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 reduces intraluminal nitric oxide in humans

It has recently been demonstrated that nitric oxide (NO) is highly concentrated in the gastric lumen and plays an important role in defending against pathogenic microorganisms in the stomach. NO in the gastric lumen is mainly delivered by extrinsic sources from saliva. We studied whether Helicobacter pylori infection affected intraluminal NO levels in humans. H. pylori infection was diagnosed on the basis of histology and culture or (¹³C)-urea breath test. Air and gastric juice in the gastric lumen were collected endoscopically. The concentration of intraluminal NO was measured by a chemiluminescence system, using an NO analyzer. The concentration of nitrite in gastric juice was measured by the Griess reaction. The intraluminal concentration of NO in H. pylori-positive patients (198.2 ± 41 parts per billion [ppb] mean ± SE; n = 70) was significantly lower than that in H. pylori-negative patients (353.0 ± 57.9 ppb; n = 43; P < 0.05). In contrast, the concentration of nitrite in gastric juice in H. pylori-positive patients (57.7 ± 12.3 μM; n = 70) was significantly higher than that in H. pylori-negative patients (25.9 ± 6.4 μM; n = 43, P < 0.01). The intraluminal concentration of NO in H. pylori-positive patients was markedly increased and the concentration of nitrite in H. pylori-positive patients was markedly decreased following the completion of eradication therapy. Based on these results, we propose that a decrease in NO and excess nitrite production in the gastric lumen are associated with H. pylori infection and may play an important role in the pathogenesis of H. pylori-related abnormalities. Received: December 14, 1998 / Accepted: June 25, 1999     

Helicobacter pylori infection and gastric juice vitamin C levels

H. pylori has recently been recognized as a novel risk factor of gastric cancer, but its precise role in gastric carcinogenesis is as yet unknown. The aim of the present study was to assess the relationship betweenH. pylori infection and vitamin C levels in gastric juice and also to examine whether eradication ofH. pylori could have any impact on these levels. Gastric juice and plasma vitamin C levels were measured in 88 dyspeptic patients who had an upper gastrointestinal endoscopy. In the subgroup ofH. pylori-positive patients, eradication was attempted with triple therapy. This subgroup was studied on two occasions, ie, before and after treatment. There were 58H. pylori-positive and 30 -negative patients. Gastric juice vitamin C levels inH. pylori-positive patients were statistically lower (P<0.001) than the levels in theH. pylori-negative patients. Triple therapy achieved eradication in 45 patients (77.6%) of the 58H. pylori-positive patients. BeforeH. pylori was eradicated in these 45 patients gastric juice vitamin C levels were significantly (P<0.001) lower than those after eradication, the latter being no different than the group of 30H. pylori-negative patients. There was a significant (P<0.001) improvement of gastritis after eradication, which paralleled the elevation of gastric juice vitamin C levels. No difference was noted in plasma vitamin C levels betweenH. pylori-negative and -positive patients or in the latter before and afterH. pylori treatment. In 13 of the 58H. pylori-positive patients where eradication was not successful there was no difference in gastric juice vitamin C levels before and after eradication and the same was observed for the degree of gastritis. It is concluded thatH. pylori-infected patients have lower gastric juice vitamin C levels in comparison toH. pylori-negative patients.H. pylori eradication restores gastric juice vitamin C levels, which may prove potentially important in the prevention of gastric cancer.This work was presented in part during the V Workshop on Gastroduodenal Pathology andHelicobacter pylori; Dublin, July 5–7, 1992, and published as an abstract (Irish Journal of Medical Sciences 161(suppl 10):25, 1992) and during the American Gastroenterological Association meeting in Boston, Massachusetts, May 15–21, 1993, and published as an abstract (Gastroenterology 104(suppl) A181, 1993).     

