Cytotoxicity associated with induction of nitric oxide synthase in rat duodenal epithelial cells in vivo by lipopolysaccharide of Helicobacter pylori: inhibition by superoxide dismutase

1 The products released by Helicobacter pylori (H. pylori) in the gastric a ntral and duodenal mucosa may be involved in mucosal ulceration by stimulat ing the local formation of cytotoxic factors such as nitric oxide (NO), sup eroxide or peroxynitrite. 2 The present study investigates the ability of purified H. pylori lipopoly saccharide (LPS) to induce nitric oxide synthase (iNOS) in rat duodenal epi thelial cells following in vivo challenge and its interaction with superoxi de in promoting cellular damage and apoptosis. 3 H. pylori LPS (0.75-3 mg kg(-1) i.v. or 3-12 mg kg(-1) p.o.) induced a do se-dependent expression of iNOS activity after 5 h in the duodenal epitheli al cells, determined by [C-14] arginine conversion to citrulline. 4 The epithelial cell viability, as assessed by Trypan Blue exclusion and M TT conversion, was reduced 5 h after challenge with H. pylori LPS, while th e incidence of apoptosis was increased. 5 The iNOS activity and reduction in cell viability following H. pylori LPS challenge i.v. was inhibited by the selective iNOS inhibitor, 1400 W (0.2- 5 mg kg(-1) i.v.). 6 Concurrent administration of superoxide dismutase conjugated with polyeth ylene glycol (250-500 i.u, kg(-1), i.v.), which did not modify the cellular iNOS activity, reduced the epithelial cell damage provoked by i.v. H. pylo ri LPS, and abolished the increased incidence of apoptosis. 7 These results suggest that expression of iNOS following challenge with H. pylori LPS provokes duodenal epithelial cell injury and apoptosis by a pro cess involving superoxide, implicating peroxynitrite involvement. These eve nts may contribute to the pathogenic mechanisms of H. pyloli in promoting p eptic ulcer disease.