| Abstract: | Infection with Helicobacter pylori is recognized as a primary factor in the etiology of gastric disease and its early pathogenic effects are manifested by up-regulation in proinflammatory cytokine release, enhancement in nitric oxide generation, and amplification of apoptotic events. We applied the animal model of H. pylori -induced gastritis to study the effect of a specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), SB 203580, on the mucosal apoptotic processes, and the expression of inducible nitric oxide synthase (NOS-2) activity and soluble tumor necrosis factor- (TNF-). Groups of rats were pretreated intragastrically with SB 203580 (5, 10, and 20 mg/kg) or vehicle, followed 60 min later by intragastric application of H. pylori lipopolysaccharide at 50  g/animal, and after 2 and 4 additional days on the twice daily regimen of SB 203580 or vehicle, the animals were killed and their gastric mucosal tissue subjected to histologic and biochemical assessment. In the absence of SB 203580, H. pylori lipopolysaccharide elicited within 2 days a pattern of acute mucosal inflammatory responses resembling that of acute gastritis which reached a maximum by the 4th day and were accompanied by an 11.6-fold enhancement in epithelial cell apoptosis, an 8.8-fold increase in the expression of soluble TNF-, and a 6.5-fold induction in NOS-2 activity. Administration of SB 203580 produced dose-dependent reduction (up to 58.7%) in the severity of mucosal inflammatory involvement elicited by H. pylori lipopolysaccharide and this effect of the agent was reflected in a marked reduction (up to 72.9%) in the lipopolysaccharide-induced NOS-2 expression, decline (up to 57.4%) in epithelial cell apoptosis, and a decrease (up to 51.5%) in the mucosal level of soluble TNF-. Our findings thus suggest that the p38 MAPK signaling pathway plays a key role in H. pylori lipopolysaccharide-induced gastric mucosal inflammatory responses leading to up-regulation of apoptotic events and induction of NOS-2 expression. |
