Eradication of Helicobacter pylori reduced the immunohistochemical detection of p53 and MDM2 in gastric mucosa

BACKGROUND: Although Helicobacter pylori has been regarded as a pathogen of gastric cancer, the mechanism by which H. pylori is involved in gastric carcinogenesis remains unknown. To clarify the role of H. pylori in carcinogenesis, the expression of tumor suppressor p53 and its regulator multiple double minute 2 (MDM2) in gastric mucosa were examined before and after H. pylori eradication. METHODS: Biopsy specimens were obtained from 31 patients with H. pylori-infected gastric mucosa. Endoscopic biopsies were repeated 6 months after successful eradication. In addition, biopsy specimens from 12 patients with non-infected gastric mucosa were obtained. Immunohistochemical analysis was performed on the specimens using primary antibodies specific for p53 and MDM2. RESULTS: Six months after H. pylori eradication, labeling indices for p53 were significantly reduced in the gastric corpus (2.3-fold; P < 0.01), and in the gastric antrum (2.0-fold; P < 0.01). Similarly, labeling indices for MDM2 were significantly reduced in the corpus (1.7-fold; P < 0.01), and in the antrum (3.5-fold; P < 0.01). In the non-infected group, labeling indices for p53 and MDM2 in the gastric mucosa were significantly lower (P < 0.01) than those of the H. pylori-infected group. CONCLUSION: A significant increase is shown in p53 and MDM2 expression in H. pylori-infected gastric mucosa as compared to normal gastric mucosa; but successful eradication of H. pylori dramatically reduced the p53 and MDM2 levels. Therefore, H. pylori infection may be associated with alteration of cell proliferation and apoptosis.     

Influence of gastritis on cyclooxygenase-2 expression before and after eradication of Helicobacter pylori infection

OBJECTIVES: Helicobacter pylori infection causes chronic gastritis and induces cyclooxygenase (COX)-2 expression. The relationship between gastritis and COX-2 expression is not well understood, especially long after the organism has been eradicated. We designed a study to elucidate this relationship. METHODS: Four endoscopic gastric biopsies from each of 118 H. pylori-infected subjects were assessed for COX-2 expression immunohistochemically, gastritis, by an updated Sydney System. In the 107 successfully eradicated subjects, the assessment was repeated once yearly, for 3 years. RESULTS: After successful eradication, COX-2 expression was reduced significantly regardless of site. Atrophy improved significantly and intestinal metaplasia improved but not in the antrum greater curvature. After 1 year COX-2 expression was not significantly different in the epithelia with and without intestinal metaplasia. Correlation between COX-2 expression and neutrophil score in the antrum (r = 0.214, P = 0.042) and inflammation in the corpus (r = 0.234, P = 0.025) disappeared after eradication. COX-2 expression correlated well with atrophy and metaplasia before and after eradication. No significant reduction in COX-2 or improvement in gastritis was found in subjects with eradication failure. CONCLUSION: H. pylori infection is associated with the enhancement of COX-2 expression in the gastric mucosa. Eradication therapy reduces COX-2 expression and hence may reduce the risk of cancer development.     

Helicobacter pylori eradication decreases the expression of glycosylphosphatidylinositol-anchored complement regulators, decay-accelerating factor and homologous restriction factor 20, in human gastric epithelium

BACKGROUND: It has previously been reported that there is a strong correlation between the expression of glycosylphosphatidylinositol (GPI)-anchored complement membrane inhibitor in gastric epithelium and the severity of inflammation of gastric mucosa. To investigate the regulation of complement activity in gastric epithelium during Helicobacter pylori (H. pylori)-associated gastritis, the expression of GPI-anchored complement membrane inhibitors, decay-accelerating factor (DAF) and 20-kDa homologous restriction factor 20 (HRF20), and membrane cofactor protein (MCP), which is a transmembrane protein, were evaluated after removal of the H. pylori stimulus. Furthermore, the expression of the complement fragment, C3c, was also investigated. METHODS: Forty-six patients with epigastric symptoms and endoscopically confirmed peptic ulcer or gastritis who had H. pylori infection of the gastric mucosa were enrolled in the present study. Biopsy specimens were obtained from the gastric antrum and corpus 1 month before and after eradication. Helicobacter pylori infection was determined by the rapid urease test, histology, and culture before eradication, and by histology, culture, and urea breath test after eradication. Gastric biopsy specimens obtained before and after eradication were evaluated for infiltration by neutrophils and mononuclear cells. The expression of complement membrane inhibitors, DAF, HRF20, and MCP and that of the main complement fragment, C3c, was immunohistochemically evaluated. RESULTS: One month after the eradication of H. pylori, the infiltration by neutrophils and mononuclear cells in the gastric mucosa decreased significantly (P < 0.0001) as compared with that before eradication. The expression of DAF, HRF20, and C3c on gastric mucosal epithelium also significantly decreased in both the antrum and the corpus (P < 0.05) 1 month after eradication. However, no change was observed in the expression of MCP. CONCLUSIONS: The decrease in the expression of GPI-anchored complement regulator and the complement after removal of a chronic microbial stimulus suggests that the gastric epithelium appears to undergo an aggressive stress of complement during H. pylori infection. Conclusively, DAF and HRF20 may play an important protective role against complement-mediated damage induced by chronic microbial stimuli in such a pathological condition.     

