Platelet-activating factor modulates gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide

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Abstract

Platelet-activating factor (PAF) is a phospholipid messenger implicated in mediation of inflammatory events associated with the resolution of inflammation. We applied the animal model of Helicobacter pylori LPS-induced gastritis in conjunction with prophylactic and therapeutic administration of a specific PAF antagonist, BN52020, to investigate the role of PAF in gastric mucosal responses to H. pylori infection. Prophylactic BN52020 administration produced up to 73.6% reduction in the severity of the LPS-induced inflammatory changes, whereas up to 38.4% increase in the severity of mucosal involvement occurred with BN52020 administered therapeutically. The prophylactic effects of BN52020 were accompanied by a drop in apoptosis and the expression of TNF-α and NOS-2, while BN52020 administered therapeutically caused a marked upregulation in apoptosis, TNF-α, and NOS-2. The untoward therapeutic effects of BN52020, moreover, were potentiated further in the presence of COX-2 inhibitor, whereas NOS-2 inhibitor caused a reduction in the extent of inflammatory changes. Our findings point to PAF as a key mediator of gastric mucosal inflammatory responses to H. pylori and suggest its modulatory role in the expression of COX-2 derived anti-inflammatory prostaglandins that are involved in controlling the extent of NOS-2 induction.

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Materials and methods

Animals. The study was conducted with Sprague–Dawley rats in compliance with the Institutional Animal Care and Use Committee. The animals were divided into groups and subjected to two different types of treatment regimen. In one, prophylactic, the animals at 16 and 4 h, before intragastric surface epithelial application of H. pylori LPS at 50 μg/animal [3], [7], were administered at 0–30 mg/kg with BN52020 (Calbiochem) or vehicle consisting of 5% gum arabic in saline, whereas in the second type of

Results

The role of PAF as a mediator of gastric mucosal inflammatory reaction to H. pylori infection and the underlying mechanism of its action were assessed in the animal model of H. pylori LPS-induced gastritis using rats subjected to intragastric administration of a specific PAF antagonist, BN52020, either before (prophylactic) or after (therapeutic) the LPS application. The results of histologic examination of the mucosa 4 days after exposure of the animals to the LPS in the absence of BN52020

Discussion

Enhancement in gastric mucosal TNF-α production, excessive NO and prostaglandin generation, and alteration in the extent of epithelial cell apoptosis are well-recognized features of gastritis associated with H. pylori infection in humans as well as characterize mucosal inflammatory responses in the animal model of H. pylori LPS-induced gastritis [3], [4], [9]. Studies indicate that up-regulation in NO and prostaglandins with H. pylori infection is the result of TNF-α-mediated activation of the

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