No additive effect between Helicobacter pylori infection and portal hypertensive gastropathy on inducible nitric oxide synthase expression in gastric mucosa of cirrhotic patients

Increased expression of inducible nitric oxide synthase (iNOS) has been reported in gastric mucosa of patients with Helicobacter pylori infection or portal hypertensive gastropathy (PHG) but whether there is an additive or synergistic impact between H. pylori and PHG on iNOS expression was unknown. Sixty cirrhotic patients and 21 age-matched control subjects without liver disease were included. Biopsies from the gastric antrum and body were obtained for quantitative histological assessment and immunohistochemical staining for iNOS. iNOS staining was detected in endothelial cells and macrophages. In the absence of PHG, H. pylori significantly induced iNOS expression in cirrhotic patients. PHG also significantly induced iNOS expression in H. pylori-negative patients. However, there was no synergistic or additive effect between H. pylori and PHG on this expression. Furthermore, expression of iNOS was significantly higher in patients with severe PHG than in those with mild PHG and without PHG.     

Helicobacter pylori stimulates inducible nitric oxide synthase in diverse topographical patterns in various gastroduodenal disorders

Overproduction of nitric oxide by inducible nitric oxide synthase (iNOS) acts cytotoxically and contributes to inflammation. We explored the roles of iNOS in the pathogenesis of Helicobacter pylori-associated diseases. Using reverse-transcribed PCR, we examined topographical patterns of iNOS mRNA expression in the gastroduodenal mucosa in H. pylori-negative controls and H. pylori-positive patients with duodenal ulcer (DU), gastric ulcer (GU), and ulcer-free gastritis. iNOS expression showed topographical variations among the tested disorders. As compared to controls, DU had a significantly higher expression of iNOS mRNA in the duodenum, GU in the antrum and duodenum, and gastritis in the antrum and corpus. H. pylori eradication yielded a significant reduction of iNOS mRNA in the duodenum of DU and in the antrum of GU. Diverse topographical patterns of H. pylori-induced iNOS expression may contribute to mechanisms by which H. pylori elicits different clinical disorders.     

Serum pepsinogen concentrations as a measure of gastric acid secretion in Helicobacter pylori-negative and -positive Japanese subjects

Background Although previous studies have indicated that serum pepsinogen I levels, as well as the pepsinogen I/II ratio, were positively correlated with maximal gastric output, the relationship may be different between Helicobacter pylori-negative and -positive subjects. The aim of this study was to investigate the relation between serum pepsinogen concentrations and gastric acid secretion in H. pylori-positive and -negative subjects separately. Methods The presence of H. pylori infection, the serum pepsinogen concentrations, and gastric acid secretion were investigated in 182 subjects without localized lesions in the upper gastrointestinal tract. Serum pepsinogen concentration was measured by radioimmunoassay, and maximal gastric acid output was estimated by an endoscopic gastrin test, as we have previously shown. Results In H. pylori-positive subjects, serum pepsinogen I levels and the pepsinogen I/II ratio were significantly correlated with gastric acid secretion, although the latter showed a better correlation (r = 0.40 and 0.53, respectively). On the other hand, in H. pylori-negative subjects, serum pepsinogen concentrations were well correlated with acid secretion (r = 0.57), but there was no relation between the pepsinogen I/II ratio and acid secretion. Conclusions The correlations between serum pepsinogens and gastric acid secretion differ, depending on the presence or absence of H. pylori infection. With the use of serum pepsinogens as a simple measure of gastric acid secretion, therefore, consideration of H. pylori infection status is needed. Because the determination of the acid secretory level has some clinical implications in both H. pylori-positive and -negative subjects, its estimation by serum pepsinogen concentrations can be of practical use.     

