisms of Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Damage ROBERTT. SCHOEN, M.D., F.A.c.P., RONALD J. VENDER, M.D. NewHaven, Connecticut
The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the gastric mucosa are well documented. The complex mechanisms of gastric damage, however, are not fully understood. This review examines current knowledge about the nor- mal function of the gastric mucosal barrier; the role of prostaglandins in cytoprotection and repair; the mechanisms by which aspirin and other weak organic acids are absorbed by the stomach; and the subsequent cascade of events-including ion trap- ping and back diffusion of hydrogen ions-that leads to gastric erosion and bleeding. A hypothesis describing NSAIDs dual insult on the stomach is advanced.
From the Department of Internal Medicine, Yale University School of Medi- cine, New Haven, Connecticut. Requests for reprints should be addressed to Robert T. Schoen. M.D., F.A.C.P.. Internal Medicine and Rheumatology, P.C., 60 Temple Street, Suite 6A. New Haven, Connecticut 06510. Manu- ;c$ submitted May 12, 1988, and accepted in revised form January 13,
T he use of sodium salicylate in 1875 to treat pa- tients with rheumatic disease [l] was followed by reports of dyspeptic indigestion in patients receiv- ing salicylates and other nonsteroidal anti-inflamma- tory drugs (NSAIDs) . Gastric mucosal damage is now recognized as the most important adverse effect of NSAIDs, causing gastrointestinal symptoms, ero- sions, ulcers, and upper gastrointestinal bleeding . The synthesis of aspirin (acetylsalicylic acid) by Hoff- man in 1899 from the more toxic salicylic acid reduced toxicity and introduced the modern era of NSAID therapy . Investigation continues in regard to the development of potent anti-inflammatory drugs that avoid gastric mucosal damage.
The problem of NSAID gastrointestinal toxicity has stimulated investigation of normal gastric defense mechanisms. Exactly how the stomach protects itself from the hydrochloric acid and pepsin it produces is not known. The protective mechanisms that must ex- ist, however, are grouped together by the term gastric mucosal barrier . The study of how aspirin and other NSAIDs induce gastric damage has been the study of how these agents break this barrier .
Gastric Defense: The Gastric Mucosal Barrier More than two centuries ago, Reaumur recognized
that gastric juice is capable of digesting meat [?I. This observation led to the concept of a gastric mucosal barrier. Claude Bernard believed that the layer of mu- cus that covers the surface epithelium of the stomach acts as a porcelain-like shell separating the epitheli- urn from its gastric contents [B]. Although mucus may indeed be important , the concept of a gastric muco- sal barrier must include modern observations of nor- mal gastric physiology, including hydrogen ion, bicar- bonate, and electrolyte secretion. For example, the electrolyte concentration in gastric juice varies with the rate of gastric secretion. At low secretory rates, gastric juice has a high sodium ion concentration and a low hydrogen ion concentration. At high secretory rates, these concentrations are reversed [lo]. This dis- covery suggested that the gastric mucosa is a diffusion barrier in which a sodium ion is exchanged for a hydro- gen ion at the mucosal cell surface [II].
Gastric Defense: Mucus and Bicarbonate Secretion In 1954, Hollander  proposed a two-component
gastric mu.cosal barrier consisting of the mucus layer together with the epithelial cells beneath it. In this model, hydrogen ion concentration is reduced at the epithelial cell surface by sodium secreted from inter- stitial fluid. Heatley  suggested that an un- stirred mucus layer allows the development of a pH gradient between the epithelial cell and the lumen. Allen and Garner  proposed that bicarbonate is se- creted by the mucosa and that mucus has gel proper- ties that limit the diffusion of hydrogen ion, creating a
April 1989 The American Journal of Medicine Volume 86 449
MECHANISMS OF NSAID-INDUCED GASTRIC DAMAGE / SCHOEN AND VENDER
Mltcosal cells (=retion)
mucus giycoprctein -
I pH7 -pHgraclient- pH l-2
rpepsn i k desr=k+d
pH gradient across the mucus layer (Figure 1). Dav- enport  viewed the mucus layer as having merely a lubricating function. He emphasized anatomic proper- ties of the lipid and protein gastric cell membrane and tight junctions between cells in limiting penetration of water-soluble compounds, including hydrogen ion. Gastric mucus is in fact a high-viscosity gel composed of glycoprotein polymers that reduce the rate at which hydrogen ion from the lumen and bicarbonate from the epithelial cells can mix . Recently, a pH gradient across the mucus layer has been demonstrated using pH-sensitive microelectrodes [14-161.
