Effects of Nonsteroidal Anti-Inflammatory Drugs on Helicobacter pylori -Infected Gastric Mucosae of Mice: Apoptosis, Cell Proliferation, and Inflammatory Activity

Abstract

Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) are two well-known important causative factors of gastric damage. While H. pylori increases apoptosis and the proliferation of gastric epithelial cells and is an important factor in peptic ulcer and gastric cancer, NSAIDs induce cell apoptosis and have antineoplastic effects. We investigated the effects of NSAIDs (a nonselective cyclooxygenase [COX] inhibitor [indomethacin] and a selective COX-2 inhibitor [NS-398]) on the apoptosis and proliferation of gastric epithelial cells and gastric inflammation in H. pylori-infected mice. C57BL/6 mice were sacrificed 8 weeks after H. pylori SS1 inoculation. Indomethacin (2 mg/kg) or NS-398 (10 mg/kg) was administered subcutaneously once daily for 10 days before sacrifice. The following were assessed: gastric inflammatory activity, gastric COX protein expression by Western blotting; gastric prostaglandin E 2 levels by enzyme immunoassay, apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, and cell proliferation by Ki67 immunostaining. Compared to the controls, H. pylori infection and/or NSAID treatment increased COX-1 and COX-2 protein expression. Gastric prostaglandin E 2 levels, apoptotic index, cell proliferation index, neutrophil activity, and the degree of chronic inflammation were all increased by H. pylori infection, and these effects were significantly decreased by indomethacin treatment. However, NS-398 treatment after H. pylori infection did not induce a significant reduction, although it did result in a tendency to decrease. These results show that NSAIDs can reverse the increased apoptosis and proliferation of epithelial cells and inflammatory activity in the stomachs of H. pylori-infected mice and that, like COX-2 activation, COX-1 induction contributes to the change of gastric mucosal cell turnover and inflammation induced by H. pylori infection.

Effects of Cyclooxygenase‐1 and ‐2 Gene Disruption onHelicobacter pylori–Induced Gastric Inflammation

“…Helicobacter pylori infection is a major cause of chronic gastritis, peptic ulceration, and gastric carcinoma [3]. Studies have shown that COX-2 is induced in gastric mucosa during H. pylori infection [4][5][6] and that NSAIDs enhance H. pylori-induced gastric inflammation and ulceration [7][8][9][10][11][12]. However, the role played by COX-2 in H. pylori-induced gastric inflammation is not entirely understood.…”

Gastric Cancer Risk and Erythrocyte Composition of Docosahexaenoic Acid with Anti-inflammatory Effects

“…Risk of development and mortality from gastric cancer among nonsteroidal antiinflammatory drugs (NSAIDs; in here, as cyclooxygenase inhibitors) users also seems to be lower than among nonusers (5)(6)(7). Some studies have reported that NSAIDs have a protective role in patients with peptic ulcers, but others have shown elevation of the risk among NSAIDs users infected with H. pylori (8,9). NSAIDs are furthermore associated with serious upper gastrointestinal bleeding and cardiovascular events, and such harmful affects are a serious public health concern in American-European populations (10)(11)(12)(13).…”

Anti-Helicobacter pylori therapy followed by celecoxib on progression of gastric precancerous lesions

“…Of the three precancerous changes (atrophy, intestinal metaplasia and dysplasia), celecoxib was effective on the regression of dysplasia. However, the evidence for chemopreventive effects on gastric precancerous lesions by NSAIDs has only been limited to animal experiments [13,[17][18][19][20][21][22] . In the animal model of carcinogenesis induced by co-treatment with H pylori and N-methyl-N-nitrosourea (MNU), mice underwent H pylori-induced gastritis with multifocal atrophy and intestinal metaplasia, and finally gastric adenocarcinoma.…”