Mucosal integrity is reestablished after superficial injuries by a rapid resealing process, termed epithelial restitution, that is regulated by several growth factors and cytokines. Growth factors are also known to stimulate the synthesis of endogenous prostaglandins that mediate important functions in intestinal epithelial cells. Therefore, we examined the effect of endogenous eicosanoid production modulators, piroxicam, dexamethasone, and nordihydroguaiaretic acid (NDGA) on intestinal epithelial restitution using two cultured cell wound-resealing models, IEC-6 and Caco-2 cells. Epidermal growth factor, transforming growth factor-beta, hepatocyte growth factor, and fetal calf serum (FCS) accelerated intestinal epithelial restitution, and piroxicam significantly suppressed these stimulatory effects. Dexamethasone mimicked the action of piroxicam. No additive effect of piroxicam and dexamethasone was observed. NDGA did not affect epithelial restitution. Piroxicam abolished the increase in 6-ketoprostaglandin F1 alpha (PGF1 alpha) release induced by FCS. Furthermore, addition of a stable PGI2 analogue, OP-41483 [5(E)-6,9-deoxa-6,9-methylene-15-cyclopentyl-16,17,18,19,20-pen tanor-PGI2], reversed the slowing of epithelial restitution induced by piroxicam. These results suggest that endogenous prostaglandins play an important role in regulating intestinal epithelial restitution.