epidermal-growth-factor and Helicobacter-Infections

Growth factors and their receptors play important roles in cell proliferation, migration, tissue injury repair and ulcer healing. In gastric mucosa, transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) by activating their common receptor, control cell proliferation. TGF-alpha predominantly plays this role under normal conditions and after acute injury, while EGF exerts its actions mainly during healing of chronic ulcers. During regeneration of injured gastric mucosa, these growth factors serve predominantly to restore the epithelial component. Other growth factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) serve to promote restoration of the connective tissue and microvessels (angiogenesis) in injured mucosa. During healing of chronic ulcers, a new epithelial lineage secreting EGF and other growth peptides develops and the majority of cells lining the ulcer margin overexpress the EGF receptor. Activation of the EGF receptor induces dramatic increases in MAP (Erk -1 and -2) kinase activity and phosphorylation levels. Inhibition of this signaling pathway dramatically delays ulcer healing. Granulation connective tissue, which grows under the stimulation of bFGF and VEGF is the major source for regeneration of connective tissue lamina propria and microvessels within the ulcer scar. Other growth factors such as insulin - like growth factor, keratinocyte growth factor, hepatocyte growth factor and trefoil peptides have been implicated in gastrointestinal (gastric ulcers, colitis) regeneration following injury. This paper is intended to provide an overview of the role of growth factors in gastrointestinal mucosal regeneration.

Topics: Animals; Cell Division; Colitis; Epidermal Growth Factor; Gastric Mucosa; Growth Substances; Helicobacter Infections; Helicobacter pylori; Humans; Intestinal Mucosa; Neovascularization, Physiologic; Regeneration; Signal Transduction; Stomach Ulcer; Transforming Growth Factor alpha; Wound Healing

Growth factors and their receptors are known to play important roles in normal cell proliferation, morphogenesis, tissue repair, and ulcer healing. Epidermal growth factor (EGF) inhibits acid secretion, exerts a trophic effect on gastroduodenal mucosa, protects gastric mucosa against injury, mediates mucosal adaptation, and accelerates gastroduodenal ulcer healing by stimulating cell migration and proliferation. EGF exerts its actions by binding to its receptor, EGF-R, a transmembrane protein tyrosine kinase, which triggers receptor dimerization, autophosphorylation, and recruitment of kinase substrates. These events result in Ras (GTP-binding protein) activation of the Ras/Raf/MAP kinase pathway, leading to phosphorylation of regulatory proteins and transcription factors and culminating in cell proliferation. Other pathways potentially activated by EGF include the phosphatidylinositol pathway and the JAK/STAT signaling pathway. Recent studies demonstrated that EGF-R-associated tyrosine kinase plays an essential role in regulating gastric mucosal cell proliferation after acute injury and further demonstrated activation of the EGF-R gene, EGF-R phosphorylation, and increased MAP kinase activity during early stages of experimental gastric ulcer healing. Finally, experimental data indicate that Helicobacter pylori vacuolating cytotoxin inhibits healing of experimental gastric ulcers, cell proliferation, binding of EGF to its receptor, EGF-induced EGF-R phosphorylation, and MAP kinase (ERK-2) activation. These H. pylori actions can explain its interference with the ulcer healing process.

Topics: Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Signal Transduction; Stomach Ulcer; Wound Healing

A huge variety of peptides and cytokines are involved in the maintenance of mucosal integrity and in the inflammatory response at sites of ulceration. Most studies have focused on the effects of an individual factor in this complex process. However, it is becoming increasingly apparent that, to fully understand their importance in vivo, we should consider their function as part of a highly integrated system. It is also becoming clear that a relatively small number of common pathways are brought into play by the host in response to a wide variety of intestinal insults.