Bicarbonate is secreted by receptor-mediated active transport by the gastric mucosa [9,17,18]. In addition, vagus nerve stimulation increases bicarbon- ate output during the cephalic phase of gastric secre- tion . Although bicarbonate is actively secreted, the rate of secretion is only about 5 to 10 percent of maximal acid output . If a mucus-bicarbonate mod- el is correct, the gel properties of mucus must signifi- cantly limit the rate of reaction between secreted bi- carbonate and luminal hydrogen ion. In addition, other factors must maintain a gradient in which hy- drogen ion is secreted in much higher concentration than bicarbonate. For example, it has been shown that gastric mucus significantly retards penetration of pep- sin from the lumen . It has also been suggested that the mucus layer may thicken in response to injury, forming a framework for re-epithelialization of the mucosa .
Gastric Defense: Surface Hydrophobicity Hills and associates  found canine gastric muco-
sa to be exceptionally hydrophobic in contrast to the duodenal mucosa, which is hydrophilic. They postu- lated that phospholipids, high levels of which have been identified in gastric mucosa and gastric secre- tions , are concentrated on the luminal surface of the gastric epithelium. This phospholipid layer cre-
450 April 1989 The American Journal of Medicine VOhne 86
Figure 1. Surface neutralization. A mod- el in which the mucosa secretes bicar- bonate, and an unstirred viscous mu- cus layer on the epithelial cell surface permits the development of a pH gradi- ent that limits diffusion of hydrogen ion from the lumen. (Adapted with permis- sion from .)
ates a hydrophobic surface, which may significantly limit the diffusion of hydrogen ion from the lumen into the mucosa .
Gastric Defense: Mucosal Blood Flow and Reconstitution Several studies show that gastric mucosal blood flow
protects the mucosa from acid injury . If the gastric mucosal barrier is disrupted by acid, intracellular hy- drogen ion is removed by a compensatory increase in mucosal blood flow. If this compensatory increase is prevented, cell death occurs . There is also evi- dence that within the gastric microcirculation, trans- port of bicarbonate from the interstitium to surface epithelial cells helps to prevent acid injury .
Mucosal re-epithelialization within 30 minutes fol- lowing injury (reconstitution) with agents such as hypertonic saline, ethanol, and aspirin occurs in the amphibian gallbladder, duodenum, and colon , as well as in the amphibian and mammalian stomach . This process may be an important repair mecha- nism throughout the entire gastrointestinal tract. In an in vitro system, reconstitution is associated with a net alkalinization of the luminal solution during the first four hours, changing to a net acid secretion com- parable to that in control tissues by six hours. If an acidic luminal pH is maintained, reconstitution does not occur . Rapid epithelial reconstitution is prob- ably important in maintaining the anatomic integrity of the gastric mucosal barrier .
Gastric Defense: Prostaglandins Prostaglandins are a vital component of gastric mu-
cosal defense. These short-acting, widely distributed, 20-carbon chain, unsaturated fatty acids are found throughout the gut in locally high concentration. A major stimulus for their synthesis is perturbation of cell membranes, including cell trauma by acid or alkali . Prostaglandins have an anti-secretory effect on gastric acid production , but the ability of prosta-
MECHANISMS OF NSAID-INDUCED GASTRIC DAMAGE / SCHOEN AND VENDER
glandins to defend the stomach against injury by lumi- nal acid and other noxious agents at concentrations that do not inhibit gastric acid secretion is called gas- tric cytoprotection . In addition, a variety of irri- tants, including ethanol, hydrochloric acid, alkali, hy- pertonic saline, and thermal injury, stimulates prostaglandin production. In association with such stimulation, gastric necrosis is prevented when ani- mals are subsequently challenged with agents that would ordinarily damage the stomach. This phenome- non, termed adaptive cytoprotection, may protect the mucosa from the damaging effect of gastric lumi- nal contents .
Adaptive cytoprotection may result from prosta- glandin-mediated mechanisms, but this is not proven. Mild irritants that are protective do not always stimu- late endogenous prostaglandin synthesis, and prosta- glandin suppression by indomethacin has not univer- sally abrogated adaptive cytoprotection . Hawkey and associates  showed that the protective effect of 20 percent ethanol is present even after prostaglandin Es release is 86 percent inhibited by indom