Intragastric Nitric Oxide/Nitrite in Helicobacter pylori-Infected Subjects

Background: Nitrite (NO₂-) in swallowed saliva is reduced to nitric oxide (NO) and other nitrogen oxides by the intragastric acidity. This mechanism is probably important for the intragastric clearance of ingested micro-organisms and nitrosating compounds. The study examines the balance between intragastric NO and NO₂- in relation to endogenous acid production and infection with Helicobacter pylori. Methods: Six healthy H. pylori-negative and six H. pylori-positive volunteers with no known gastroduodenal pathology were examined after an overnight fast. Gastric NO was measured using a chemiluminescence technique and pH as well as NO₂- were analysed in gastric aspirates. Results: Gastric NO was slightly lower in H. pylori     

Gastric expression of inducible nitric oxide synthase and myeloperoxidase in relation to nitrotyrosine in Helicobacter pylori-infected Mongolian gerbils

Objective. For obscure reasons Helicobacter pylori infection of the gastric mucosa is maintained despite a pronounced host defence response. The present study elucidates possible H. pylori-related interference in the oxy- and nitro-radical formation pathways. Material and methods. Male Mongolian gerbils were infected with two different H. pylori strains, TN2GF4 and SS1. At 3, 6, 12 or 18 months after inoculation, gastric expressions of myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and nitrotyrosine were assessed by Western blotting. Results. Expression of both iNOS and MPO was markedly up-regulated in the H. pylori-infected animals compared with non-infected controls. The TN2GF4-infected animals initially (at 3 and 6 months) demonstrated pronounced expression of both iNOS and MPO. The SSI-infected animals exhibited a slower onset with significantly increased iNOS after 12 and 18 months. Nitrotyrosine expression was slightly elevated in the infected groups at 3 and 6 months compared with that in the controls. Nitrotyrosine levels then decreased and were no longer significantly different from those of controls (TN2GF4-infected animals) or were lower (SS1-infected animals) than in the controls. Conclusions. The results indicate that peroxynitrite formation as reflected by nitrotyrosine expression is low or even inhibited in chronic H. pylori infection despite pronounced expression of enzymes representing both the oxy- and nitro-radical formation pathways. The results support the theory that H. pylori survival is related to functional inhibition of mucosal enzymatic NO and/or oxy-radical formation.     

Helicobacter pylori Infection Influences Tumor Growth of Human Gastric Carcinomas

Background: Helicobacter pylori infection is considered a risk factor for gastric carcinoma. However, the effect of eradication therapy in gastric carcinoma patients is not well known. The aim of this study was to investigate the relationship between H. pylori infection and tumor growth of gastric carcinoma. Methods: Fifty-one patients with gastric carcinoma participated in the study. Thirty-three were H. pylori-positive, 6 were H. pylori-negative, and 12 were diagnosed with gastric carcinoma after eradication of H. pylori. To investigate tumor growth of gastric carcinoma, cell proliferation and angiogenesis of the tumors were evaluated by immunohistochemical techniques using Ki-67 and CD34. Results: The Ki-67 labeling index was 47.9?±?2.6 (mean?±?s) in the H. pylori-positive group, 38.1?±?3.6 in the H. pylori-eradicated group, and 22.2?±?5.5 in the H. pylori-negative group. It was significantly lower in the H. pylori-eradicated and H. pylori-negative groups than in the H. pylori-positive one, and a significant difference was also found between the H. pylori-positive and H. pylori-eradicated groups. The microvessel counts were 62.5?±?3.0, 50.2?±?4.0, and 66.0?±?9.8 in the positive, eradicated, and negative groups, respectively. A significant difference was found between the H. pylori-positive and H. pylori-eradicated groups. Conclusion: Our results suggest that H. pylori infection is associated with cell proliferation, and its eradication may influence tumor vascularity of gastric carcinoma. Therefore, H. pylori eradication therapy may contribute to the suppression of tumor growth.     

Stem Cell Factor Expressed in Human Gastric Mucosa in Relation to Mast Cell Increase in Helicobacter pylori-Infected Gastritis

We previously reported mast cell increases in H. pylori gastritis. To determine the mechanism, we investigated the kinetics of mast cells and mast cell growth factor (stem cell factor, SCF) in H. pylori-positive and -negative gastric mucosa. Biopsy specimens from 12 H. pylori-negative and 28 positive subjects were examined. Sections were stained for mast cells, proliferating cell nuclear antigen (PCNA), and SCF. Densities of mast cells, PCNA-positive mast cells, and SCF-positive cells were significantly greater in H. pylori-positive than -negative subjects. SCF was expressed in mast cells and fibroblasts. The density of SCF-positive fibroblasts increased in H. pylori-positive gastritis and decreased after cure of infection. SCF mRNA was detected in H. pylori-positive gastric mucosa. Fibroblasts isolated from the normal gastric mucosa expressed SCF mRNA after incubation with H. pylori water extract. SCF may be one of the factors for mast cell increase. Fibroblasts may participate in mast cell increase and inflammation in H. pylori infection.     