Multifocal atrophic gastritis: pathogenesis and therapeutic implications

OBJECTIVE: This study, carried out on 51 patients with multifocal atrophic gastritis (MAG) and 92 age and sex-matched dyspeptic controls, was designed to examine both exocrine (gastric acid) and endocrine (gastrin) gastric secretion before and after therapeutic intervention including Helicobacter pylori eradication and vitamin C treatment. METHODS: Fasting and gastrin-releasing peptide-induced gastric acid secretion, serum levels of gastrin and proinflammatory (IL-1beta, IL-8, TNF-alpha) as well as gastric mucosal gene expression of ornithine decarboxylase (ODC), cyclooxygenase 2 (COX-2) and growth factors (epidermal growth factor and transforming growth factor alpha) were determined before and after the eradication of Helicobacter pylori and therapy with large doses (1 g/d) of vitamin C for 3 months. RESULTS: The H. pylori eradication, assessed by C-urea breath test, and vitamin C therapy failed to reverse the histological atrophy of the gastric mucosa but improved significantly the functional status of the atrophied mucosa, especially its exocrine and endocrine secretory activities, attenuated the expression of premalignant markers such as ODC and COX-2, raised the production of growth factors and diminished the release of proinflammatory cytokines. CONCLUSIONS: These results indicate that MAG may be considered as an environmental disease of the gastric mucosa, whose functional status can be improved by the eradication of H. pylori combined with antioxidant therapy with large doses of vitamin C.     

Helicobacter pylori upregulates prion protein expression in gastric mucosa： A possible link to prion disease

AIM: Pathological prion protein (PrPSC) is responsible for the development of transmissible spongiform encephalopathies (TSE). While PrPc enters the organism via the oral route, less data is available to know about its uptake and the role of gastrointestinal inflammation on the expression of prion precursor PrPc, which is constitutively expressed in the gastric mucosa. METHODS: We studied PrPc expression in the gastric mucosa of 10 Helicobacter pylori-positive patients before and after successful H pylori eradication compared to non-infected controls using RT-PCR and Western blotting. The effect of central mediators of gastric inflammation, i.e., gastrin, prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) on PrPc expression was analyzed in gastric cell lines. RESULTS: PrPc expression was increased in H pylori-infection compared with non-infected controls and decreased to normal after successful eradication. Gastrin, PGE2, and IL-1β dose-dependently upregulated PrPc in gastric cells, while TNF-α had no effect. CONCLUSION: H pylori infection leads to the upregula-tion of gastric PrPc expression. This can be linked to H pylori induced hypergastrinemia and increased mucosal PGE2 and IL-1β synthesis. H pylori creates a milieu for enhanced propagation of prions in the gastrointestinal tract.     

