Helicobacter pylori infection is associated with increased expression of macrophage migratory inhibitory factor--by epithelial cells, T cells, and macrophages--in gastric mucosa

The macrophage migratory inhibitory factor (MIF) plays a pivotal role in inflammatory and immune diseases; however, its role in gastrointestinal diseases has not been clarified. This study intended to determine the expression of MIF, by gastric epithelial cells, T cells, and macrophages, in Helicobacter pylori-induced gastritis. Sixty-four patients (30 males, 34 females; mean age, 47 years) referred for upper endoscopy were recruited. Biopsy specimens from the gastric antrum and corpus were obtained for (1) detection of H. pylori and histological examination, (2) single and double immunostaining to test for expression of MIF protein in epithelial cells, T cells, and macrophages, and (2) in situ hybridization for expression of MIF mRNA within the lamina propria. In mucosal specimens from each of the 2 sites, both the percentage of MIF(+) epithelial cells and the numbers of MIF mRNA(+) inflammatory cells, MIF(+) T cells, and MIF(+) macrophages were significantly higher in H. pylori-positive patients than in H. pylori-negative patients. Overall, the percentage of MIF(+) epithelial cells and the numbers of MIF mRNA(+) cells, MIF(+) T cells, and MIF(+) macrophages were higher in the antrum than in the corpus. The percentage of MIF(+) epithelial cells and the numbers of MIF mRNA(+) cells, MIF(+) T cells, and MIF(+) macrophages increased in chronic gastritis, but, in the absence of H. pylori infection, this increase disappeared for all except MIF(+) T cells. Therefore, H. pylori infection is associated with increased expression of the MIF protein and MIF mRNA in gastric epithelial and inflammatory cells; along with other cytokines, MIF may play a significant role in gastric inflammation related to H. pylori infection.     

Accumulation of mast cells and macrophages in focal active gastritis of patients with Crohn's disease

BACKGROUND/AIMS: Recent studies have shown that focal active gastritis seems to be the typical gastric pathology in Crohn's disease. The aim of this study was to compare the incidence of focal active gastritis, Helicobacter pylori infection and distribution of gastric mast cells and macrophages in patients with Crohn's disease, ulcerative colitis and H. pylori gastritis without inflammatory bowel disease. METHODOLOGY: Patients with histologically confirmed Crohn's disease (n = 25) or ulcerative colitis (n = 25) and control patients without inflammatory bowel disease (n = 25) were included in this study. Biopsy specimens were obtained from the antrum and corpus of each patient, and stained with hematoxylin and eosin and immunostained using antibodies to tryptase (AA1) and CD68. The number of mast cells and macrophages located in the lamina propria was determined. RESULTS: Focal active gastritis was detected in 54% of H. pylori-negative patients with Crohn's disease, but it was not found in patients with ulcerative colitis nor in the control group. The density of mast cells and macrophages in the lamina propria of H. pylori-positive patients was significantly higher than in H. pylori-negative patients in all groups. In the Crohn's disease group, the number of mast cells (antrum; 83 +/- 11, body; 89 +/- 11/mm2) and macrophages (antrum; 94 +/- 22, body; 92 +/- 17/mm2) in the lamina propria of H. pylori-negative patients with focal active gastritis was halfway between that in H. pylori-positive and H. pylori-negative patients. In focal active gastritis, mast cells accumulated at the border of focal active gastritis, whereas macrophages accumulated in the center of such lesions. CONCLUSIONS: Our findings indicated that the diagnosis of focal active gastritis, using immunostain for mast cells and macrophages, is the histological hallmark of gastric Crohn's disease. Macrophages might be associated with the formation of focal active gastritis in patients with Crohn's disease.     

Helicobacter pylori infection upregulates endothelial nitric oxide synthase expression and induces angiogenesis in gastric mucosa of dyspeptic patients

