Role of ERK and p38 mitogen-activated protein kinase cascades in gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide.

Abstract

The animal model of H. pylori lipopolysaccharide (LPS)-induced gastritis was used to study the role of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in the mucosal release of tumor necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1) in response to H. pylori infection. Rats, pretreated with specific inhibitors of p38 and ERK pathways, SB203580 and PD98059, were submitted to intragastric application of H. pylori LPS and maintained on the daily regimen of the inhibitors for 4 days. In the absence of inhibitors, the LPS elicited a pattern of mucosal inflammatory responses resembling that of acute gastritis, and reflected in a massive increase in the mucosal level of ET-1 and TNF-alpha. Administration of SB203580 led to a 63.4% reduction in the extent of inflammatory involvement, the level of ET-1 fell by a 42% and TNF-alpha declined by a 52.3%, whereas PD98059 elicited a 21.2% reduction in the extent of inflammatory involvement and a 22.7% decrease in TNF-alpha, but had no effect on the LPS-induced increase in ET-1. A combination of both inhibitors, while exerting additive effect on TNF-alpha, produced no additional reduction in ET-1 and the extent of inflammatory involvement achieved with SB203580 alone. The findings suggest that the p38 MAPK signaling pathway plays a key role in the mediation of gastric mucosal inflammatory reaction to H. pylori infection.