Helicobacter Pylori-associated Gastritis Research Articles

Implication of NF-κB in Helicobacter pylori-associated gastritis

OBJECTIVE: Transcription factor NF-κB plays a pivotal role in inflammatory responses by up-regulating mRNA expression of bioactive molecules such as chemokines and adhesion molecules. The present study was designed to elucidate the implication of NF-κB in Helicobacter pylori–associated gastritis (HAG). METHODS: We examined 41 patients with HAG and 18 H. pylori–negative control subjects. Expression of activated NF-κB was studied in situ by immunohistochemistry using α-p65 mouse monoclonal antibody (α-p65 mAb), which recognizes activated NF-κB. To identify the cell types in which NF-κB was activated, we performed immunohistochemical analysis using antibodies against vascular endothelial cells, macrophages, and B and T lymphocytes. We also examined the colocalization of activated NF-κB with the expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells. We measured the levels of NF-κB–dependent chemokines including interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES) and macrophage inflammatory protein-1α (MIP-1α) in antral mucosa by ELISA (ELISA). RESULTS: Activated NF-κB was detected in the nuclei of epithelial cells in antral mucosa, especially of patients with HAG. NF-κB positivity index (NF-κB PI), representing the percentages of epithelial cells with positive nuclear staining for activated NF-κB, was significantly higher in patients with HAG than in H. pylori–negative controls. NF-κB PI correlated significantly with histological scores of gastritis. Moreover, activated NF-κB was identified in the nuclei of vascular endothelial cells, macrophages, and B lymphocytes within the lamina propria in HAG. Colocalization of activated NF-κB with ICAM-1 expression in the same endothelial cells was demonstrated. The IL-8 levels significantly correlated with the NF-κB PI. CONCLUSIONS: In addition to epithelial cells, macrophages, vascular endothelial cells, and B lymphocytes contained activated NF-κB. In these cells, activated NF-κB may be involved in the inflammation process in HAG through the up-regulation of chemokines or adhesion molecules.

Implication of NF-kappaB in Helicobacter pylori-associated gastritis.

Transcription factor NF-kappaB plays a pivotal role in inflammatory responses by up-regulating mRNA expression of bioactive molecules such as chemokines and adhesion molecules. The present study was designed to elucidate the implication of NF-kappaB in Helicobacter pylori-associated gastritis (HAG). We examined 41 patients with HAG and 18 H. pylori-negative control subjects. Expression of activated NF-kappaB was studied in situ by immunohistochemistry using alpha-p65 mouse monoclonal antibody (alpha-p65 mAb), which recognizes activated NF-kappaB. To identify the cell types in which NF-kappaB was activated, we performed immunohistochemical analysis using antibodies against vascular endothelial cells, macrophages, and B and T lymphocytes. We also examined the colocalization of activated NF-kappaB with the of intercellular expression adhesion molecule-1 (ICAM-1) on endothelial cells. We measured the levels of NF-kappaB-dependent chemokines including interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES) and macrophage inflammatory protein-1alpha (MIP-1alpha) in antral mucosa by ELISA (ELISA). Activated NF-kappaB was detected in the nuclei of epithelial cells in antral mucosa, especially of patients with HAG. NF-kappaB positivity index (NF-kappaB PI), representing the percentages of epithelial cells with positive nuclear staining for activated NF-kappaB, was significantly higher in patients with HAG than in H. pylori-negative controls. NF-kappaB PI correlated significantly with histological scores of gastritis. Moreover, activated NF-kappaB was identified in the nuclei of vascular endothelial cells, macrophages, and B lymphocytes within the lamina propria in HAG. Colocalization of activated NF-kappaB with ICAM-1 expression in the same endothelial cells was demonstrated. The IL-8 levels significantly correlated with the NF-kappaB PI. In addition to epithelial cells, macrophages, vascular endothelial cells, and B lymphocytes contained activated NF-kappaB. In these cells, activated NF-kappaB may be involved in the inflammation process in HAG through the up-regulation of chemokines or adhesion molecules.

Profiling of bacterial flora in gastric biopsies from patients with Helicobacter pylori-associated gastritis and histologically normal control individuals by temperature gradient gel electrophoresis and 16S rDNA sequence analysis.