BACKGROUND: Helicobacter pylori (H. pylori) infection induces nitric acid (NO) overproduction through inducible NO synthase (NOS) expression, subsequent DNA damage and enhanced antiapoptosis signal transduction sequence in the human gastric mucosa, whereas its possible effect on endothelial nitric oxide synthase (eNOS) expression has not as yet been investigated. The aim of this study was to evaluate the effect of H. pylori infection in the expression of eNOS in gastric mucosa. PATIENTS AND METHODS: We prospectively studied 30 nonsmoking dyspeptic patients (12 men, 18 women, mean age 54.26+/-12.89 years). The diagnosis of H. pylori infection was based mainly on histology. The histological grading of H. pylori infection was evaluated according to the modified Sydney classification. Histological grading of eNOS expression and microvessel density as estimated by CD34 expression were determined by immunohistochemistry (degree 0-3) and correlated with H. pylori infection and histological degree of gastritis. RESULTS: Twelve patients were H. pylori-positive and 18 patients were H. pylori-negative. The two groups were matched for age (P=0.139), sex (P=0.342) and similar degree of gastritis. Intensity of eNOS and CD34 expression in the corpus and antrum were significantly correlated (P<0.001). eNOS expression was correlated with H. pylori infection in the mucosa of the body and antrum (P=0.013 and 0.037, respectively) but not with gastric inflammation and activity (P=0.848 and 0.871, respectively, for the corpus and P=0.565 and 0.793, respectively, for the antrum). H. pylori-positive patients showed higher expression of CD34-positive blood vessels in the mucosa of the antrum (P=0.048). CD34 expression was correlated with gastric inflammation and activity (P=0.03 and 0.044, respectively) in the mucosa of the antrum of H. pylori-positive patients. CONCLUSION: H. pylori infection upregulates eNOS, and induces angiogenesis, contributing to H. pylori-associated pathophysiology in gastric mucosa.     

Cyclooxygenase-2 expression in gastric antral mucosa before and after eradication of Helicobacter pylori infection

OBJECTIVE: Helicobacter pylori (H. pylori) causes chronic gastritis. The inducible prostaglandin synthetase cyclooxygenase 2 (COX-2) plays an important role in inflammatory conditions. We hypothesized that H. pylori-associated chronic gastritis would express COX-2 protein. Our aim was to evaluate the effect of eradication of H. pylori infection on COX-2 expression in the antral mucosa of patients before and after antibiotic therapy. METHODS: Tissues were obtained from patients with non-ulcer dyspepia undergoing H. pylori eradication. Ten patients with proven H. pylori infection and subsequent successful eradication were studied. Three biopsies of antral mucosa were evaluated before and after H. pylori eradication. The amount of acute and chronic inflammation was quantitated. Immunohistochemical staining for COX-2 was expressed as a percentage of the total number of cells and correlated with the degree of chronic inflammation. RESULTS: Specific immunostaining for COX-2 was observed in antral mucosa of patients infected with H. pylori. Patchy cytoplasmic staining was seen in surface epithelial cells and strong cytoplasmic staining for COX-2 was seen in parietal cells. Spotty cytoplasmic staining for COX-2 was also seen in lamina propria plasma cells, as well as there being macrophages present in the germinal centers of lymphoid aggregates. COX-2 expression could be detected both before and after eradication of H. pylori. The mean percentage of cells staining for COX-2 was significantly higher in H. pylori-infected mucosa, compared with mucosa after successful H. pylori eradication (33.4% +/- 5.4 vs 18.9% +/- 3.3, p = 0.038). COX-2 immunostaining correlated best with the chronic inflammation score (r2 = 0.78, p < 0.001). There was a strong correlation for those subjects who were H. pylori infected, as well as for those who had successful H. pylori eradication. CONCLUSIONS: H. pylori associated acute and chronic antral inflammation was associated with immunohistochemical detection of COX-2 protein in epithelial cells, in addition to associated mononuclear cells and parietal cells. Expression was reduced, but not eliminated, in the epithelium after successful eradication of H. pylori. Despite the reduction in COX-2 expression after H. pylori eradication, expression of COX-2 in epithelial cells remained and strongly correlated with the extent of the chronic inflammatory cell infiltrate. The clinical implications of H. pylori-associated induction of COX-2 expression for patients on selective COX-2 inhibitors, in addition to the role of COX-2 in gastric carcinogenesis, deserve further study.     

Secretory leukocyte protease inhibitor expression in various types of gastritis: a specific role of Helicobacter pylori infection

