Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage

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<ul><li><p>: REVIEW </p><p>Mechanisms of Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Damage ROBERTT. SCHOEN, M.D., F.A.c.P., RONALD J. VENDER, M.D. NewHaven, Connecticut </p><p>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. </p><p>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, </p><p>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) [2]. Gastric mucosal damage is now recognized as the most important adverse effect of NSAIDs, causing gastrointestinal symptoms, ero- sions, ulcers, and upper gastrointestinal bleeding [3]. 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 [4]. Investigation continues in regard to the development of potent anti-inflammatory drugs that avoid gastric mucosal damage. </p><p>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 [5]. The study of how aspirin and other NSAIDs induce gastric damage has been the study of how these agents break this barrier [6]. </p><p>Gastric Defense: The Gastric Mucosal Barrier More than two centuries ago, Reaumur recognized </p><p>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 [9], 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]. </p><p>Gastric Defense: Mucus and Bicarbonate Secretion In 1954, Hollander [12] proposed a two-component </p><p>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 [13] suggested that an un- stirred mucus layer allows the development of a pH gradient between the epithelial cell and the lumen. Allen and Garner [9] 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 </p><p>April 1989 The American Journal of Medicine Volume 86 449 </p></li><li><p>MECHANISMS OF NSAID-INDUCED GASTRIC DAMAGE / SCHOEN AND VENDER </p><p>Mltcosal cells (=retion) </p><p>HCO; - </p><p>Na+- </p><p>mucus giycoprctein - </p><p>I pH7 -pHgraclient- pH l-2 </p><p>Cl-Na+ </p><p>rpepsn i k desr=k+d </p><p>glycoprotein subunits </p><p>Lumen (mixing) </p><p>-H+ </p><p>- ci- </p><p>pH gradient across the mucus layer (Figure 1). Dav- enport [7] 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 [9]. Recently, a pH gradient across the mucus layer has been demonstrated using pH-sensitive microelectrodes [14-161. </p><p>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 [19]. Although bicarbonate is actively secreted, the rate of secretion is only about 5 to 10 percent of maximal acid output [9]. 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 [20]. It has also been suggested that the mucus layer may thicken in response to injury, forming a framework for re-epithelialization of the mucosa [21]. </p><p>Gastric Defense: Surface Hydrophobicity Hills and associates [22] found canine gastric muco- </p><p>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 [23], are concentrated on the luminal surface of the gastric epithelium. This phospholipid layer cre- </p><p>450 April 1989 The American Journal of Medicine VOhne 86 </p><p>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 [9].) </p><p>ates a hydrophobic surface, which may significantly limit the diffusion of hydrogen ion from the lumen into the mucosa [24]. </p><p>Gastric Defense: Mucosal Blood Flow and Reconstitution Several studies show that gastric mucosal blood flow </p><p>protects the mucosa from acid injury [3]. 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 [25]. 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 [26]. </p><p>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 [27], as well as in the amphibian and mammalian stomach [28]. 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 [29]. Rapid epithelial reconstitution is prob- ably important in maintaining the anatomic integrity of the gastric mucosal barrier [29]. </p><p>Gastric Defense: Prostaglandins Prostaglandins are a vital component of gastric mu- </p><p>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 [30]. Prostaglandins have an anti-secretory effect on gastric acid production [31], but the ability of prosta- </p></li><li><p>MECHANISMS OF NSAID-INDUCED GASTRIC DAMAGE / SCHOEN AND VENDER </p><p>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 [32]. 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 [30]. </p><p>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 [33]. Hawkey and associates [34] showed that the protective effect of 20 percent ethanol is present even after prostaglandin Es release is 86 percent inhibited by indomethacin. They found extensive superficial disruption of the sur- face epithelium following 20 percent ethanol adminis- tration and postulated that this desquamated debris may form a protective covering that could account for adaptive cytoprotection. </p><p>Although it is uncertain that adaptive cytoprotec- tion critically depends on prostaglandin synthesis, it is clear that prostaglandins enhance many of the postu- lated components of gastric mucosal