Topics: Cytokines; Epidermal Growth Factor; Helicobacter Infections; Helicobacter pylori; Humans; Peptic Ulcer; Transforming Growth Factors; Trypsin Inhibitor, Kazal Pancreatic

Topics: Animals; Epidermal Growth Factor; Gastric Mucosa; Granulocytes; Helicobacter Infections; Helicobacter pylori; Humans; Peptic Ulcer; Prostaglandins

We designed this study to follow exocrine, endocrine and microstructural changes in duodenal ulcer patients with H. pylori infection in the course and after quadruple eradication regimen. Quadruple therapy appeared to be highly effective method of both ulcer healing and H. pylori eradication. We observed enhanced regeneration of gastric mucosa in the course of treatment. Almost immediate decrease of plasma gastrin and increase of plasma somatostatin and EGF concentration in gastric juice were noticed.

Topics: Amoxicillin; Anti-Ulcer Agents; Bismuth; Duodenal Ulcer; Epidermal Growth Factor; Gastric Juice; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Metronidazole; Omeprazole; Somatostatin

Microstructural, endo- and exocrine changes in gastric mucosa of Non-Ulcer Dyspepsia patients with H. pylori infection in the course of eradication has been studied. Before, during and after anti H. pylori therapy plasma gastrin and somatostatin levels, EGF and somatostatin concentration in gastric juice and basal and pentagastrin stimulated gastric acid secretion were measured. Moreover microstructure of gastric mucosa specimens has been studied. Maximal Acid Output initially higher in NUD patients than in healthy volunteers increased slightly in the course of eradication. Plasma gastrin decreased while EGF and somatostatin concentration in gastric juice increased. After treatment the ratio of patients with pronounced features (activity) of gastritis was significantly reduced.

Topics: Amoxicillin; Bismuth; Dyspepsia; Epidermal Growth Factor; Gastric Juice; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Metronidazole; Omeprazole; Somatostatin; Stomach Ulcer

To investigate the effect of Anwei Qingyou formula on the clinical treatment of patients with peptic ulcer (PU) and its effect on the levels of epidermal growth factor (EGF) and prostaglandin E2 (PGE2).. Medical records of 83 patients with PU, treated in our hospital from January 2020 to January 2021, were retrospectively analyzed. Among them, 40 patients received conventional triple therapy (scheme I), that is, oral omeprazole, clarithromycin and amoxicillin, twice a day, and 43 patients received conventional triple therapy + Anwei Qingyou formula, taken orally twice a day (scheme II). The improvement of clinical symptoms, the quality of ulcer healing, clinical effectiveness and recurrence rate were analyzed after 4 weeks of treatment. Patients were followed up for six months.. After treatment with corresponding regimen, the total clinical effective rate of scheme II was 97.57% (42/43), which was significantly higher than 82.50% (33/40) of scheme I. Six-month follow-up results showed that the recurrence rate in scheme II patients was 4.65% (2/43), which was significantly lower than 20.00% (8/40) in the scheme I group (χ 2 = 5.479, 4.607, all P < .05). After one course of treatment, the levels of serum EGF and PGE2 in scheme II group were higher than those in scheme I group (P < .05).. In combination with the conventional western medicine treatment, Anwei Qingyou formula administration in PU patients effectively improves the overall control of the disease and therapeutic effectiveness.

Topics: Amoxicillin; Anti-Bacterial Agents; Anti-Ulcer Agents; Clarithromycin; Dinoprostone; Drug Therapy, Combination; Epidermal Growth Factor; Helicobacter Infections; Helicobacter pylori; Humans; Omeprazole; Peptic Ulcer; Retrospective Studies