OBJECTIVES: Secretory leukocyte protease inhibitor (SLPI) represents a multifunctional protein of the gastrointestinal mucosa exerting antimicrobial and anti-inflammatory effects. SLPI expression is generally induced during inflammation; however, Helicobacter pylori-mediated gastritis is associated with significantly decreased antral SLPI levels. The aim of the study was to investigate whether SLPI downregulation of gastric mucosa represents a specific phenomenon of H. pylori infection or is generally linked to gastric inflammation. METHODS: SLPI expression was retrospectively analysed by immunohistochemistry in 85 paraffin-embedded samples: H. pylori-induced (n=13), non-steroidal anti-inflammatory drug (NSAID)-enhanced (n=18), autoimmune (n=11), lymphocytic gastritis (n=26) and H. pylori-negative controls (n=17). The intensity of the staining was semiquantitatively analysed using an immunoreactivity score. Statistical analysis of differences was performed using an analysis of variance test. RESULTS: In comparison with the control group, the SLPI expression of antral mucosa in H. pylori-mediated and lymphocytic gastritis was significantly lower (P<0.001), whereas epithelial SLPI expression was not affected in NSAID-enhanced and autoimmune gastritis either in the antrum or corpus, respectively. Both the H. pylori-mediated and lymphocytic gastritis revealed a significantly lower expression of SLPI in infiltrating immune cells (P<0.01), whereas immune cells infiltrating the corpus in autoimmune gastritis showed higher SLPI levels than the immune cells of other groups (P<0.03). CONCLUSION: The local downregulation of SLPI in antral mucosa is specifically linked to H. pylori infection and is not a general phenomenon of gastric inflammation.     

Expression of cytokeratins in Helicobacter pylori -associated chronic gastritis of adult patients infected with cagA ＋ strains： An immunohistochemical study

AIM:To investigate the expression of differentcytokeratins(CKs)in gastric epithelium of adult patientswith chronic gastritis infected with Helicobacter pylori(Hpylori)cagA strains.METHODS:The expression of CK 7,8,18,19 and 20was studied immunohistochemically in antral gastricbiopsies of 84 patients.All the CKs were immunostainedin cagA H pylori gastritis(57 cases),non-H pylori gastritis(17 cases)and normal gastric mucosa(10 cases).RESULTS:In cagA H pylori gastritis,CK8 wasexpressed comparably to the normal antral mucosafrom surface epithelium to deep glands.Distributionof CK18 and CK 19 was unchanged,i.e.transmucosal,but intensity of the expression was different in foveolarregion in comparison to normal gastric mucosa.Cytokeratin 18 immunoreactivity was significantly higherin the foveolar epithelium of H pylori-positive gastritiscompared to both Hpylori-negative gastritis and controls.On the contrary,decrease in CK19 immunoreactivityoccurred in foveolar epithelium of H pylori-positive gastritis.In both normal and inflamed antral mucosawithout Hpylori infection,CK20 was expressed strongly/moderately and homogenously in surface epithelium andupper foveolar region,but in H pylori-induced gastritissignificant decrease of expression in foveolar regionwas noted.Generally,in both normal antral mucosa andH pylori-negative gastritis,expression of CK7 was notobserved,while in about half cagA H pylori-infectedpatients,moderate focal CK7 immunoreactivity of theneck and coiled gland areas was registered,especially inareas with more severe inflammatory infiltrate.CONCLUSION:Alterations in expression of CK 7,18,19 and 20 together with normal expression of CK8 occurin antral mucosa of H pylori-associated chronic gastritisin adult patients infected with cagA strains.Alterationsin different cytokeratins expression might contribute toweakening of epithelial tight junctions observed in Hpylori-infected gastric mucosa.     

环氧合酶-2表达与幽门螺杆菌相关性胃十二指肠疾病的研究

目的　探讨环氧合酶 2表达与幽门螺杆菌Helicobacterpylori ,H .pylori相关性胃十二指肠疾病的关系 ,并通过抗菌治疗评价根除H pylori感染对胃窦黏膜中COX 2表达的影响。方法　用免疫组化方法半定量检测 2 64例经胃镜和组织病理学检查患有十二指肠球部溃疡、胃溃疡、复合性溃疡、胃癌、单纯性慢性胃炎及胃黏膜正常者的胃窦黏膜COX 2蛋白的表达 ,比较H pylori感染与非感染者之间的差异。对检出的 3 5例H pylori的单纯慢性胃炎进行H pylori抗菌根除治疗 ,比较根除前后胃窦黏膜COX 2蛋白的表达变化。根据 2 0 0 0年 5月全国慢性胃炎研讨会共识意见 (江西 井冈山 )对胃黏膜炎症、活动性、异型增生、肠化生和H pylori密 ,度进行半定量测定。结果　胃黏膜表面上皮、腺上皮细胞和固有层间质细胞的浆中可见COX 2蛋白表达 ,但阳性染色细胞多集中在表层上皮。 2 53例中 ,14 3例H pylori者 (56 52 % )COX 2平均阳性细胞率显著高于 110例H pylori者 (43 48% ) ,(P =0 ) ,各疾病组H pylori患者的COX 2平均阳性细胞率均显著高于H pylori者 (P =0 ) ,各疾病组H pylori患者COX 2平均阳性细胞率也均显著高于正常对照组 (P <0 0 5)。 2 7例H pylori根除后的胃黏膜COX 2平均阳性细胞率明显下降 (P =0 ) ,但仍明显高于正     

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.     

Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa

BACKGROUND AND AIMS: Constitutive cyclooxygenase (COX) 1 is believed to mediate prostaglandin dependent gastric protection. However, gastric mucosa contains cells capable of expressing inducible COX-2. We therefore investigated COX-1 and COX-2 expression, localisation, and activity in normal and abnormal human gastric mucosa. METHODS: COX-1 and COX-2 distribution was investigated by light and electron microscopic immunohistochemistry and by western blot analysis, and their contribution to prostaglandin (PG)E(2) synthesis using selective enzyme inhibitors. RESULTS: There was strong parietal cell COX-1 and COX-2 immunoreactivity in all sections and isolated cells, with macrophage and myofibroblast reactivity in some sections. Immunostaining was specifically abolished by antigen absorption. Western blot analysis confirmed COX-1 and 2 expression. COX-1 and COX-2 immunostaining was increased in Helicobacter pylori gastritis, particularly the mid glandular zone and lamina propria inflammatory cells. This was associated with increased ex vivo PGE(2) synthesis (62.4 (13.5) pg/mg v 36.3 (15.5) pg/mg in uninflamed mucosa; p=0. 017) which was significantly inhibited by COX-1 but not COX-2 inhibition. Increased COX-2 immunostaining in macrophages, endothelial cells, and myofibroblasts (with reduced epithelial expression) was seen at the rim of ulcers. CONCLUSION: COX-2, as well as COX-1, is expressed by normal human gastric mucosa and is increased at the rim of ulcers. Although both are increased with H pylori, COX-1 contributes more than COX-2 to gastric PGE(2) production.     

Distribution of Campylobacter pylori and Gastritis in the Stomach of Patients with and without Duodenal Ulcer

The presence of Campylobacter pylori and histological changes of gastric mucosa were studied in 50 consecutive patients with gastric complaints. C. pylori was isolated from the antrum, body, and fundus of 40 patients with (n = 20) and without (n = 20) duodenal ulcer. The incidence of gastritis was not significantly different in the antrum of C. pylori-positive patients with and without ulcer. Otherwise, oxyntic mucosa of both body and fundus regions exhibited gastritis in 64.1% of the C. pylori-positive non-ulcer patients, whereas those with duodenal ulcer presented oxyntic mucosa that was histologically normal or near normal.     

Roles of Helicobacter pylori infection and cyclooxygenase-2 expression in gastric carcinogenesis

AIM: Cyclooxygenase (COX)-2 is over expressed in gastrointestinal neoplasm. Helicobacter pylori (H pylori) infection is causally linked to gastric cancer. However, the expression of COX-2 in various stages of H pylori-associated gastric carcinogenesis pathway has not been elucidated. Therefore, the aim of this study was to clarify the role of H pylori induced COX-2 expression during carcinogenesis in the stomach. METHODS: Gastric biopsies from 138 subjects (30 cases of chronic superficial gastritis (CSG), 28 cases of gastric glandular atrophy (GA), 45 cases of gastric mucosal intestinal metaplasia (IM), 12 cases of moderate gastric epithelial dysplasia and 23 cases of gastric cancer) were enrolled. H pylori infection was assessed by a rapid urease test and histological examination (modified Giemsa staining). The expression of COX-1 and COX-2 in human gastric mucosa was detected by immunohistochemical staining. RESULTS: H pylori infection rate was 64.3% in GA and 69.5% in gastric cancer, which was significantly higher than that (36.7%) in CSG (P<0.05). The positive expression rates of COX-2 were 10.0%, 35.7%, 37.8%, 41.7% and 69.5% in CSG, GA, IM, dysplasia and gastric cancer, respectively. From CSG to GA, IM, dysplasia and finally to gastric cancer, expression of COX-2 showed an ascending tendency, whereas COX-1 expression did not change significantly in the gastric mucosa. The level of COX-2 expression in IM and dysplasia was significantly higher in H pylori-positive than in H pylori-negative subjects (P<0.01). CONCLUSION: COX-2 expression induced by H pylori infection is a relatively early event during carcinogenesis in the stomach.     

