The vacuolating cytotoxin VacA produced by Helicobacter pylori causes massive cellular vacuolation in vitro and gastric tissue damage in vivo, leading to gastric ulcers, when administered intragastrically. Here we report that mice deficient in protein tyrosine phosphatase receptor type Z (Ptprz, also called PTP-zeta or RPTP-beta, encoded by Ptprz) do not show mucosal damage by VacA, although VacA is incorporated into the gastric epithelial cells to the same extent as in wild-type mice. Primary cultures of gastric epithelial cells from Ptprz+/+ and Ptprz-/- mice also showed similar incorporation of VacA, cellular vacuolation and reduction in cellular proliferation, but only Ptprz+/+ cells showed marked detachment from a reconstituted basement membrane 24 h after treatment with VacA. VacA bound to Ptprz, and the levels of tyrosine phosphorylation of the G protein-coupled receptor kinase-interactor 1 (Git1), a Ptprz substrate, were higher after treatment with VacA, indicating that VacA behaves as a ligand for Ptprz. Furthermore, pleiotrophin (PTN), an endogenous ligand of Ptprz, also induced gastritis specifically in Ptprz+/+ mice when administered orally. Taken together, these data indicate that erroneous Ptprz signaling induces gastric ulcers.

Primary levofloxacin resistance was common in Japan and primarily related to gyrA mutations at Asn-87 and Asp-91.

Persistent Helicobacter pylori colonization in the stomach induces gastritis and peptic ulcer and interferes with ulcer healing. Most strains of H. pylori produce a cytotoxin, VacA, that induces cytoplasmic vacuolation in epithelial cells with structural and functional changes, leading to gastric injury. VacA is known to cause cell death by mitochondrial damage. We hypothesized that VacA might disrupt other signaling pathways; to that end, we examined the effects of VacA on MAPKs to elucidate their role in the abnormalities seen in VacAtreated cells. VacA stimulated phosphorylation of p38 and Erk1/2, but not JNK, in AZ-521 cells. Both phosphorylation and kinase activation of p38 were maximal 10 -30 min after addition of VacA and declined thereafter. Treatment with anti-VacA antibody or the p38 inhibitor SB203580 blocked p38 phosphorylation caused by VacA and inhibited VacA-induced phosphorylation of activating transcription factor 2 (ATF-2), which is implicated in transcriptional control of stress-responsive genes. These data indicate that VacA stimulates a p38/ ATF-2-mediated signal pathway. However, 10 M SB203580, which is sufficient to decrease p38 phosphorylation, did not inhibit VacA-induced cellular vacuolation, decrease in mitochondrial membrane potential, or cytochrome c release from mitochondria. These results suggest that VacA-induced activation of p38/ATF-2-mediated signal pathway is independent of cellular vacuolation, decrease in mitochondrial membrane potential, or cytochrome c release from mitochondria caused by VacA. The cytotoxin may thus act independently on several cellular targets, leading to disruption of signaling, regulatory, and metabolic pathways.Persistent Helicobacter pylori infection results in the development of chronic gastritis, peptic ulcer, and gastric cancer. Pathogenic strains of H. pylori produce and secrete a potent vacuolating cytotoxin, VacA, that is capable of directly inducing progressive vacuolation (1), mitochondrial damage (2), cytochrome c release (3), and apoptotic death of epithelial cells (4). Both epidemiological study (5) and animal experiments (6 -10) have demonstrated that VacA is a major virulence factor associated with the damage to gastric mucosa. VacA is produced as a 140-kDa precursor and cleaved at the bacterial outer membranes, generating the 87-95-kDa mature toxin (11). The mature toxin contains two major domains, the N-terminal region of 37 kDa that exhibits vacuolating activity and the C-terminal region of 58 kDa responsible for toxin binding to target cells (12)(13)(14)(15).In gastric tissues infected with H. pylori, many apoptotic cells were observed due to inflammation resulting from overproduction of cytokines induced by H. pylori (9, 16 -19). Recent work on the gastric mucosal inflammatory response to persistent H. pylori infection suggested that the p38 mitogen-activated protein kinase (MAPK) 1 signal pathway plays a significant role (20,21). Activation of p38 MAPK in response to environmental stress and inflammatory cytokines can result in ap...

The key to successful eradication of H. pylori, using lansoprazole or rabeprazole with clarithromycin and amoxicillin, is clarithromycin susceptibility, not CPY2C19 polymorphism.