The aim of this study was to establish bacterial profiles in gastric biopsy specimens from patients with Helicobacter pylori-associated gastritis by means of temporal temperature gradient gel electrophoresis (TTGE) of PCR-amplified 16S rDNA fragments. Specimens from eight patients with asymptomatic gastritis and five histologically normal controls revealed a Helicobacter-specific band in the TTGE profile with increased amounts of Helicobacter-specific DNA in the biopsies from most of the gastritis patients. DNA from other genera including Enterococcus, Pseudomonas, Streptococcus, Staphylococcus and Stomatococcus was also found in the stomach. In the absence of gastric inflammation, Helicobacter spp. appeared to be part of a complex, presumably indigenous microbial flora found in the biopsy specimens from the stomach.

Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient mice.

To elucidate the pathogenesis of Helicobacter pylori-associated gastritis, we studied immune responses of C57BL/6J wild-type (WT), SCID, and gene deficient (IFN-gamma-/- and IL-4-/-) mice following infection with a pathogenic isolate of H. pylori (SPM326). During early infection in WT mice, mononuclear and polymorphonuclear cells accumulated in the gastric lamina propria, and the numbers of cells in the inflamed mucosa expressing IFN-gamma, but not IL-4, mRNA rose significantly (p < 0.005), consistent with a local Th1 response. Splenic T cells from the same infected WT mice produced high levels of IFN-gamma, no detectable IL-4, and low amounts of IL-10 following in vitro H. pylori urease stimulation, reflecting a systemic Th1 response. Infected C57BL/6J SCID mice did not develop gastric inflammation despite colonization by many bacteria. Infected C57BL/10J and BALB/c mice also did not develop gastric inflammation and displayed a mixed Th1/Th2 splenic cytokine profile. These data imply a major role for the Th1 cytokine IFN-gamma in H. pylori-associated gastric inflammation in C57BL/6J mice. Compared with WT animals, infected IL-4-/- animals had more severe gastritis and higher levels of IFN-gamma production by urease-stimulated splenocytes (p < 0.01), whereas IFN-gamma-/- mice exhibited no gastric inflammation and higher levels of IL-4 production by stimulated splenocytes. These findings establish C57BL/6J mice as an important model for H. pylori infection and demonstrate that up-regulated production of IFN-gamma, in the absence of the opposing effects of IL-4 (and possibly IL-10), plays a pivotal role in promoting H. pylori-induced mucosal inflammation.

Intraperitoneal immunization can induce quiescence of Helicobacter pylori-associated active gastritis

Intraperitoneal immunization can induce quiescence of Helicobacter pylori-associated active gastritis

Accumulation of p53 gene mutations in Helicobacter pylori-associated gastritis of 8 years infection in Japanese monkey

Accumulation of p53 gene mutations in Helicobacter pylori-associated gastritis of 8 years infection in Japanese monkey

Expression and activation of NF-kappa B in the antrum of the human stomach.

Both in vitro studies and experiments in mice suggest a key role for transcription factor NF-kappa B as a mediator of mucosal inflammation. Experiments in vitro show that NF-kappa B activation may be a critical event in the production of proinflammatory molecules in Helicobacter pylori-associated gastritis. This study examines the expression and activity of NF-kappa B in situ in antral biopsies of 69 consecutive patients with immunohistochemical techniques. In the uninflamed stomach, NF-kappa B was highly expressed and active in a subset of epithelial cells, which were identified as predominantly G cells. In accordance with this activity, G cells were shown to express high levels of the NF-kappa B target cytokine TNF-alpha, a well-documented stimulator of gastrin production. In patients with H. pylori-associated gastritis, NF-kappa B activity was markedly enhanced. Activation occurred preferentially in the epithelial cells. The number of cells showing activated NF-kappa B correlated with the activity of gastritis, a measure of neutrophil influx, whereas no correlation was found with the chronicity of inflammation, a measure of the presence of mononuclear inflammatory cells. This correlation is direct evidence of the importance of NF-kappa B-dependent signal transduction for neutrophil influx in H. pylori-associated gastritis.

