Glyprolines exert protective and repair-promoting effects in the rat stomach: potential role of the cytokine GRO/CINC-1.

Glyprolines have been reported to exert protective effects in the stomach. In this study, we examined the potential effects of intranasal administration of Pro-Gly-Pro (PGP) and N-acetyl-Pro-Gly-Pro (AcPGP) on experimental gastric ulcer formation and healing. We also studied gastric release of the cytokine GRO/CINC-1, and its potential role in ulcer development and healing. Gastric ulcers were induced in rats by applying acetic acid to the serosa of the stomach. PGP and AcPGP were then administered at a dose of 3.7 μmol/kg once daily on either days 1 - 3 (ulcer formation) or days 4 - 6 (ulcer healing). Measurement of ulcer area and histological examination of gastric tissue were carried out on days 4 and 7 after application of acetic acid. In vitro studies involved addition of the glyprolines to cultured rat gastric epithelial cells with or without lipopolysaccharide. Reverse transcription PCR, real-time PCR and ELISA were used for cytokine analysis. PGP and AcPGP significantly reduced ulcer areas on the 4(th) day and accelerated the healing on the 7(th) day compared with the control. After acetic acid-induced ulceration, the expression of GRO/CINC-1 mRNA in gastric tissue was increased 9-fold versus the sham-operated group. Treatment with PGP or AcPGP both significantly suppressed the expression of GRO/CINC-1 mRNA in gastric tissue. However, the glyprolines did not alter LPS-induced mRNA expression or release of GRO/CINC-1 from cultured rat gastric epithelial cells, even though those cells were harvested from rats subjected to the ulcer-induction procedure. The results of this study show that intranasal administration of PGP and AcPGP significantly increased resistance against acetic acid-induced ulceration and accelerated healing in the rats. These effects may be due, at least in part, to their ability to reduce the acetic acid-induced GRO/CINC-1 expression and production in gastric tissue.