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A high-salt diet in humans and experimental animals is known to cause gastritis, has been associated with a high risk of atrophic gastritis, and is considered a gastric tumor promoter. In laboratory rodents, salt is known to cause gastritis, and when coadministered, it promotes the carcinogenic effects of known gastric carcinogens. Because Helicobacter pylori has been associated with a progression from gastritis to gastric cancer, we designed a study to determine whether excessive dietary NaCl would have an effect on colonization and gastritis in the mouse model of H. pylori infection. Seventy-two, 8-week-old female C57BL/6 mice were infected with H. pylori strain Sydney, and 36 control mice were dosed with vehicle only. One-half of the infected and control mice were fed a high-salt diet (7.5% versus 0.25%) for 2 weeks prior to dosing and throughout the entire experiment. Twelve infected and 6 control animals from the high-salt and normal diet groups were euthanized at 4, 8, and 16 weeks. At 8 and 16 weeks postinfection (WPI), the colony-forming units per gram of tissue were significantly higher (P0.05) in the corpus and antrum of animals in the high-salt diet group compared with those on the normal diet. Quantitative urease was significantly higher (P0.05) at 4 and 8 WPI in the corpus and antrum of animals on the high-salt diet when compared with controls. At 16 WPI, mice in both the normal and the high-salt diet groups developed moderate to marked atrophic gastritis of the corpus in response to H. pylori infection. However, the gastric pits of the corpus mucosa in mice on the high-salt diet were elongated and colonized by H. pylori more frequently than those in mice on the normal diet. The high-salt diet was also associated with a significant increase in proliferation in the proximal corpus and antrum and a multifocal reduction in parietal cell numbers in the proximal corpus, resulting in the elongation of gastric pits. We conclude that excessive NaCl intake enhances H. pylori colonization in mice and in humans and that chronic salt intake may exacerbate gastritis by increasing H. pylori colonization. Furthermore, elevated salt intake may potentiate H. pylori-associated carcinogenesis by inducing proliferation, pit cell hyperplasia, and glandular atrophy.

Helicobacter pylori infection and adenomatous polyposis coli (Apc) gene mutations have been linked to gastric cancer in humans, but possible synergistic interaction(s) between these risk factors have not been examined. Fourteen C57BL/6 wild-type and 14 Apc1638 heterozygous mice were inoculated with Helicobacter felis at 6 weeks of age and compared at various time points with a similar number of uninfected control mice of the same genotype. Both infected and uninfected Apc1638 mice had a limited incidence of atypical proliferation foci in the mucosa of the antrum and pyloric junction at 4.5 and 6 months of age, whereas polyps of the antrum and pylorus were present in all mice, regardless of infection status, at 7.5 months. In contrast, no altered gastric mucosal foci were observed in control or infected C57BL/6 mice at any time point. Interestingly, the infected Apc1638 mice had less epithelial proliferation and inflammation in the body of the stomach, lower anti-H. felis serum IgG antibody responses (although both the wild-type and Apc mutant mice had a Th1-like immune response, based on a predominantly IgG2a immunoglobulin response), and higher bacteria and urease scores than did infected wild-type C57BL/6 mice. In conclusion, the Apc1638 truncating mutation leads to gastric dysplasia and polyposis of the antrum and pyloric junction, but H. felis infection of the Apc mutant mouse does not lead to an increased rate of gastric neoplasia. In addition, our data suggest this Apc mutation may actually lead to decreased immune, inflammatory, and gastric hyperplastic responses to Helicobacter infection, suggesting the possibility of a novel role for this tumor suppressor gene in the immune and local tissue responses to gastric bacterial infection.

Oxygen radicals have been widely implicated in neoplastic transformation; however, little is known regarding their mode of action. In an attempt to delineate potential mechanisms of action, an analysis of superoxide effects on cell growth was studied in normal and two nontumorigenic, immortal cell lines derived from normal Syrian hamster embryo (SHE) fibroblasts. The two immortal cell lines differed in their ability to suppress tumorigenicity of tumor cells in cell hybrids. One cell line suppressed tumorigenicity (sup+), while a second clone was unable to suppress tumorigenicity (sup-). Paraquat was used to generate superoxide through its capacity to be reduced by NAD(P)H and to generate superoxide radicals. The growth response of the various cell types was measured by colony-forming ability as well as by tritiated thymidine incorporation using autoradiography. At low paraquat concentrations (25 microM), primary SHE cells and two sup+ clones showed up to a 40% enhancement in colony formation, while two sup- clones showed no increase. Toxicity was observed at high doses, starting at approximately 100 microM paraquat. Since oxygen radicals are also mutagenic, primary SHE cells were examined for chromosomal aberrations. Chromatid gaps and breaks were induced at all concentrations of paraquat used. Thus, superoxide not only causes cellular toxicity at high doses but at low doses enhances cell growth of certain cells (primary SHE cells and sup+ cells) but not others (sup- cells). Therefore, differing responses of cells at different stages of neoplastic progression must be considered in understanding oxygen radical effects in growth control and carcinogenesis.