The gastric mucosa possesses a number of mechanisms permitting resistance to damage from its own secreted acid. No single mechanism can account for gastric mucosal defense. Mucosal permeability to acid, active ion transport, blood flow, mucus secretion, epithelial restitution, and prostaglandin synthesis are among the multiple factors involved in gastric mucosal defense. Non-steroidal anti-inflammatory drugs (NSAIDs) cause gross mucosal damage by affecting these defenses. The net effect of NSAIDs is to make the mucosa more susceptible to the damaging effects of acid in the lumen. Acid plays a dual role in this process, by increasing drug absorption (which in turn increases mucosal permeability) and by diffusing from the lumen into the mucosa. If a sufficient amount of acid entering the tissue is unbuffered, necrosis occurs. NSAIDs affect tissue bicarbonate in several ways. These drugs decrease cellular production and secretion of bicarbonate, but increase tissue entry of bicarbonate from blood. NSAIDs also have a dual effect on blood flow. Microvascular stasis occurs at sites of gross mucosal damage, but blood flow increases at visibly normal sites. Mucus is impermeable to pepsin, slows acid diffusion to some degree, traps bicarbonate to create an alkaline interface, and traps cell slough, forming another putative barrier. NSAIDs inhibit mucus secretion and modify its structure. Perhaps related to mucus is the hydrophobic property of the mucosa attributable to an absorbed layer of surfactant. Aspirin reduces surface hydrophobicity, an effect that may increase ion permeability. In addition to secreting mucus, the cells lining the luminal surface also play a key role in maintaining the permeability and active transport properties of the mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)