Effects of cyclooxygenase-1 and -2 gene disruption on Helicobacter pylori-induced gastric inflammation

BACKGROUND: Cyclooxygenases (COXs) play important roles in inflammation and carcinogenesis. The present study aimed to determine the effects of COX-1 and COX-2 gene disruption on Helicobacter pylori-induced gastric inflammation. METHODS: Wild-type (WT), COX-1 and COX-2 heterozygous (COX-1+/- and COX-2+/-), and homozygous COX-deficient (COX-1-/- and COX-2-/-) mice were inoculated with H. pylori strain TN2 and killed after 24 weeks of infection. Uninfected WT and COX-deficient mice were used as controls. Levels of gastric mucosal inflammation, epithelial cell proliferation and apoptosis, and cytokine expression were determined. RESULTS: COX deficiency facilitated H. pylori-induced gastritis. In the presence of H. pylori infection, apoptosis was increased in both WT and COX-deficient mice, whereas cell proliferation was increased in WT and COX-1-deficient, but not in COX-2-deficient, mice. Tumor necrosis factor (TNF)-alpha and interleukin-10 mRNA expression was elevated in H. pylori-infected mice, but only TNF-alpha mRNA expression was further increased by COX deficiency. Prostaglandin E2 levels were increased in infected WT and COX-2-deficient mice but were at very low levels in infected COX-1-deficient mice. Leukotriene (LT) B4 and LTC4 levels were increased to a similar extent in infected WT and COX-deficient mice. CONCLUSIONS: COX deficiency enhances H. pylori-induced gastritis, probably via TNF-alpha expression. COX-2, but not COX-1, deficiency suppresses H. pylori-induced cell proliferation.     

Local expressions of TGF-beta1, TGF-beta1RI, CTGF, and Smad-7 in Helicobacter pylori-associated gastritis

OBJECTIVE: Transforming growth-factor (TGF)-beta1 and Smad-7 play important roles in Helicobacter pylori (H. pylori)-associated gastritis. Connective tissue growth factor (CTGF) can facilitate the TGF-beta/Smad signaling by switching off Smad-7. The purpose of this study was to examine the in situ expressions of these cytokines in the gastric antrum with or without H. pylori infection. MATERIAL AND METHODS: Antral specimens from 166 patients (96 M, 70 F, median age 52 years, range 26 to 76 years) were used in this study. H. pylori infection status was determined by histological examination and (UBT) [13C]-urea breath test. Degrees of severity and activity of chronic gastritis were scored for all specimens. Immunohistochemistry was used to demonstrate local expressions of TGF-beta1, TGF-beta1 type 1 receptor (TGF-beta1RI), Smad-7, and CTGF in the gastric antrum. RESULTS: The results demonstrated that mononuclear cells (MNCs) in lamina propria were the major source of these cytokines. The number of MNCs stained with TGF-beta1, TGF-beta1RI, CTGF, and Smad-7 was significantly higher in H. pylori-positive patients than in H. pylori-negative patients. Furthermore, there was a positive correlation between these cytokine-producing MNCs and the severity of chronic gastritis. CONCLUSIONS: H. pylori infection is associated with increased expression of TGF-beta1, TGF-beta1RI, Smad-7, and CTGF in the gastric antrum. Our results also suggest that the feed-back loop consisting of TGF-beta1, Smad-7, and CTGF may play an important role in the pathogenesis of H. pylori-associated gastritis.     

Helicobacter pylori and Cell Proliferation of the Gastric Mucosa: Possible Implications for Gastric Carcinogenesis

Objectives: Helicobacter pylori infection is recognized as a risk factor for gastric adenocarcinoma. "Mitogenesis increases mutagenesis," so the effects of H. pylori infection on the gastric mucosal proliferative compartment have been investigated. Methods: In 25 H. pylori-positive and 19 H. pylori-negative subjects, epithelial cell proliferative activity and the pattern of the proliferative compartment were separately evaluated in relation to both the different type of mucosa (antrum and corpus) and the H. pylori positivity/negativity after ³H-thymidine labeling. Results: Both mucosal cell kinetics and the pattern of the proliferative compartment in the antrum appeared different from those of the corpus. Comparing H. pylori -positive and H. pylori -negative subjects, differences were detected only in the total number of cells in the antrum, whereas all of the cell kinetics parameters, except the labeling index, were greater in the corpus of the former group. A superficialization of the proliferative compartment was shown in H. pylori -positive subjects. Changes were more evident in subjects with more severe gastritis but were also present in H. pylori -positive subjects without corpus gastritis. Conclusions: These results show that H. pylori infection is associated with modifications in the proliferative compartment of the gastric mucosa. Both infection per se and chronic gastritis seem to be relevant for such changes.     