 To explore the predictive value of serum gastrin (GAS), epidermal growth factor (EGF) levels in gastric ulcer complicated with acute upper gastrointestinal bleeding.. A descriptive study.. Department of Emergency, Beijing Jiangong Hospital, China, from January 2019 to June 2020.. One hundred and twenty-five patients with gastric ulcer and acute upper gastrointestinal bleeding were selected as Group A. One hundred and twenty-five patients with gastric ulcer and no upper gastrointestinal bleeding were selected as Group B. Logistic regression analysis was used to analyse the risk factors of gastric ulcer complicated with acute upper gastrointestinal bleeding. The value of serum GAS, EGF in early diagnosis of gastric ulcer with upper gastrointestinal bleeding was evaluated by receiver operating characteristic (ROC) curve.. Univariate analysis showed statistically significant differences between Group A and Group B in taking non-steroidal anti-inflammatory drugs (NSAIDs), helicobacter pylori (Hp) infection, serum GAS and EGF (all p <0.001). Logistic regression analysis showed that raised serum GAS and serum EGF were independent risk factors for gastric ulcer and upper gastrointestinal bleeding (both p <0.001). The ROC area of serum EGF to predict gastric ulcer and acute upper gastrointestinal bleeding was 0.810 (95% CI: 0.753-0.867, p <0.001), greater than ROC area of serum GAS. At serum EGF of ≤109.95 pg/mL, had the 84.8%, sensitivity to predict gastric ulcer and acute upper gastrointestinal bleeding with specificity of 68.8%.. The predictive value of serum GAS and EGF is high for gastric ulcer complicated with acute upper gastrointestinal bleeding; the predictive value of serum EGF is greater than that of serum GAS. Key Words: Gastric ulcer, Acute upper gastrointestinal bleeding, Serum, Gastrin (GAS), Epidermal growth factor (EGF), Logistic regression, Receiver operating characteristic (ROC) curve.

Topics: Anti-Inflammatory Agents, Non-Steroidal; China; Epidermal Growth Factor; Gastrins; Gastrointestinal Hemorrhage; Helicobacter Infections; Helicobacter pylori; Humans; Risk Factors; Stomach Ulcer

Topics: Adolescent; Agammaglobulinemia; alpha 1-Antitrypsin; Anemia; Biomarkers; Epidermal Growth Factor; Feces; Gastritis; Gastritis, Hypertrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Protein-Losing Enteropathies; Tomography, Emission-Computed, Single-Photon

To investigate levels of epidermal growth factor (EGF) and prostaglandin E2 (PGE2) in Han Chinese patients with Helicobacter pylori-positive gastric low-grade intraepithelial neoplasia (LGIN).. In this prospective, observational study, gastric specimens from patients with LGIN were collected by gastroscopy with consecutive biopsy. EGF and PGE2 concentrations in serum and gastric juice from patients with LGIN were measured by enzyme-linked immunosorbent assay. Presence of H. pylori infection was assessed in patients with LGIN and healthy controls.. Out of 5 638 patients and 548 controls, H. pylori infection in patients with chronic gastritis was associated with disease type (endoscopic classification) and disease severity. Patients with H. pylori-positive LGIN had significantly higher concentrations of serum EGF and lower concentrations of serum PGE2 versus patients with H. pylori-negative LGIN. Serum EGF and PGE2 levels in patients with LGIN were not significantly associated with disease type, but were significantly associated with disease severity.. H. pylori infection was associated with chronic gastritis type (endoscopic classification) and disease severity. Abnormal EGF and PGE2 levels may be associated with H. pylori-positive LGIN in Han Chinese patients in central China.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma in Situ; Case-Control Studies; China; Dinoprostone; Epidermal Growth Factor; Female; Gastric Juice; Gastric Mucosa; Gastritis; Gastroscopy; Gene Expression; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Neoplasm Grading; Prospective Studies; Stomach Neoplasms