Bile acid reflux and possible inhibition of Helicobacter pylori infection in subjects without gastric surgery

Bile acids are generally known to inhibit growth of Helicobacter pylori in vitro, but whether they do so in humans with no gastric surgery has been uncertain. The present study addresses this issue. Among healthy control subjects with preserved acid secretion, H. pylori-positive subjects were older and had lower gastric bile acid concentrations than H. pylori-negative subjects (P < 0.05). Among gastric ulcer patients with preserved acid secretion, H. pylori-positive patients had a higher basal acid output than H. pylori-negative patients (P < 0.05). Among H. pylori-positive subjects with preserved acid secretion, duodenal ulcer patients had a higher basal and maximum acid output than healthy control subjects (P < 0.01). In conclusion, gastric bile acids may suppress initial stages of H. pylori infection in subjects without gastric surgery. However gastric bile acids may have little effect on peptic ulcer disease, once H. pylori infection is established.     

Expression of COX‐1, COX‐2 and inducible nitric oxide synthase in superficial gastritis,mucosal dysplasia and gastric carcinoma

OBJECTIVE : To investigate the significance of the expression of cyclooxygenase‐1 (COX‐1), cyclooxygenase‐2 (COX‐2) and inducible nitric oxide synthase (iNOS) in superficial gastritis, gastric mucosal dysplasia and gastric carcinoma, and to study the relationship between COX‐2, iNOS, gastric carcinoma and Helicobacter pylori infection. METHODS : Polyclonal antibodies to COX‐1, COX‐2 and iNOS were used detect their expression and the status of H. pylori infection in 92 specimens of paraffin‐embedded gastric tissue. Of the 92 patients, 33 had superficial gastritis, 30 had gastric mucosal dysplasia and 29 had gastric cancer. Helicobacter pylori was detected by toluidine blue staining. RESULTS : Expression of COX‐2 and iNOS in gastric cancer (65.5%, 62.1%) was significantly higher than that in gastritis (18.2%, 18.2%; P < 0.01). Expression of COX‐2 and iNOS in gastritis with H. pylori infection was higher than that in gastric mucosal dysplasia with H. pylori infection. The expression of COX‐2 and iNOS occurred concomitantly in gastritis, dysplasia and gastric cancer. CONCLUSION : Inflammation and H. pylori infection may be able to stimulate the expression of COX‐2 and iNOS, which might be involved in gastric carcinogenesis.     

Gastric Juice Levels of Lactoferrin and Helicobacter pylori Infection

Background: Recently, in vitro studies suggested that lactoferrin (Lf) might play an important role in the physiopathology of Helicobacter pylori-associated gastritis. However, whether Lf is present in the gastric juice and its relationship with H. pylori infection have not as yet been reported. In the present investigation the presence of Lf in gastric juice and its correlation with H. pylori infection were assessed. Methods: This study comprised 30 H. pylori-positive and 14 -negative patients with chronic gastritis. Gastric juice levels of Lf were measured with enzyme-linked immunoassays. Gastric juice concentration of Lf was also investigated in accordance with the histologic findings of biopsy specimens in the gastric body and antrum. Results: Lf concentration in gastric juice was significantly higher in H. pylori-positive than in -negative patients (P=0.033). The pH values are known to influence the levels of Lf. However, intragastric Lf levels were also significantly increased in H. pylori-positive patients as compared with H. pylori-negative patients after correcting the Lf levels for pH values (P = 0.029) or after adjusting the pH values of the gastric juice with NaHCO₃ solution in both groups of patients (P = 0.0007). in addition, the gastric juice levels of Lf correlated significantly with the gastric mucosal concentrations of Lf in the gastric body (P < 0.005, r=0.568) and the antrum (P < 0.05, r=0.401). Conclusions: This study showed for the first time that Lf is present in gastric juice and that it correlates with H. pylori infection. Lf may constitute a good marker for H. pylori-associated gastritis. Although correlation does not prove causation, this study suggests that Lf might play an important role in the physiopathology of H. pylori-associated gastritis.     