Focal gastric inflammatory infiltrates in inflammatory bowel diseases: prevalence, immunohistochemical characteristics, and diagnostic role

OBJECTIVES: To date, few studies have evaluated gastric histology in patients with inflammatory bowel disease (IBD). The aim of this prospective controlled study was to establish the frequency of focal gastritis in Crohn’s disease (CD) and ulcerative colitis (UC) patients, as well as to evaluate its immunohistochemical characteristics and clinicoanatomical determinants. METHODS: We evaluated 141 consecutive patients with known CD of the large and/or small bowel, 79 patients with UC, and 141 CD- and UC-free controls; all underwent upper gastrointestinal (GI) endoscopy and 13C urea-breath test. Biopsy specimens taken from the antrum, angulus, and gastric body were evaluated by histology and immunohistochemistry. A series of variables, including CD activity index, duration, extent and location of disease, intestinal resection, number of recurrences, and previous and current medical therapy, as well as the presence of dyspeptic symptoms and mucosal lesions at endoscopy, were determined in all CD patients and correlated with the presence or absence of focal gastritis. RESULTS: Helicobacter pylori-associated gastritis was found in 47 patients with CD (33%), in 37 patients with UC (47%), and in 60% of CD-/UC-free controls ( p < 0.01). In H. pylori-negative CD patients focal gastritis was found in 43% of cases (40/94), compared with 12% (5/42) of UC patients and 19% (11/57) of controls ( p < 0.05). Specificity and positive predictive value of focal gastritis in CD were 84% and 71%, respectively. It was characterized by a focal perifoveolar or periglandular lymphomonocytic infiltrate, with CD8 +/CD4 + cells predominant both in CD and UC patients. There were no significant correlations between the occurrence of focal gastritis and any clinicoanatomical CD features. CONCLUSIONS: Focal gastritis is relatively common in CD patients although it is not exclusive to this condition. Its recognition could be useful in the diagnostic workup of any patient with suspected or indeterminate inflammatory bowel disease, as it makes a diagnosis of CD more likely.

Focal gastric inflammatory infiltrates in inflammatory bowel diseases: prevalence, immunohistochemical characteristics, and diagnostic role.

To date, few studies have evaluated gastric histology in patients with inflammatory bowel disease (IBD). The aim of this prospective controlled study was to establish the frequency of focal gastritis in Crohn's disease (CD) and ulcerative colitis (UC) patients, as well as to evaluate its immunohistochemical characteristics and clinicoanatomical determinants. We evaluated 141 consecutive patients with known CD of the large and/or small bowel, 79 patients with UC, and 141 CD- and UC-free controls; all underwent upper gastrointestinal (GI) endoscopy and 13C urea-breath test. Biopsy specimens taken from the antrum, angulus, and gastric body were evaluated by histology and immunohistochemistry. A series of variables, including CD activity index, duration, extent and location of disease, intestinal resection, number of recurrences, and previous and current medical therapy, as well as the presence of dyspeptic symptoms and mucosal lesions at endoscopy, were determined in all CD patients and correlated with the presence or absence of focal gastritis. Helicobacter pylori-associated gastritis was found in 47 patients with CD (33%), in 37 patients with UC (47%), and in 60% of CD-/UC-free controls (p < 0.01). In H. pylori-negative CD patients focal gastritis was found in 43% of cases (40/94), compared with 12% (5/42) of UC patients and 19% (11/57) of controls (p < 0.05). Specificity and positive predictive value of focal gastritis in CD were 84% and 71%, respectively. It was characterized by a focal perifoveolar or periglandular lymphomonocytic infiltrate, with CD8+/CD4+ cells predominant both in CD and UC patients. There were no significant correlations between the occurrence of focal gastritis and any clinicoanatomical CD features. Focal gastritis is relatively common in CD patients although it is not exclusive to this condition. Its recognition could be useful in the diagnostic workup of any patient with suspected or indeterminate inflammatory bowel disease, as it makes a diagnosis of CD more likely.

Helicobacter pylori-Associated Gastric Ulcer Exhibits Enhanced Mucosal Chemokine Activity at the Ulcer Site

Background and Aim: Although mucosal α- and β-chemokines are considered to be involved in the pathogenesis of Helicobacter pylori-associated gastritis, little is known how these chemokines are related to the ulcerogenesis in peptic ulcer patients. We examined the levels of interleukin (IL)-8 and macrophage inflammatory protein-1α (MIP-1α) in organ cultures and the numbers of inflammatory cells infiltrating the lamina propria by using the mucosal tissues obtained from gastric ulcer (GU) patients with and without H. pylori infection. Methods: Levels of IL-8 and MIP-1α secreted in organ cultures were measured by an enzyme-linked immunosorbent assay. Numbers of myeloperoxidase-positive neutrophils, CD68-positive macrophages, and mononuclear cells were determined in tissue sections. Results: The mucosal tissues of both the gastric antrum and the ulcer site obtained from patients with H. pylori-positive GU showed significantly higher levels of IL-8 and MIP-1α and increased numbers of inflammatory cells compared with the corresponding mucosal tissues from those with H. pylori-negative GU or the antral mucosal tissues from H. pylori-negative controls. When the values were compared between the mucosal tissues from the gastric antrum and those from the ulcer site, the latter group of tissues showed significantly higher levels of IL-8 and MIP-1α and increased numbers of neutrophils and macrophages than the former group regardless of its healing process in patients with H. pylori-positive GU. Conclusion: Mucosal α- and β-chemokines may be important to the ulcerogenesis in H. pylori-associated GU disease.

