No abstract

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.

The ras mutation is a common and critical step in carcinogenesis. Autocrine growth factors are also known to play an important role in cancer cell growth and transformation. However, the contribution of autocrine growth factors in regulation of proliferation and apoptosis of activated ras‐stimulated intestinal epithelium is not fully understood. Therefore, we constructed activated ras‐transfected intestinal epithelial cell clones (IEC‐ras) to examine the role of epidermal growth factor (EGF)‐related peptides in the behavior of IEC‐ras. Overexpression of EGF family growth factors (transforming growth factor α, heparin‐binding EGF‐like growth factor, amphiregulin and betacellulin) and stronger phosphorylation of the EGF receptor was observed in IEC‐ras compared with control cells. IEC‐ras proliferated more rapidly than control cells, and a specific EGF receptor kinase inhibitor, AG1478, abolished the increased proliferation of IEC‐ras. Heparitinase and chlorate also prevented increased proliferation of IEC‐ras. Additionally, IEC‐ras expressed more bcl‐2 and was more resistant to apoptosis induction by UV radiation and mitomycin C. AG1478 suppressed bcl‐2 expression and inhibited resistance to apoptosis of IEC‐ras. Heparitinase and chlorate had effects similar to those of AG1478. Our data indicate that heparin‐binding EGF family growth factors play an important role in both increased proliferation and resistance to apoptosis of ras‐stimulated intestinal epithelial cells. Int. J. Cancer 73:917–923, 1997. © 1997 Wiley‐Liss, Inc.

Endothelin may play a role in the host response to acute mucosal damage. Mucosal ET production is significantly affected by mucosal injury.