抄録
The first gastroprotective drugs (e.g., sofalcone, sucralfate) which prevent and/or accelerate healing of gastric ulcers, without inhibiting acid secretion, were first introduced in Japan, before Andre Robert's historic article on "gastric cytoprotection" in 1979. Since Robert's studies were focused on prostaglandins (PG), they became the center of GI research for more than 30 years. Endogenous PG were implicated in mediating the gastroprotective effect of other drugs (e.g., sofalcone, sucralfate), despite that the COX inhibitor indomethacin diminished, but never abolished gastroprotection by other drugs. Another endogenous substance, i.e., sulfhydryls (SH), investigated in parallel with PG, also play a mechanistic role in gastroprotection, esp., since SH alkylators like N-ethylmaleimide counteract virtually any form of gastroprotection.
In Robert's terms as 'prevention of chemically induced acute mucosal lesions', no single mechanism could explain the beneficial effects of diverse protective agents, but I argue that two endogenous substances (i.e., PG, SH), in addition to histamine, are the main mechanistic mediators of acute gastroprotection: PG & histamine, because as mediators of acute inflammation, they increase vascular permeability (VP), & SH scavenge free radicals. Based on research work of the last about 35 years, in part from our lab, a new mechanistic explanation of gastroprotection may be formulated: it's a complex but orderly & evolution-based physiologic response of the gastric mucosa under pathologic conditions. Namely, one of the first physiologic defense responses of any organ is inflammation that starts with rapid vascular changes [e.g., increased VP and blood flow], followed by cellular events (e.g., infiltration by acute and chronic inflammatory cells). Thus, PG and histamine, by increasing VP create a perivascular edema that dilutes and delays toxic agents reaching the subepithelial capillaries. Increased mucus and/or bicarbonate secretion causes luminal dilution of gastrotoxic chemicals that is further reinforced by a perivascular, histodilutional component. This mechanistic explanation would encompass the protective actions of diverse agents such as PG, small doses of histamine, motility stimulants, dilute irritants (i.e., "adaptive cytoprotection"). Thus, although markedly increased VP is pathologic, slight increase in VP seems to be protective, i.e., a key element in the complex pathophysiologic response during acute gastroprotection.