The interaction of H. pylori infection and NSAIDs in cyclooxygenase-2 mRNA expression in gastric antral, corpus mucosa, and gastric ulcer

BACKGROUND: Although Helicobacter pylori infection and use of nonsteroidal anti-inflammatory drugs (NSAIDs) are the two major causes of gastric ulcer, their interaction remains controversial. We constructed a prospective cohort study to evaluate how these two factors influence the expression of COX-2 mRNA in gastric antral, corpus mucosa, and gastric ulcer. METHODS: Tissues were obtained by endoscopic biopsy of gastric antral, corpus mucosa, and gastric ulcer. The presence of H. pylori was determined by culture or histology using Giemsa stain. NSAID use was assessed by structured questionnaire and medical record review. The expression of COX-2 mRNA was detected by the TaqMan quantitative RT-PCR system. RESULTS: H. pylori infection was associated with increased COX-2 expression only in antral mucosa (0.77 +/- 0.13 vs. 0.31 +/- 0.07, P < 0.01). NSAID use was significantly associated with decreased COX-2 expression in ulcer (4.49 +/- 1.50 vs. 9.82 +/- 2.48, P < 0.05) but not in antral or corpus mucosa. Regarding the interaction between H. pylori and NSAID, we found that H. pylori infection was associated with increased COX-2 expression in antral mucosa for both NSAID users and nonusers. In NSAID users, H. pylori infection was not associated with increased COX-2 expression in ulcer edge. CONCLUSION: H. pylori infection was associated with increased COX-2 expression in gastric antral mucosa for both NSAID users and nonusers, but not in gastric ulcer, where the effect of NSAID inhibition plays a major role. With these observations, we can interpret indirectly that H. pylori eradication does not interfere with gastric ulcer healing in NSAID users.     

Helicobacter pylori infection affects Toll-like receptor 4 expression in human gastric mucosa

BACKGROUND/AIMS: Toll-like receptor 4 (TLR4), which requires a helper molecule, MD-2, is a main receptor for lipopolysaccharide (LPS) from gram-negative bacteria. The expression of TLR4 in H. pylori infection in human gastric mucosa, however, is unclear. The aim of this study was to determine the effect of H. pylori infection on the TLR4 and MD-2 expression in human gastric mucosa. METHODOLOGY: Biopsy samples from the antrum and corpus were obtained from 45 patients (25 patients without H. pylori infection including 5 patients with successful eradication of H. pylori, and 20 patients with H. pylori infection). These samples were used for TLR4, MD-2 mRNA expression study and immunohistochemical study. RESULTS: In patients without H. pylori infection, the expressions of TLR4 and MD-2 were bigger in the corpus mucosa than in the antral mucosa. In patients with H. pylori infection, the expressions of TLR4 and MD-2 significantly increased in the antral and corpus mucosa. Immunohistochemical study revealed similar results as the TLR4 mRNA expression. After the eradication of H. pylori, the expressions of TLR4 and MD-2 were the same levels in both sites as those in patients without H. pylori infection. CONCLUSIONS: The results indicated that H. pylori infection significantly increased TLR4 and MD-2 expressions in the antral and corpus mucosa.     

Gastrin and Helicobacter pylori in low-grade MALT lymphoma patients

BACKGROUND: This study of patients with Helicobacter pylori infection and low-grade MALT lymphoma aimed to investigate: 1) the effect of H. pylori eradication therapy on the serum gastrin level, 2) whether changes of the serum gastrin level after therapy could predict the prognosis of patients with this tumour, and 3) the relationship between the gastric H. pylori load, the serum gastrin level and the status of MALT lymphoma. METHODS: Thirteen patients with documented low-grade MALT lymphoma and H. pylori infection were enrolled and received H. pylori eradication therapy as the sole initial treatment. The presence of H. pylori, the serum gastrin level, the endoscopic findings, the pathologic features of the biopsies and resected specimens, and the endoscopic ultrasonography findings were evaluated before and after therapy. Follow-up was carried out every 3-6 months. RESULTS: H. pylori eradication was eventually achieved in all 13 patients. The pretreatment fasting serum gastrin level decreased from 177.1 +/- 107.4 pg/ml to 129.2 +/- 78.1, 96.4 +/- 66.6 and 80.1 +/- 42.7 pg/ml after 0-3, 3-6 and 6-9 months, respectively (all P < 0.05). Successful eradication of H. pylori was followed by a decrease of the fasting serum gastrin level and complete regression of initial low-grade MALT lymphoma was observed in all patients. However, two patients subsequently developed recurrent high-grade MALT lymphoma or high-grade lymphoma. In one of them, the serum gastrin level rose again above the pretreatment value. In the other, however, the fasting gastrin level fell throughout the study period. The median fasting serum gastrin level before H. pylori eradication therapy was higher in the patients with tumours of the gastric body (203.4 +/- 108.9 pg/ml) than in those with tumours of the antrum and angulus (89.3 +/- 28.0 pg/ml) (P = 0.06). CONCLUSIONS: Hypergastrinaemia may be associated with an increased risk of gastric MALT lymphoma.     

