Noriko Nakajima

Helicobacter pylori, neutrophils, interleukins, and gastric epithelial proliferation.

Infection of Helicobacter pylori causes chronic gastritis and plays an important role in the pathogenesis of gastroduodenal ulceration. H. pylori has also been suggested to be involved in the genesis of adenocarcincoma and MALT lymphoma of the stomach. H. pylori infection is associated with increased gastric epithelial proliferation, which can be reversed by a successful eradication of the organism. Although the mechanisms of increased gastric epithelial proliferation is not known, the enhanced epithelial proliferation is important in developing gastric carcinoma. Whether or not H. pylori de nove stimulates gastric epithelial proliferation is controversial, but gastric infection with H. pylori activates a mucosal inflammatory response by consisting of large numbers of polymorphonuclear and mononuclear cells, that also includes expression of various cytokines including interleukin-8. We review the mechanisms of H. pylori in enhanced gastric epithelial cell proliferation and cytokines in patients with H. pylori infection.

The Expression of Murine Double Minute 2 (MDM2) on Helicobacter pylori-Infected Intestinal Metaplasia and Gastric Cancer

The overexpression of murine double minute 2 (MDM2) is found in several human tumors, and increased expression of MDM2 inactivates the apoptotic and cell cycle arrest function of p53. Interleukin-16 (IL-16) is a pleiotrophic cytokine and the properties of IL-16 suggest that it involve in the pathophysiological process of chronic inflammatory diseases. In this study, we investigated the expression of MDM2 in intestinal metaplasia and gastric cancer as well as the effect of H. pylori infection and IL-16 on epithelial cell proliferation and MDM2 expression in gastric cells in vitro. The expression of MDM2 on gastric biopsies was studied immunohistochemistry. AGS cells were incubated with a combination of IL-16 and Helicobacter pylori (H. pylori). Gastric epithelial cell proliferation was studied by BrdU uptake and the expressions of MDM2 were studied by ELISA. There was no significant difference on the expression of MDM2 between with and without H. pylori infected chronic gastritis. In H. pylori infected gastric mucosa; the MDM2 expression was higher on intestinal metaplasia and gastric cancer than chronic gastritis. IL-16 administration was increased MDM2 expression and cell proliferation on AGS cells, which was decreased by H. pylori infection. In conclusion, the expression of MDM2 in long-term H. pylori infected gastric mucosa may indicate a risk for carcinogenesis. IL-16 secretion in H. pylori infected mucosa is one of the factors for gastric cancer. The expression of MDM2 on mucosa can be a mediator for gastric cancer.

Gastric epithelial cell proliferation and apoptosis in Helicobacter pylori-infected mice

Background: Helicobacter pylori causes gastritis and is strongly associated with gastroduodenal ulcer and gastric cancer. The bacterium is associated with an increased rate of epithelial proliferation, which can be reversed by eradication of the organism. The mechanism of this response is not known, but this epithelial proliferation is one of the risk factors for developing gastric carcinoma. Recently, apoptosis also was found to be increased in the gastric mucosa of persons carrying H. pylori.

Effects of Transforming Growth Factor α and β on Rabbit Gastric Epithelial Cell Proliferation: A Preliminary Report

The effects of epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), insulin-like growth factor-I (IGF-I), and transforming growth factor beta (TGF beta) on tritiated thymidine incorporation into DNA by rabbit gastric epithelial cells were investigated. EGF, TGF alpha, and IGF-I at concentrations of 10(-10) and 10(-9) M all produced a serum-like stimulatory effect, whereas TGF beta at both concentrations was inhibitory. Coadministration of TGF alpha had no additional effect on EGF-stimulated tritiated thymidine incorporation into DNA. On the other hand, coadministration of TGF beta abolished EGF-stimulated tritiated thymidine incorporation into DNA, suggesting possible interactions between the two growth factors.

Endoscope Images of Schönlein-Henoch Purpura

Background/Aims: Schönlein-Henoch purpura (SHP) is a systemic condition characterized by purpura associated with leukocytoclastic vasculitis. SHP diagnosis is more difficult in infrequent cases where gastrointestinal (GI) symptoms precede purpura. This report examines 11 cases of SHP at our hospital with specific regard to the incidences and details of GI symptoms. Methods: The clinical manifestations and endoscopic findings were investigated for their utility in SHP diagnosis. Results: Among the 11 cases, 3 showed GI symptoms prior to other manifestations. In terms of GI symptoms, abdominal pain was reported in all 11 cases, diarrhea in 4 cases, and bloody stools in 3 cases. Endoscopic findings were seen in the stomach in 7/10 cases, in the small intestine including the duodenum in 10/11 cases, and in the large intestine in 6/10 cases. The frequency of ulcer formation was significantly higher in the small intestine (including the duodenum) than in the stomach. Multiple specific erythematosus lesions were observed in the stomach and large intestine. Conclusion: Familiarity with characteristic endoscopic findings and careful observation of all GI findings are essential for diagnosing SHP in cases in which GI tract symptoms precede cutaneous findings.

Zinc supplementation therapy improves the outcome of patients with chronic hepatitis C.