Effects of Helicobacter pylori infection on Zollinger-Ellison syndrome

Both Zollinger-Ellison syndrome (ZES) and Helicobacter pylori infection are major etiologic factors for peptic ulcer. The aim of this study was to investigate the effect of H. pylori infection on ZES with special reference to acid secretion. Sixteen patients with ZES were selected (median age, 59 years; range, 39–66 years; M/F, 9/7), and H. pylori status, ulcer location, gastric acid secretion, serum pepsinogen (PG) I and II concentrations, and PG I/II ratio were determined. The seroprevalence of H. pylori infection was 50%, whereas active H. pylori infection was seen in only 25% of the patients. Thirteen patients had duodenal ulcer (DU), 1 had gastric ulcer (GU), and 2 had both GU and DU. DU was seen in both H. pylori-positive and H. pylori-negative patients, whereas GU was found only in H. pylori-positive patients. Both basal and maximal acid outputs were significantly lower in H. pylori-positive patients than in H. pylori-negative patients (P < 0.05). Moreover, both serum PG I and the PG I/II ratio were significantly lower in H. pylori-positive patients than in H. pylori-negative patients. These results indicate that ZES is an independent risk factor for DU, but H. pylori infection may play some role in the development of GU in ZES. In patients with ZES, H. pylori infection may reduce both hypersecretion from parietal cells and PG I secretion from chief cells, and hyperacidity of the stomach in ZES may have eradicated H. pylori in some patients. Received: March 30, 2000 / Accepted: May 26, 2000     

Serum Anti-Helicobacter pylori IgG Antibody Titer in H. pylori-negative Cases with a Different Gastric Mucosal Atrophy Status

Objective This retrospective study was performed to investigate the anti-Helicobacter pylori IgG antibody serum titers in H. pylori-negative subjects with different degrees of gastric mucosal atrophy including C0 grade atrophy. Methods The absence of H. pylori infection was determined based on both negative serum anti-H. pylori IgG antibody test findings and no endoscopic evidence of that infection. Cases negative for the antibody and with positive endoscopic findings of H. pylori infection were defined as H. pylori-positive. The serum anti-H. pylori IgG antibody titers were analyzed in H. pylori-negative (n=1,087), -positive (n=69), and post-eradicated (n=278) subjects. Results The serum antibody titer in subjects with H. pylori-positive endoscopy findings was significantly higher than that in H. pylori-negative subjects, even when the serum titer indicated a negative result. In addition, the anti-H. pylori IgG antibody serum titer was higher in H. pylori-negative subjects with a greater degree of gastric mucosal atrophy. In a comparison between H. pylori-negative C0 and C1 gastric mucosal atrophy cases, the antibody serum titer in those classified as C0 was significantly lower. An analysis of H. pylori post-eradicated cases showed that the serum antibody titer decreased over time after successful eradication. Conclusion The disappearance of H. pylori infection in H. pylori-negative individuals may occur later in those with a greater degree of gastric mucosal atrophy. The serum antibody titer difference between the H. pylori-negative C0 and C1 groups might have been caused by the differences in distribution between H. pylori-uninfected subjects and those in whom the infection had disappeared, thus additional investigation is needed to clarify the significance of gastric mucosal classification including the C0 grade.     