Effects of Helicobacter pylori eradication on the natural history of lymphocytic gastritis

BACKGROUND: Lymphocytic gastritis is characterised by an accumulation of lymphocytes in the surface epithelium of the stomach. Lymphocytic gastritis has been linked to coeliac disease and Helicobacter pylori infection. AIMS: To determine whether H pylori eradication leads to resolution of the lymphocytic infiltrate and clinical improvement in patients with lymphocytic gastritis, and to determine their HLA status. METHODS: The Leeds Dyspepsia Questionnaire (LDQ) was administered to 13 patients with lymphocytic gastritis. H pylori serology, (13)C urea breath test (UBT), and upper gastrointestinal endoscopy with sampling of the duodenum, antrum, and corpus were done in all cases and the HLA status was determined. Eleven patients had at least one positive test for H pylori. Patients with lymphocytic gastritis and H pylori infection were treated with a one week course of omeprazole, clarithromycin, and metronidazole. Gastric and duodenal intraepithelial lymphocyte (IEL) counts were performed, along with histological assessment of gastric and duodenal biopsies before and after H pylori eradication. RESULTS: Two months after treatment there was a significant reduction in gastric IEL counts in both antrum and corpus. There was no significant change in duodenal IEL counts before and after eradication. According to the Sydney grading there was significant improvement in corpus inflammation after eradication. The patients histologically H pylori positive before treatment became H pylori negative. Dyspepsia scores also improved significantly after treatment. CONCLUSIONS: H pylori eradication treatment in patients with lymphocytic gastritis causes significant improvement in the gastric IEL infiltrate, corpus inflammation, and dyspeptic symptoms. H pylori serology is frequently positive when histology and UBT are negative. Lymphocytic gastritis may represent a specific immune response to H pylori infection.     

Influence of age, sex, and Helicobacter pylori infection before and after eradication on gastric alcohol dehydrogenase activity

BACKGROUND: Gastric alcohol dehydrogenase may contribute to the metabolism of orally ingested ethanol and decrease the bioavailability of the drug. The aims of this study were to assess the impact of Helicobacter pylori infection and its eradication on gastric alcohol dehydrogenase activity and to relate the findings to gastric histology. Furthermore, the role of age- and sex-related differences in gastric alcohol dehydrogenase activity were studied. METHODS: A total of 76 subjects (39 women and 37 men) underwent upper gastrointestinal endoscopy, and biopsies were obtained from the corpus and antrum. The specimens were used for determining gastric alcohol dehydrogenase activity, histological examination, and urease testing. Subjects with H. pylori infection (n = 36) received medication to eradicate the infection, and repeat biopsies were taken 2 and 12 months later. RESULTS: No significant difference in gastric alcohol dehydrogenase activity was found between men and women (p > 0.05). Gastric alcohol dehydrogenase activity did not differ significantly between the subjects older than 50 years (n = 39) and those 50 years or younger (n = 37). In subjects with H. pylori infection, gastric alcohol dehydrogenase activity was significantly reduced in the antrum (p < 0.05). After eradication of H. pylori, alcohol dehydrogenase activity in the antrum increased significantly within 2 months (p < 0.01). Antral biopsies with the most pronounced inflammation and histological changes had significantly decreased alcohol dehydrogenase activity (p < 0.05). In contrast, no significant differences were found in corpus. CONCLUSIONS: H. pylori infection is associated with decreased antral alcohol dehydrogenase activity, which seems to be related to the severity of the inflammatory changes in the mucosa. Eradication of H. pylori normalizes antral alcohol dehydrogenase activity within 2 months.     