Atrophy, acid suppression and Helicobacter pylori infection: a tale of two studies.

Much of what is currently accepted regarding Helicobacter pylori-associated gastritis and its relationship with gastric adenocarcinoma rests on the assumption that atrophic gastritis can be correctly identified and reproducibly recognized. Several studies have indicated that pathologists have a low level of agreement on this topic, and the terms 'gastric atrophy' and 'atrophic gastritis' remain imprecisely defined and poorly understood. Furthermore, the genesis and progression of the atrophic changes that take place in the gastric mucosa of some individuals infected with H. pylori are incompletely characterized. The lack of a strict definition of atrophic gastritis is at least partially responsible for recent concerns regarding the effects of prolonged pharmacological gastric acid inhibition in patients with H. pylori infection. One recent paper concluded that patients with reflux oesophagitis and H. pylori infection who are treated with longterm acid inhibition have an increased risk of atrophic gastritis. As this term evokes associations with an increased risk of gastric cancer, the possibility was subsequently raised that anti-secretory maintenance therapy might increase the risk of cancer in H. pylori-positive patients. A second report, however, concluded that long-term acid-inhibitory therapy for an average of three years is no different from fundoplication in the development of gastric atrophy. Also, because no intestinal metaplasia developed in any of the patients, and only atrophic gastritis associated with intestinal metaplasia is considered a precursor of gastric cancer, there is no evidence to support the hypothesis that long-term acid inhibition in individuals with H. pylori infection increases the risk of gastric cancer.

Changes in the mucosal expression of interleukin 15 in Helicobacter pylori-associated gastritis

Transcripts for interleukin (IL) 15 were detected in the gastric mucosal samples of 5/5 (100%) patients with no evidence of Helicobacter pylori infection and in 4/14 (28%) H. pylori-infected patients ( P<0.05). Both IL-15 mRNA and IL-15 protein were detected in 1/6 (17%) patients who successfully underwent H. pylori eradication therapy, before treatment and in 5/6 (83%) cases after eradication. Even though a parallel significant ( P<0.03) improvement of gastritis score occurred after eradication, the severity of gastritis did not differ according to the mucosal IL-15 expression among H. pylori-infected patients, irrespective of the CagA serology. This study demonstrates, for the first time, that transcripts for IL-15 are expressed in the human gastric mucosa. Changes occurring during H. pylori colonisation and after eradication raise the hypothesis that H. pylori may down-regulate IL-15 expression in the gastric mucosa.

Leptin and Its Receptor in Normal Human Gastric Mucosa and in Helicobacter pylori-Associated Gastritis

Background: Leptin, a newly discovered weight-reducing hormone, is mainly produced in fat cells. Recently, this hormone has been reported to be produced in rat gastric mucosa cells. In the present study we analyzed the localization and expression of leptin and its receptors in normal human gastric mucosa and in patients with Helicobacter pylori-associated gastritis. Methods: Plasma leptin levels and gastric mucosa leptin content were determined in 39 patients with dyspepsia. Cellular localization of leptin and of the signaling receptor (Ob-RL) were assessed by immunohistochemistry. Reverse transcriptase polymerase chain reaction (RT-PCR) for leptin receptor isoforms was performed on gastric epithelial cells isolated by laser-capture-microdissection. Results: Leptin content of the corpus gastric mucosa in H. pylori

Bovine milk inhibits both adhesion of Helicobacter pylori to sulfatide and Helicobacter pylori-induced vacuolation of vero cells.