Helicobacter heilmannii is a zoonotic bacterium that has been associated with gastric disease in humans. In this study, the mRNA expression of mucins in the stomach of BALB/c mice was analyzed at several time points during a 1-year infection with this bacterium, during which gastric disease progressed in severity. Markers for acid production by parietal cells and mucous metaplasia were also examined. In the first 9 weeks postinfection, the mRNA expression of Muc6 was clearly upregulated in both the antrum and fundus of the stomach of H. heilmannii-infected mice. Interestingly, Muc13 was upregulated already at 1 day postinfection in the fundus of the stomach. Its expression level remained high in the stomach over the course of the infection. This mucin is, however, not expressed in a healthy stomach, and high expression of this mucin has so far only been described in gastric cancer. In the later stages of infection, mRNA expression of H(+)/K(+)-ATPase α/β and KCNQ1 decreased, whereas the expression of Muc4, Tff2, Dmbt1, and polymeric immunoglobulin receptor (pIgR) increased starting at 16 weeks postinfection onwards, suggesting the existence of spasmolytic polypeptide-expressing metaplasia in the fundus of the stomach. Mucous metaplasia present in the mucosa surrounding low-grade mucosa-associated lymphoid tissue (MALT) lymphoma-like lesions was also histologically confirmed. Our findings indicate that H. heilmannii infection causes severe gastric pathologies and alterations in the expression pattern of gastric mucins, such as Muc6 and Muc13, as well as disrupting gastric homeostasis by inducing the loss of parietal cells, resulting in the development of mucous metaplasia.

Topics: Animals; Antigens, Surface; Disease Models, Animal; Epidermal Growth Factor; Female; Gastric Mucosa; Gene Expression Profiling; Helicobacter heilmannii; Helicobacter Infections; Intercellular Signaling Peptides and Proteins; Metaplasia; Mice; Mice, Inbred BALB C; Peptides; Trefoil Factor-2

Increased expression of epidermal growth factor (EGF), its receptor (EGFR), and c-erb-B2 protein, which is homological with the EGF receptor, in gastric mucosa, may play a role in gastric carcinogenesis. We assessed if the infection and eradication of Helicobacter pylori (H. pylori) affects the gastric expression of growth factors and serum gastrin concentrations.. We examined immunohistochemically gastric EGF and both receptors' expression in: gastric cancer (GC; n=29), chronic gastritis with H. pylori infection (GHp+; n=40) before and after eradication and in patients without H. pylori infection (GHp-; n=42).. Before the eradication therapy, gastric mucosal EGF and both receptor's expressions in GHp+ patients were increased compared to GHp- (p<0.05), but were similar to GC. After eradication, EGF and the receptor's expression significantly decreased in the gastric body. Both EGFR and c-erb-B2 expression in the antrum were still higher than in GHp- (p<0.05), and remained comparable to GC.. In patients with H. pylori infection the gastric mucosal EGF, EGFR, and c-erb-B2 expressions are similar to those observed in gastric cancer. The persistence of the antral expression of receptors after eradication, at a level comparable to the gastric cancer group, suggests their eventual role in the progression of changes initiated by H. pylori toward carcinogenesis.

Topics: Aged; Anti-Bacterial Agents; Drug Therapy, Combination; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Gastritis; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Host-Pathogen Interactions; Humans; Male; Middle Aged; Receptor, ErbB-2; Stomach Neoplasms

Gastric secretion can provide valuable information especially when Helicobacter pylori (Hp) infection results in chronic atrophic gastritis (CAG) and intestinal metaplasia (IM) preceding adenocarcinoma (AdCa).. Looking for a potential biomarker of malignant transformation in the setting of chronic inflammation we studied the levels of prostaglandin E2 (PGE(2)), as well as peptide growth factors [epidermal growth factor (EGF) and transforming growth factor α (TGFα)], harbingers of injury and repair, in gastric juice aspirated at endoscopy from patients with CAG, CAG/IM, AdCa, and controls.. The PGE(2), EGF and TGFα concentrations in the gastric juice were measured using radioimmunoassays (RIAs).. In patients with AdCa gastric juice PGE(2) increased fivefold versus controls (P < 0.01) and almost threefold versus patients with CAG (P < 0.05). The EGF levels in patients with AdCa were fourfold higher versus controls (P < 0.001) and almost threefold higher versus CAG (P < 0.05). In patients with CAG/IM the EGF levels were also almost 3 times higher versus controls. The TGFα levels in patients with AdCa were half the value of controls and CAG (P < 0.05). In patients with CAG/IM the levels were as low as 1/5 of controls or CAG (P < 0.05).. Testing the gastric juice for PGE(2), EGF, and TGFα in patients with endoscopy and biopsy proven CAG, may be helpful in follow up of patients who may potentially progress to IM and ultimately AdCa. This could be considered as an adjunct to histologic assessment especially that even the best surveillance biopsy specimen regimens are inherited with sampling errors.