defense. Prosta- glandins stimulate bicarbonate secretion [33] and the synthesis of mucus [35]. Prostaglandins increase mu- cus gel thickness [36]. As a result, prostaglandin Es enhances the pH gradient in mucus between the lu- men and epithelial cell surface [37]. </p><p>Prostaglandin Es increases the surface hydropho- bicity of gastric mucosa [38] by increasing surface- active phospholipids [39]. Both prostaglandin E and I enhance mucosal blood flow following gastric acid pro- duction [40], preventing erosions that are seen when such vasodilatation does not occur [41]. Prostaglan- dins may also protect the mucosa by stimulating sodi- um-active transport [42]. </p><p>Prostaglandins probably also have a repair function, stimulating rapid resolution of disrupted surface epi- thelium [43], although this has not always been found [44]. Repair mechanisms may include migration of basal cells toward the lumen to repair mucosal injury [45]. Also possible is enhanced DNA, RNA, protein, and collagen synthesis, which has been demonstrated in cutaneous tissue [46], but not for the gastric mucosa [471. </p><p>Gastric Defense: Sulfhydryl Compounds Ethanol induces a decrease in gastric non-protein </p><p>sulfhydryl compounds in association with mucosal erosions [48]. Aspirin- [49] and ethanol- [48] induced erosions can be prevented by preadministration of sulfhydryl compounds. These observations suggest that sulfhydryl compounds may mediate gastric cyto- protection. It is possible that prostaglandin-induced cytoprotection requires sulfhydryl compounds, since sulfhydryl blocking agents such as N-ethylmaleiamide prevent the mucosal cytoprotective effect of prosta- glandin Fsn [48]. In addition, ethanol-induced gastric damage is greater following administration of both a prostaglandin inhibitor, indomethacin, and a sulfhy- </p><p>dry1 blocker, N-ethylmaleiamide, than following ei- ther compound alone [50]. </p><p>Sulfhydryl compounds, such as reduced glutathi- one, which is found in high concentration in the stom- ach [51], bind free radicals that form following tissue injury by noxious agents [52]. Sulfhydryl compounds may also protect mucus, since mucus subunits are joined by disulfide bridges that, if reduced, render mucus water-soluble [53]. A vasoprotective effect for sulfhydryl compounds following ethanol-induced in- jury is also postulated [50]. </p><p>Much of the current understanding of the gastric mucosal barrier has been gained from investigating changes in mucosal integrity caused by acute manipu- lation with NSAIDs such as aspirin. Several studies, however, show that the stomach may become less sus- ceptible to these compounds over time [54,55] by com- pensatory mechanisms, which may include increased cell turnover and the emergence of younger cell popu- lations [56]. This phenomenon is called gastric adap- tation [55]. </p><p>NSAID Damage: Breaking the Gastric Mucosal Barrier Aspirin and most other NSAIDs are weak organic </p><p>acids. A solution of two aspirin tablets in 100 ml of drinking water has a pH of about 2.5 [57]. Aspirin damages the gastrointestinal tract in the absence of hydrochloric acid [58] and induces lesions in the buc- cal mucosa by direct acid damage [59]. Aspirin and indomethacin also increase basal [60] and maximally stimulated gastric acid secretion [61,62], which may contribute to NSAID-induced damage. </p><p>NSAID Damage: Ion Trapping Aspirin and other NSAIDs also damage the gastric </p><p>mucosal barrier by altering cell membrane permeabili- ty, allowing back diffusion of hydrogen ion. Weak organic acids such as aspirin are concentrated in the mucosal cell as a result of ion trapping [63-651. Be- cause of its lipid and protein membrane, the mucosal cell absorbs lipid-soluble compounds such as aspirin more readily than it does water-soluble compounds. </p><p>For example, acetic acid, which is lipid-soluble, dif- fuses across the mucosa three times faster than hydro- chloric acid, which is not [7]. In the strongly acid envi- ronment of normal gastric juice (pH 2.5), aspirin (pKa 3.5) is mostly non-ionized. As an undissociated acid, aspirin freely diffuses into the mucosal cell. Once in- side the cell, the much higher pH of the intracellular environment (pH 7) favors acid dissociation. In this ionized state, aspirin is water-soluble and trapped inside the cell. These events favor a strong concentra- tion gradient, moving dissociated ions of weak organic acids such as aspirin (pKa 3.5) [66] (Figure 2), indo- methacin (pKa 5.2), phenylbutazone (pKa 4.8), and other acidic NSAIDs into the gastric mucosa. This rapid absorption has been demonstrated for a variety of weak organic acids, including acetic acid (pKa 4.78), propionic acid (pKa 4.86), and butyric acid (pKa 3.90): as well as acetylsalicylic acid [7,67]. </p><p>NSAID Damage: Back Diffusion The rapid intracellular pen...</p></li></ul>

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