Adhesion of Helicobacter pylori to gastric mucosal cells is an initial important step in colonization and infection. To study adhesion, we investigated whether milk inhibits the adhesion of Helicobacter pylori to sulfatide, an acidic glycosphingolipid that exists in human gastric mucosa and to which Helicobacter pylori adheres. As a measure of functional significance, we also studied whether milk inhibits Helicobacter pylori-induced vacuolation of Vero cells. We used sulfatide-coated polystyrene plates and studied the effect of bovine milk on the adhesion of Helicobacter pylori to sulfatide. We used Vero cells for Helicobacter pylori-induced vacuolation. Bovine milk 100- to 200-fold diluted significantly inhibited both adhesion of Helicobacter pylori to sulfatide and Helicobacter pylori-induced vacuolation in Vero cells. Bovine milk significantly inhibited adhesion of Helicobacter pylori to MKN-45 cells and Lewis b antigen-coated polystyrene plates. In addition, these results suggest that bovine milk contains active substances that inhibit both adhesion of Helicobacter pylori to mucosa and vacuole formation. Bovine milk may have a protective effect on the gastric mucosa in Helicobacter pylori-associated gastritis.

Analysis of p53 Gene Mutations in Helicobacter pylori-Associated Gastritis Mucosa in Endoscopic Biopsy Specimens

Background: No previous report has shown the relationship between Helicobacter pylori infection and a direct sequence analysis of p53 gene mutation in a biopsy sample of human gastric mucosa. Methods: A total of 60 endoscopic biopsies samples (21 patients with H. pylori-positive gastritis and 9 patients with H. pylori-negative gastritis), including antral mucosa and corpus mucosa, were used in this study. Direct DNA sequencing of exons 5, 6, 7, and 8 of the p53 gene was performed by the dyedeoxy terminator method. Results: Mutations in the p53 gene were identified in non-hot spot codons in exon 7 and 8 in 11 of 21 samples (52.4%) from H. pylori-positive gastritis patients. There was no mutation in H. pylori-negative gastritis patients. Conclusions: This finding shows that H. pylori infection can induce p53 point mutations and appears to be involved in the pathway leading to dysplasia or carcinoma.

Mucosal macrophage inflammatory protein-1alpha activity in Helicobacter pylori infection.

Mucosal chemokines are considered to be important in the pathogenesis of Helicobacter pylori-associated gastritis. The aims of this study are to examine the levels of macrophage inflammatory protein-1alpha (MIP-1alpha) in organ cultures, the expression of MIP-1alpha mRNA and the cellular source of MIP-1alpha, using the antral mucosal specimens obtained from H. pylori-positive and -negative patients. Enzyme-linked immunosorbent assay was used to measure the levels of MIP-1alpha in organ cultures of mucosal tissues and cell cultures of fractionated mucosal cells. The expression of MIP-1alpha mRNA and protein was analysed in fresh biopsy tissues with reverse transcriptase-polymerase chain reaction (RT-PCR) and double immunofluorescence microscopy, respectively. The mucosal specimens obtained from H. pylori-positive patients exhibited significantly higher values of MIP-1alpha activity in organ cultures with increased numbers of CD68+ macrophages, myeloperoxidase+ neutrophils and mononuclear cells in the lamina propria compared with those from H. pylori-negative patients. The RT-PCR analysis detected MIP-1alpha mRNA in more than 50% of the specimens with H. pylori infection, but not in those without infection. In cell cultures, the macrophage fraction contained substantially higher amounts of MIP-1alpha on a per cell basis than the lymphocyte fraction and MIP-1alpha activity was not detected in cultures of gastric epithelial cells. This observation was also confirmed by a double immunofluorescence microscopic study in which most (>90%) MIP-1alpha-positive infiltrating cells were CD68+ macrophages. This study indicates that synthesis and secretion of MIP-1alpha are increased in H. pylori-infected antral mucosa and that mucosal macrophages are the main cell type responsible for this phenomenon.

Chemokines in the gastric mucosa in Helicobacter pylori infection

Background—Although chemokines have been suggested to play an important role in Helicobacter pyloriassociated gastritis, few studies have investigated the role of chemokines other than interleukin 8 (IL-8) in gastric mucosa.Aims—To...

Fas-mediated apoptosis in autoimmune and Helico-bacter pylori-associated gastritis

Fas-mediated apoptosis in autoimmune and Helico-bacter pylori-associated gastritis

Expression of HLA-DR, but not ICAM-1 or B7 as costimulatory molecules by gastric epithelial cells in Helicobacter pylori-associated gastritis

Expression of HLA-DR, but not ICAM-1 or B7 as costimulatory molecules by gastric epithelial cells in Helicobacter pylori-associated gastritis

Role of ENA-78 in helicobacter pylori-associated gastritis

Role of ENA-78 in helicobacter pylori-associated gastritis