Topics: Adenocarcinoma; Adult; Aged; Biomarkers, Tumor; Digestive System Neoplasms; Dinoprostone; Epidermal Growth Factor; Female; Gastric Juice; Gastritis, Atrophic; Helicobacter Infections; Humans; Intestines; Male; Metaplasia; Middle Aged; Pilot Projects; Transforming Growth Factor alpha

To assess whether there is a correlation between the severity of gastritis and concentration of chosen growth factors in the serum of children infected with H. pylori.. The study included 64 children of whom 50% (Group I) were infected with H. pylori and had gastritis; 18.7% (Group II) of the examined children had a positive titre of IgG against H. pylori and normal gastric mucosa. Controls (Group III) comprised 31.3%. The gastric mucosa was evaluated histopathologically according to the Sydney System. The serum concentrations of growth factors: EGF, TGF-alpha, VEGF, were determined using ELISA.. Mean concentrations of the growth factors were also the highest in Group I compared to Group II and Group III (EGF - 137.3+/-10.4 pg/mL, TGF-alpha - 0.4+/-1.2 pg/mL, VEGF - 146.8 pg/mL). Analysis of correlations between growth factors and the severity of gastritis as well as the activity of antral gastric mucosa inflammation proved that mean EGF concentration in H. pylori infected children was the highest (149.5+/-84.8 pg/mL) in severe gastritis, whereas mean concentrations of TGF-alpha (2.0+/-4.3 pg/mL) and of VEGF (148.1+/-92.6 pg/mL) were the highest in moderate gastritis. Mean concentrations of EGF (155.1+/-116.4 pg/mL) and of VEGF (156.0+/-118.9 pg/mL) were the highest in high activity antral gastritis, whereas the mean concentration of TGF-alpha was the highest (2.0+/-4.2 pg/ml) in moderate activity gastritis.. In the children with H. pylori infection, serum concentrations of EGF, TGF-alpha, VEGF were the highest in moderate and severe antral gastritis.

Topics: Adolescent; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Gastric Mucosa; Gastritis; Helicobacter Infections; Humans; Infant; Intercellular Signaling Peptides and Proteins; Transforming Growth Factor alpha; Vascular Endothelial Growth Factor A

The family of epidermal growth factor (EGF, EGFR, c-erbB-2) plays a pivotal role in gastric cancer progression, invasion and metastasizing. Helicobacter pylori infection is known to contribute significantly to the formation and progression of gastric cancer. However, the mechanisms responsible for this process have not been yet elucidated. We analysed the relationship between H. pylori infection and expression of proteins belonging to the family of epidermal growth factor (EGF, EGFR, c-erbB-2). Fifty-five patients with gastric cancer were analysed for Helicobacter pylori infection. The expressions of EGF, EGFR, c-erbB-2 proteins were determined using an immunohistochemical method. No statistically significant correlation was found between the degree of H. pylori infection and the expressions of EGF, EGFR and c-erbB-2 in gastric cancer. However, c-erbB-2 expression in the main mass of tumour correlated with tumour expression of EGF and EGFR and with c-erbB-2 expression in local lymph nodes. The expression of c-erbB-2 in lymph nodes was statistically significantly related to the expressions of EGF and EGFR both in the main mass of tumour and in lymph nodes. The expression of EGF was found to correlate with EGFR in the main mass of tumour and the expression of EGF in lymph nodes was related to lymph node EGFR level. Our study did not confirm the relationship between H. pylori infection and the expression of epidermal growth factor in gastric cancer.

