ABSTRACT
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.
Subject(s)
Anti-Ulcer Agents/therapeutic use , Chemokine CXCL1/genetics , Oligopeptides/therapeutic use , Proline/analogs & derivatives , Stomach Ulcer/drug therapy , Acetic Acid , Animals , Anti-Ulcer Agents/pharmacology , Cells, Cultured , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Gastric Mucosa/metabolism , Male , Oligopeptides/pharmacology , Proline/pharmacology , Proline/therapeutic use , RNA, Messenger/metabolism , Rats, Wistar , Stomach/drug effects , Stomach/pathology , Stomach Ulcer/chemically induced , Stomach Ulcer/metabolism , Stomach Ulcer/pathologyABSTRACT
Direct correlation of the cytokine gene expression level in peripheral blood mononuclear cells (BMNCs) and gastric mucosa (GM) cells with the development of gastric ulcers of various etiologies was shown for the first time. Ethanol-induced ulceration causes an increased transcription of IFNa, IL-8, and IL-12 mRNA in BMNCs. GM damages caused by water immersion stress were accompanied by an increased transcription of TNFa. The sizes of acetate-induced damages were positively correlated with the expression of IL-10 and IL-8 genes in BMNCs and with the expression of IFNa, IL-2, IL-12, and TNF genes in GM cells. Intranasal administration of Pro-Gly-Pro (PGP) reduced ethanol-induced ulceration, activating the transcription of IFNγ, IL-2, and IL-4 mRNA in BMNCs and prevents the formation of stress- and acetateinduced ulcers by inhibiting the expression of IL-8 and IL-10 genes, respectively.
