INDUCTION OF PROLIFERATION IN ISOLATED GUINEA-PIG GASTRIC EPITHELIUM DURING RESTITUTION AFTER SUPERFICIAL INJURY

Immediate repair of the gastrointestinal epithelium after superficial injury is called restitution. It is based on the migration of the surv iving mucoid neck cells over the area of injury. The involvement of gr owth factors in the process has been recently documented. They are kno wn to enhance the process (ie, EGF, FGF, TGF-beta) and to activate the basolateral Na+-H+-antiport (EGF). They may exert their effect by act ivating intracellular tyrosine kinases or by inducing chemotaxis. Yet, their precise mechanism of action in the process is unknown. The aim of the present study was to investigate the effect of modulation of th e signal transduction pathway on the occurrence of proliferative mucoi d neck and foveolar cells in guinea pig gastric epithelium. Therefore guinea pig gastric epithelium was mounted in Ussing chambers in vitro and perfused 4 hr after superficial injury with 1.25 M NaCl. The poten tial difference over the epithelium and tissue resistance were recorde d simultaneously. The tissue was exposed either to cycloheximide, geni stein, or to 4-phorbol myristate 13-acetate (PMA) during the 4-hr reco very, and the expression of proliferative cells was assessed by staini ng the tissue for proliferative cells (Ki-67). The mean proliferative index of tissues subjected to NaCl injury was significantly higher tha n that of uninjured control tissues after 4 hr of restitution. Inhibit ion of the signaling pathway with genistein decreased the proliferativ e index significantly, while its stimulation with phorbol myristate in creased it. Both electrophysiologic and morphologic restitution were s ensitive to genistein, but not to PMA or cycloheximide. Superficial ep ithelial injury results in a significantly increased occurrence of pro liferative cells in isolated guinea pig gastric epithelium. This endog enous activation of the tissue is sensitive to inhibition by tyrosine kinases and to stimulation by protein kinases. Electrophysiologic and morphologic recovery are also affected by the modulation of the signal ing pathway. This suggests that it is involved in the immediate repair process.