Helicobacter pylori is recognized as a primary etiologic factor in the development of gastric disease. We applied the animal model of H. pylori lipopolysaccharide-induced acute gastritis to study the effect of the anti-ulcer agent, ebrotidine, on the course of mucosal inflammatory responses by analyzing over a period of 10 days the extent of epithelial cell apoptosis and the mucosal expression of endothelin-1 (ET-1), tumor necrosis factor α (TNFα), and the activity of constitutive (cNOS) and inducible (NOS-2) nitric oxide synthase. Rats, pretreated twice daily for 3 days with ebrotidine at 100 mg/kg or the vehicle, were subjected to intragastric application of H. pylori lipopolysaccharide at 50 µg/animal, and after 2, 4, and 10 additional days on the drug or vehicle regimen their mucosal tissue was used for histological and biochemical assessment. In the absence of ebrotidine, H. pylori lipopolysaccharide elicited within 2 days extensive mucosal inflammation accompanied by a significant increase in epithelial cell apoptosis (13.5-fold) and the mucosal expression of TNFα (11.7-fold), NOS-2 (9.3-fold), and ET-1 (2.9-fold), while cNOS activity showed a 5.5-fold decrease. The extent of mucosal inflammatory involvement reached a maximum by the 4th day and showed a decline by the 10th day. This was reflected in a marked reduction in epithelial cell apoptosis, a decrease in the mucosal expression of ET-1, TNFα and NOS-2, and the recovery in cNOS activity. Treatment with ebrotidine caused a reduction in the extent of mucosal inflammatory involvement elicited by the lipopolysaccharide and this effect of ebrotidine was reflected at the end of a 10 day period in a 61.3% reduction in inflammation, and a decrease in apoptosis (83%), TNFα (51.8%), ET-1 (27.6%) and NOS-2 (62.9%), while the expression of cNOS increased by 78.6%. The findings indicate that an increase in the ET-1 level elicited by H. pylori lipopolysaccharide, combined with a decline in cNOS, trigger the induction of TNFα which propagates the inflammatory process. We also show that ebrotidine is capable of suppressing the H. pylori-induced gastric mucosal inflammatory responses.
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