Topics: Carcinoma; Disease Progression; Epidermal Growth Factor; ErbB Receptors; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Receptor, ErbB-2; Stomach Neoplasms

Erosive esophagitis frequently develops after successful Helicobacter pylori eradication. Since salivary secretion of epidermal growth factor (EGF) plays a crucial role in the pathogenesis of gastroesophageal reflux disease, the current study objective was to find out whether erosive esophagitis development after Helicobacter pylori eradication is associated with the secretion of EGF in saliva.. A total of 115 H. pylori infected patients (positive results of CLO-test, histology and serology) with a duodenal ulcer were recruited for the study. Gastroscopic examinations and saliva collections were performed twice, prior to H. pylori eradication and one year after its cessation. The salivary EGF was determined using a radioimmunological method.. Salivary EGF secretion was lower in H. pylori infected subjects with erosive esophagitis than without (0.82+/-0.66 vs 1.70+/-3.49 ng/min, p=0.021). However, a year after successful H. pylori eradication, salivary EGF did not differ between the groups (2.17+/-2.06 vs 1.79+/-2.06 ng/min); the lack of difference was due to high peptide secretion in patients who developed erosive esophagitis after eradication.. Erosive esophagitis development following H. pylori eradication is not the result of decreased salivary EGF secretion.

Topics: Adolescent; Adult; Aged; Duodenal Ulcer; Epidermal Growth Factor; Esophagitis; Female; Follow-Up Studies; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Saliva; Young Adult

Both gastrin and Helicobacter pylori have been shown capable of up-regulating gene expression and protein shedding of heparin-binding epidermal growth factor (HB-EGF). Furthermore, the bacteria have previously been shown to induce serum hypergastrinemia in infected individuals. The aim of this work was to assess the extent to which the ability of H. pylori to up-regulate expression of HB-EGF can be attributed to its effect on gastrin. Gastric cells, transfected with either gastrin small interfering RNA or antisense plasmid or the gastrin/cholecystokinin-2 receptor (CCK-2R), were cultured for 24 hours with H. pylori(+/-), a CCK-2R antagonist. Gene expression levels were measured using reverse transcription-PCR, whereas protein changes were measured using ELISA, Western blotting, and immunofluorescence. H. pylori induced significantly higher levels of HB-EGF gene expression and ectodomain shedding in the CCK-2R-transfected cells than the vector control (P < 0.01). Addition of the CCK-2R inhibitor significantly decreased gene and shedding up-regulation. Gastrin down-regulation reduced the effect of the bacteria on HB-EGF gene and protein expression levels. Endogenous gastrin and CCK-2R expression were also found to be significantly up-regulated in all cell lines as a result of exposure to H. pylori (P < 0.02). Gastric mucosal tissue from H. pylori-infected individuals had significantly higher CCK-2R expression levels than noninfected (P < 0.003), and in hypergastrinemic mice, there was an increase in HB-EGF-expressing cells in the gastric mucosa and colocalization of HB-EGF with CCK-2R-positive enterochromaffin-like cells. In conclusion, gastrin and the CCK-2R play significant roles in the induction of HB-EGF gene and protein expression and ectodomain shedding by H. pylori.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Disease Models, Animal; DNA, Antisense; Enterochromaffin Cells; Epidermal Growth Factor; Gastrins; Helicobacter Infections; Helicobacter pylori; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Mice; Plasmids; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Stomach Neoplasms; Transfection; Up-Regulation

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.. 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.. 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.. 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.