Gastrokine 1 expression in patients with and without Helicobacter pylori infection

BACKGROUND: To understand the molecular changes underlying Helicobacter pylori-related gastric diseases is mandatory to prevent gastric cancer. Proteomic technology is providing a rapid expansion of the basic knowledge, particularly in the discovery of new biomarkers involved in the tumourigenesis. AIM: To characterise changes in protein expression level of the gastric mucosa in H. pylori-infected patients. METHODS: The population enrolled comprised 41 dyspeptic patients. Proteins extracted from gastric mucosal specimens were analysed by 2-dimensional electrophoresis, sequenced by MALDI-TOF and identified by Edman's degradation. RESULTS: Twenty-one out of 41 patients had H. pylori infection of whom 17 had anti-CagA IgG antibodies. Several proteins were identified, of which Rho guanosine diphosphatase dissociation inhibitor alpha and heat shock protein 27 increased and glutathione transferase and antrum mucosa protein-18 decreased in H. pylori-positive in respect to H. pylori-negative patients. Interestingly, antrum mucosa protein-18, currently referred as gastrokine-1, showed two isoforms differing in the first N-terminal amino acid residue. Both gastrokine-1 isoforms were observed in the H. pylori-negative group whereas a lower expression or even absence of the gastrokine-1 basic isoform was found in a subgroup (7/21) of H. pylori-positive patients with moderate-severe gastritis. CONCLUSION: Our study demonstrated the presence of gastrokine-1 isoforms of which the basic isoform was reduced in a subset of patients with H. pylori infection.     

Helicobacter pylori infection reduces intraluminal nitric oxide

BACKGROUND: Nitric oxide (NO) plays an important role in gastrointestinal mucosal protection. We have previously shown that Helicobacter pylori infection is associated with a lower concentration of NO in the human stomach. The aim of this study is to explore the pathogenesis of this finding using an animal model. METHODS: Mongolian gerbils were divided into four groups: H. pylori-negative and -positive, each with and without the intraperitoneal addition of superoxide dismutase (SOD). Intraluminal NO and serum nitrate were measured by using a chemiluminescence system. Inducible nitric oxide synthase (iNOS) levels in gastric mucosa were measured by using the NOSdetect Assay Kit. RESULTS: iNOS levels in H. pylori-positive gerbils were significantly greater than in those without infection. Intraluminal NO levels in H. pylori-positive gerbils were significantly lower than those in H. pylori-negative ones and increased after SOD administration. Serum nitrate levels in H. pylori-positive gerbils were significantly greater than those in H. pylori negative ones and decreased after SOD administration. CONCLUSIONS: The low level of NO in the gastric lumen in H. pylori infection is likely a result of superoxide production related to H. pylori-induced inflammation.     

Helicobacter pylori infection affects the expression of PCNA, p53, c-erbB-2 and Bcl-2 in the human gastric mucosa.

OBJECTIVE: Helicobacter pylori infection has been related to gastric carcinogenesis. This association is based on epidemiological data, pathological changes observed in the gastric mucosa, and chemical products from bacteria that may induce damage of DNA. In the present study we examined gastric endoscopic biopsies from patients with chronic gastritis, with and without H. pylori infection, and surgical biopsies from gastric cancer patients to evaluate whether this bacteria may induce changes in the expression of molecular markers associated with carcinogenesis. PATIENTS AND METHODS: the study involved 57 biopsies from the antral region of the stomach of patients with chronic gastritis and gastric cancer that were analyzed by immunohistochemistry. Molecular markers examined were: PCNA (Proliferating Cell Nuclear Antigen), p53, c-erbB-2, Bcl-2, and p21 H-ras. RESULTS: PCNA content of epithelial cells was significantly higher in H. pylori infected biopsies. Treatment aimed to eradicate H. pylori decreased the level of PCNA-positive cells in the group of patients that became H. pylori-negative as well as in H. pylori-positive patients. Nuclear p53 expression (used here as a surrogate marker for p53 mutation/inactivation) and c-erbB-2 expression were observed only in the group of patients that remained with the bacteria after treatment. A higher bcl-2 expression in lymphoid cells was observed in H. pylori-positive biopsies, and treatment did not change the expression of this protein. No significant expression of p21 H-ras was observed in the studied biopsies. CONCLUSION: this study suggests that H. pylori is involved in the induction of molecular changes that might predispose human gastric mucosa cells to pre-neoplastic and neoplastic events.