Gastric mucosal inflammatory responses toHelicobacter pylori lipopolysaccharide: Suppression of caspase-3 and nitric oxide synthase-2 by omeprazole and sucralfate

Aims:Helicobacter pylori lipopolysaccharide is a primary virulence factor responsible for eliciting acute mucosal inflammatory responses associated withH. pylori infection. In this study, we investigated the activity of a key apoptotic protease, caspase-3, and the expression of inducible nitric oxide synthase (NOS-2) duringH. pylori lipopolysaccharide-induced acute gastritis, and evaluated the effect of anti-ulcer agents, omeprazole and sucralfate, on this process.Methods: Rats, pretreated twice daily with omeprazole at 40 mg/kg, sucralfate at 100 mg/kg, or the vehicle, were subjected to intragastric application ofH. pylori lipopolysaccharide at 50 mug/animal, and after 4 additional days on the anti-ulcer drug or vehicle regimen their mucosal tissue was used for histologic assessment, assays of epithelial cells apoptosis, and the measurements of caspase-3 and NOS-2 activities.Results: In the absence of anti-ulcer agents,H. pylori lipopolysaccharide induced acute reaction characterized by the inflammatory infiltration of the lamina propria, hyperemia, and epithelial hemorrhage. This was accompanied by an 11.2-fold increase in epithelial cell apoptosis, a 6.5-fold induction in mucosal expression of NOS-2, and a 5.4-fold increase in caspase-3 activity. Treatment with proton pump inhibitor, omeprazole, produced a 39.6% reduction in the extent of mucosal inflammatory changes elicited byH. pylori lipopolysaccharide and a 75.5% decrease in the epithelial cells apoptosis, while the activity of caspase-3 decreased by 26.8% and that of NOS-2 showed a 46.7% decline. The gastroprotective agent, sucralfate, evoked a 62.3% reduction in the extent of mucosal inflammatory changes caused by the lipopolysaccharide, epithelial cell apoptosis decreased by 85.8%, and NOS-2 showed a 68.2% decline, while the activity of caspase-3 decreased by 39.7%.Conclusions: Our findings implicate caspase-3 involvement in gastric mucosal inflammatory responses toH. pylori lipopolysaccharide, and point towards participation of NOS-2 in the amplification of the cell death-signaling cascade. We also show that anti-ulcer agents, omeprazole and sucralfate, are capable of suppressing the H. pylori-induced mucosal inflammatory responses by interfering with the events propagated by NOS-2 and caspase-3.