Direct and adaptive cytoprotection.

Abstract

Cytoprotection confers increased cellular resistance to various damaging challenges. For example, the administration of certain prostaglandins (PG) prevents injury or facilitates recovery from injury in tissues exposed to noxious substances, such as ethanol, aspirin, and indomethacin. In addition, naturally occurring PG (E and I types) may play a physiological role in protecting the gastroduodenal mucosa against corrosion by gastric juice. Within a responsive tissue, not all cells may be protected by PG against severe damage. Thus, while PG will not prevent necrosis of the gastric epithelial monolayer during exposure to 100% ethanol, it does protect the deeper gastric cells of the mucosa from destruction. Cytoprotection of the gastroduodenal mucosa is independent of the antisecretory activity of PG. The ED100 cytoprotective dose of a prostaglandin may be less than 1% of the ED50 antisecretory dose of the same agent, and some cytoprotective prostaglandins are not antisecretory in some animal models. The best of the proposed mechanisms to account for cytoprotection include stimulation of mucus or HCO3 secretion, and mucosal vasodilation. However, there are no definitive data to substantiate these hypotheses and, in fact, evidence does exist to disprove each theory. Gastric mucosal exposure to mildly damaging concentrations of an agent will increase mucosal resistance to subsequent exposure to a much greater and more damaging concentration of the same agent. This "adaptive cytoprotection" can be abolished by indomethacin, an inhibitor of endogenous prostaglandin synthesis.