Molecular mechanisms of pancreatic cancer and potential targets of treatment

Background: This study of patients with Helicobacter pylori infection and low-grade MALT lymphoma aimed to investigate: 1) the effect of H. pylori eradication therapy on the serum gastrin level, 2) whether changes of the serum gastrin level after therapy could predict the prognosis of patients with this tumour, and 3) the relationship between the gastric H. pylori load, the serum gastrin level and the status of MALT lymphoma. Methods: Thirteen patients with documented low-grade MALT lymphoma and H. pylori infection were enrolled and received H. pylori eradication therapy as the sole initial treatment. The presence of H. pylori , the serum gastrin level, the endoscopic findings, the pathologic features of the biopsies and resected specimens, and the endoscopic ultrasonography findings were evaluated before and after therapy. Follow-up was carried out every 3-6 months. Results: H. pylori eradication was eventually achieved in all 13 patients. The pretreatment fasting serum gastrin level decreased from 177.1 ± 107.4 pg/ml to 129.2 ± 78.1, 96.4 ± 66.6 and 80.1 ± 42.7 pg/ml after 0-3, 3-6 and 6-9 months, respectively (all P < 0.05). Successful eradication of H. pylori was followed by a decrease of the fasting serum gastrin level and complete regression of initial low-grade MALT lymphoma was observed in all patients. However, two patients subsequently developed recurrent high-grade MALT lymphoma or high-grade lymphoma. In one of them, the serum gastrin level rose again above the pretreatment value. In the other, however, the fasting gastrin level fell throughout the study period. The median fasting serum gastrin level before H. pylori eradication therapy was higher in the patients with tumours of the gastric body (203.4 ± 108.9 pg/ml) than in those with tumours of the antrum and angulus (89.3 ± 28.0 pg/ml) ( P = 0.06). Conclusions: Hypergastrinaemia may be associated with an increased risk of gastric MALT lymphoma.     

Increased expression of cyclooxygenase-2 in first-degree relatives of gastric cancer patients

AIM: To study the expression of cydooxygenase-2 (COX-2) in human gastric cancer tissues and their paired adjacent mucosa, as well as mucosa from gastric antrum and corpus of the first-degree relatives of the recruited cancer patients. METHODS: The expression of COX-2 mRNA in 38 patients with gastric cancer and their 29 first-degree relatives and 18 healthy controls was assessed by the real time RT-PCR. The expression of COX-2 protein was determined by Western blot. RESULTS: A marked increase in COX-2 mRNA expression was found in 20 of 37 (54%) cancerous tissues compared to their respective paired normal mucosa (P<0.001). Interestingly, increased COX-2 mRNA expression was also found in mucosa of the corpus (6/29) and antrum (13/29) of their first-degree relatives. Increased COX-2 mRNA expression was more frequently observed in the antrum biopsies from cancer patients than in the antrum biopsies from healthy controls (P<0.05). In addition, 3 of 23 (13%) patients with atrophic mucosa and 6 of 35 (17%) patients with intestinal metaplasia showed increased COX-2 mRNA expression. Furthermore, COX-2 expression increased in H pylori-positive tissues, especially in antrum mucosa. CONCLUSION: Increased COX-2 expression is involved in gastric carcinogenesis, and may be necessary for maintenance of the malignant phenotype and contribute to Helicobacter pylori-associated malignant transformation.     

Endoscopic, histological and serologic findings of gastric hyperplastic polyps after eradication of Helicobacter pylori: comparison between responder and non-responder cases

BACKGROUND: Evidence indicates that eradication of Helicobacter pylori leads to the disappearance of hyperplastic polyps in the stomach. However, there are some exceptions. We have compared endoscopic and serologic findings of responder and non-responder cases with hyperplastic polyps to try to identify the cause(s), other than H. pylori infection, of the formation or growth of gastric hyperplastic polyps. METHODS: We retrospectively studied 33 patients whose hyperplastic polyps disappeared after eradication of H. pylori and 10 patients whose hyperplastic polyps did not disappear after eradication. The patients were examined both endoscopically and serologically before, 1-3 months after and 12-15 months after the eradication. RESULTS: The responder and non-responder groups were similar with respect to age, sex, coexisting diseases, and histologic findings. The number and maximum size of polyps tended to be larger before treatment in the non-responder group than in the responder group. The serum gastrin level was higher in the non-responder group than in the responder group before, 1-3 months after and 12-15 months after the eradication (p=0.0096, p>0.2, p=0.0014). On histologic examination, similar reductions in the degree of inflammatory cell infiltration in the gastric mucosa of the antrum and body were seen in both the responder and non-responder groups. In the non-responders, the size and numbers of the polyps regressed in 5 of the 10 patients. The score of glandular atrophy in the antrum and the serum gastrin levels in the non-regressed cases was higher than those in the regressed cases at 1-3 and 12-15 months after eradication. CONCLUSION: Persistent high gastrin levels were found in the non-responder cases with gastric hyperplastic polyps.