Influence ofHelicobacter pylori on gastric mucosal adaptation to naproxen in man

Our objective was to determine whetherH. pylori influences gastric mucosal injury and adaptation caused by naproxen. Twenty-four healthy volunteers, 12H. pylori-positive and 12H. pylori-negative, were given a 28-day course of naproxen 500 mg twice a day. They were each gastroscoped to assess gastric mucosal damage and mucosal blood flow before and at 1, 7, and 28 days during treatment. Maximal gastric mucosal damage (median grade+IQR) occurred during the first 24 hr in both groups and was of similar magnitude (H. pylori-positive: 2.5, 2.0–3.0P<0.01;H. pylori-negative: 2.0, 1.0–3.0P<0.01). This damage was associated with a fall in antral but not corpus mucosal blood flow. With continued NSAID administration, gastric damage resolved confirming adaptation (H. pylori-positive 1.0, 0–2.0,H. pylori-negative: 1.0, 0–1.0) and antral mucosal blood flow returned to baseline in both groups by day 28. These observations suggest that initial gastric mucosal injury is not influenced byH. pylori colonization and adaptation occurs regardless of its presence.     

Gastric Carcinoid Tumors Without Autoimmune Gastritis in Japan: A Relationship with Helicobacter pylori Infection

In Japan, most cases of gastric carcinoid tumor (GCT) are unassociated with either autoimmune gastritis (AIG) showing type-A chronic atrophic gastritis (CAG-A) or Zollinger-Ellison syndrome (ZES). However, the pathogenesis of this tumor remains unknown. Recent studies have determined that Helicobacter pylori infection induces gastric carcinoid in Mongolian gerbils and that H. pylori lipopolysaccharide exerts a mitogenic effect on ECL cells. We examined five patients with histologically diagnosed GCT, 40 patients with H. pylori-positive gastric ulcer (Hp+GU), 24 patients with H. pylori-positive duodenal ulcer (Hp+DU), and 12 patients with AIG showing CAG-A topographically. We compared the prevalence of H. pylori infection, and the levels of gastrin and pepsinogen (PG) in the serum of patients with GCT with those of patients with Hp+GU, or Hp+DU, and AIG. We also investigated the histological characteristics of the tumor and the gastric corpus mucosa in the GCT patients. The levels of serum gastrin and PG I and II were measured using an RIA kit. In all five (100%) patients with GCT, H. pylori infection was present, without any evidence of AIG or ZES. The serum levels of gastrin in the GCT patients were higher than those in either Hp+GU or Hp+DU patients and lower than those in the AIG patients. In contrast, serum PG I levels and the PG I/II ratio were lower in the GCT group than in the Hp+GU or Hp+DU groups. Histologically, all GCTs were ECL cell tumors and peritumoral corporal mucosal atrophy was observed in four of the five patients with GCT. In conclusions, H. pylori infection and hypergastrinemia were found in the patients with GCT without AIG. This finding suggests that H. pylori infection may induce corporal mucosal atrophy and hypergastrinemia that can produce a GCT with time.     

Association of Adenosine Deaminase,Superoxide Dismutase,and Catalase Activities with <Emphasis Type="Italic">Helicobacter pylori</Emphasis>

Our purpose was to investigate associations between adenosine deaminase (ADA), superoxide dismutase (SOD), and catalase (CAT) activities and H. pylori.Ninety-nine patients were studied. Eight antral mucosal biopsies were taken for biochemical assessment of ADA, CAT, AND SOD activity and histological assessment. H. pyloridensity wAS evaluated according to the updated Sydney system. Patients were divided into three groups according to Sydney classification. ADA activity was found to be higher in patients having H. pyloriin the present study. Also, ADA activity was higher in patients with a severe density of H. pylori. SOD level was found to be significantly higher with increased H. pyloridensity in our study (P< 0.05). In addition, SOD activity was higher in it H. Pylori-positive than H. pylori-negative patients. We did not find CAT activity in some antral tissue specimens. The significantly high levels of ADA activity in patients with H. pyloriinfection may reflect the regulator role of ADA in acid secretion. The higher ADA level with increased H. pyloridensity and H. pyloripositivity indicate the probable malign lymphoid process of the stomach. But these findings must be confirmed with larger studies that include different gastric lesions.