We administered zinc supplementation therapy over three years to patients with chronic hepatitis C and reported and that the aspartate aminotransferase (AST) and alanine aminotaransferase (ALT) levels decreased, and platelet counts increased, significantly in the group with increased serum zinc concentrations. We are continuing this treatment to clarify the long-term consequences and report here the changes in serum zinc concentrations over seven years and compare the cumulative incidence of hepatocellular carcinoma (HCC). We administered polaprezinc to 32 patients, randomly selected for zinc therapy (treatment group), while another 30 formed the control group. We measured the serum zinc and albumin concentrations and conducted a prospective study to determine long-term outcomes. The changes and rates of change of serum zinc concentrations after seven years were 76.7 ± 18.2 µg/dl and +0.302 ± 0.30% in the treatment group and 56.7 ± 12.4 µg/dl and +0.033 ± 0.21% in the control group and had increased significantly (p = 0.0002, p = 0.0036). Progression of liver disease seemed to vary, depending on serum albumin concentrations. In the group with baseline serum albumin concentrations of 4.0 g/dl or more, the change and rate of change of serum zinc concentrations increased significantly, and the cumulative incidence of HCC tended to decrease, in the treated group. According to multivariate analysis, the factors that contribute to a reduction in the incidence of HCC are zinc therapy (risk ratio: 0.113, 95% CI: 0.015–0.870, p = 0.0362), and platelet counts (0.766, 0.594–0.989, 0.0409). Zinc supplementation therapy seems to improve liver pathology and reduce the incidence of HCC.

Green Tea Polyphenols Reduce Gastric Epithelial Cell Proliferation and Apoptosis Stimulated by Helicobacter pylori Infection

Recently the finding of gastric cancer in Helicobacter pylori (H. pylori)-infected mouse models was reported. Studies of humans and animal models have shown that H. pylori infection stimulates gastric epithelial cell proliferation and apoptosis. Polyphenols contained in green tea and related compounds were reported to have a variety anti-tumor effects and bactericidal properties. We studied the effect of green tea polyphenols on gastric cell proliferation and apoptosis in an H. pylori-infected mouse model. This model was prepared by inoculating Balb/c mice with 108 cfu of H. pylori (NCTC 11637 strain) by gavage. Beginning 18 weeks after inoculation, 0.5% polyphenols were given in drinking water every day for 2 weeks. Mice were sacrificed 1 h after bromodeoxyuridine (BrdU) was given i.p. for preparation of paraffin-embedded specimens. Cell proliferation and apoptosis were examined by the avidin-biotin complex method using anti-BrdU antibody and the TUNEL method, respectively. H. pylori infection resulted in increased BrdU-labeled cells in both the antrum and the bodies. Administration of polyphenols suppressed this increased proliferation. H. pylori infection increased apoptotic cells in both the antrum and the corpus in comparison with controls. This increase was not seen in H. pylori-infected mice given polyphenols. We conclude the administration with polyphenols might suppress gastric carcinogenesis that is in part related to H. pylori infection.

Lansoprazole reverses Helicobacter pylori-inhibited gastric epithelial cell growth.

Helicobacter pylori is associated with retarded healing and recurrence of peptic ulcer. Acid inhibitory agents, including proton pump inhibitors (PPIs), accelerate healing of peptic ulceration. Because epithelial cell proliferation is important for ulcer healing, we studied the effects of H. pylori and lansoprazole, a novel PPI, on gastric epithelial cell growth in vitro. Cell viability was significantly decreased when they incubated with 108 CFU/ml H. pylori. Nevertheless, all doses tested, from 106 to 108 CFU/ml H. pylori inhibited cell growth in a dose-dependent fashion. Co-incubation with AG-2000, an acid-converted derivative of lansoprazole, reversed H. pylori-inhibited cell growth. These results indicate that the antiulcer action of lansoprazole may involve a reversible effect on H. pylori-inhibited cell growth in addition to its well-established acid inhibitory action on parietal cells.

The expression of IGF-1R in Helicobacter pylori-infected intestinal metaplasia and gastric cancer.

Overexpression of IGF-1R has been demonstrated in gastrointestinal cancers, and its expression is reported as the result of the loss of tumor suppressors. IL-16 is involved in the pathophysiological process of chronic inflammatory diseases. The aim of this study is to determine the changes in the expression of IGF-1R in intestinal metaplasia (IM) and gastric cancer (GC) as well as the effect of Helicobacter pylori (H. pylori) and IL-16 on cell proliferation and IGF-1R expression in gastric cells. AGS cells were incubated with combinations of IL-16 and H. pylori. Gastric cell proliferation was studied by BrdU uptake. In H. pylori infected mucosa, IGF-1R was significantly higher in IM than chronic gastritis (CG), and also higher in GC than CG and IM. H. pylori significantly decreased BrdU uptake. IL-16 increased BrdU uptake and IGF-1R on AGS cells which had been decreased by H. pylori. Co-incubation with IL-16 increased the expression of IGF-1R mRNA in H. pylori infected cells. We conclude that the expression of IGF-1R in H. pylori infected gastric mucosa may indicate an early stage of carcinogenesis. The IL-16 secretion by H. pylori can be a trigger for the expression of IGF-1R, and it may also be a factor for gastric carcinogenesis.

Effects of single parenteral indomethacin injection in rat fundic and antral epithelial proliferation.

To study the effects of a single parenteral dose of indomethacin on gastric epithelial proliferation, we performed the following study. Male Wistar rats weighing about 200 g were divided into two groups and given single intraperitoneal injections of indomethacin 5 mg/kg, either suspended in 0.5% carboxymethyl cellulose sodium salt or vehicle alone, after an overnight fast. After 6 h, all rats were injected by tail vein with tritiated thymidine, 1 μCi/g body weight, to label proliferating cells and were killed 1 h later. Sections from fundic and antral mucosae were processed for light autoradiography. Parenteral indomethacin resulted in spotty erosions in fundic mucosa. Histologically, there was congestion with or without epithelial disruption. These areas were excluded in the proliferation measurements. There was a significant decrease not only in the number of labeled cells but also in the thickness of the proliferative zone with the thinning of the entire mucosal thickness in the fundic mucosa. None of the measurements in antral mucosa showed significant difference. These results showed that a single parenteral injection of indomethacin inhibits epithelial proliferation and decreases mucosal thickness in fundic, but not antral mucosa of the rat.