Mechanisms of Gastroprotection

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Abstract
Gastric mucosa is constantly exposed to various irritants, but it usually maintains its integrity owing to several lines of defense, including mucus-alkaline secretion, mucosal hydrophobicity, rich mucosal blood flow, stabilization of tissue lysosomes, maintenance of mucosal sulfhydryls, and rapid proliferation and renewal of mucosal cells. Prostaglandins (PG) inhibit experimental gastric mucosal damage and ulcerations induced by a wide variety of agents, hence PG have been proposed to contribute to the overall protective process by activation of various mucosal defence lines– particularly by prevention of vasocongestion, ischemia, and deep hemorrhagic necrosis. The relation between tissue PG generation and mucosal protection does not appear to be closely related, and probably only minute amounts of PG are required to maintain mucosal integrity. In contrast to PG, other products of arachidonate metabolism, such as TxA2, LTC4 or LTD4, and the related lipid, platelet-activating factor, appear to mediate mucosal damage mainly by the disturbance in mucosal microcirculation and tissue ischemia. Gastroprotection can be achieved by stimulation of mucosal biosynthesis of protective PG or by the inhibition of the release or action of the proulcerogenic arachidonate metabolites. Certain natural substances, such as sulfhydryls, epidermal growth factor, or polyamines, protect the mucosa via a PG-independent mechanism, probably by enhancing the tissue repair processes. The resistance of mucosa to injury can be also increased by challenging with mild irritants ('adaptive cytoprotection'), and this has been attributed to the stimulation of mucosal PG biosynthesis, but a certain role may also be played by a physical barrier formed from the alkaline mucoid debris ('mucoid cap'), which mitigates the effects of subsequent exposure to the necrotizing agents and permits rapid epithelial repair and reconstitution. Some anti-ulcer drugs, which are believed to act primarily by neutralization of gastric acid (antacids) or by coating the mucosa (sucralfate, colloidal bismuth preparations), have been reported to have gastroprotective properties against various irritants, possibly due to the stimulation of mucosal production of PG. Protection of human gastroduodenal mucosa by PG and other gastroprotective agents against the challenge by irritants such as aspirin or ethanol has been demonstrated, and the clinical benefit of these agents in the therapy of peptic ulceration is currently under active investigation.