Topics: Adult; Aged; Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; Case-Control Studies; Cyclooxygenase 2; Cytokines; Epidermal Growth Factor; Female; Gastric Acid; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Ornithine Decarboxylase; RNA, Messenger; Transforming Growth Factor alpha

Activation of the coagulation system is a critical response for both the repair of tissue injury and the host defense against microbial pathogens. Activation of the coagulation cascade culminates with the generation of thrombin. In vitro studies have shown that thrombin protects gastric epithelial cells from injury. The present study was undertaken to assess in vivo the relationship between gastric intramucosal generation of thrombin and Helicobacter pylori infection.. This study comprised 59 patients with gastroduodenal disorders. There were 27 patients with H. pylori infection (Hp+), 14 without it (Hp-), and 18 patients with cured H. pylori infection (Hp c). The gastric intramucosal concentrations of thrombin-antithrombin complex (TAT), epidermal growth factor (EGF), prostaglandin E2 (PGE2), and vacuolating cytotoxin A (VacA) were measured by specific immunoassays.. The level of TAT was significantly increased in patients with Hp+ compared to Hp- and Hp c. The levels of TAT, EGF and PGE2 were higher in VacA (+) patients than in those with VacA (-). VacA induced significant expression of tissue factor in gastric epithelial cells in vitro. The gastric intramucosal level of VacA antigen was proportionally and significantly correlated with TAT, EGF and PGE2 in Hp+ patients. The level of TAT was proportionally and significantly correlated with EGF in Hp+ patients but not in Hp- and HP c patients.. These results showed that VacA produced by H. pylori is associated with increased thrombin generation, and that thrombin may play a protective role in H. pylori-associated gastroduodenal disorders.

Topics: Adult; Aged; Antithrombin III; Bacterial Proteins; Cell Line; Dinoprostone; Epidermal Growth Factor; Female; Gastric Mucosa; Gastrointestinal Diseases; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Peptide Hydrolases; Thrombin; Up-Regulation

Helicobacter pylori (H. pylori) infection is the cause of peptic ulcer diseases, and gastric cancer. Hydrolysis of urea generating ammonia may cause cytotoxic effects on the gastric epithelium. The ammonia may induce the synthesis of epidermal growth factor (EGF) in gastric epithelium as an adaptive cytoprotective mechanism. The first aim was to examine the concentration of ammonia and EGF in gastric juice before and after H. pylori eradication in functional dyspepsia patients. The second aim was to examine the correlation among ammonia concentration, EGF concentration, and inflammatory score of gastritis.. The concentration of ammonia and EGF were measured by ELISA. The grade and severity of gastritis were measured according to the updated Sydney system.. The concentration of ammonia in gastric juice was much higher in the H. pylori positive subjects (10,787 +/- 6,584 micro mol/L) than in the negative subjects (2,339 +/- 1,158 micro mol/L, p<0.0001). The concentrations of EGF in gastric juice was much higher in the positive subjects (1,462 +/- 393 pg/mL) than in the negative subjects (1,088 +/- 499 pg/mL, p<0.005). The concentration of ammonia and EGF in gastric juice showed significant correlation (r=0.63, p<0.0001). The concentrations of ammonia and histologic severities showed significant correlation (r=0.41, p<0.0001). Moreover, the level of EGF in gastric juice and histologic severities showed positive correlation (r=0.20, p<0.005).. As the concentration of ammonia in gastric juices increased, the concentration of EGF was also increased in functional dyspepsia with H. pylori infection. The concentration of EGF in gastric juice may play a role in the adaptive cytoprotection in H. pylori- induced gastritis.

Topics: Adult; Ammonia; Epidermal Growth Factor; Female; Gastric Juice; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged

Saliva plays a role in mucosal protection and ulcer healing.. : To study whether decreased salivary production leads to peptic ulcer disease in connective tissue disease patients associated with xerostomia.. Two hundred and two connective tissue disease patients (90 with xerostomia and 112 without xerostomia) were enrolled. Their demographic data and use of medications were recorded. Peptic ulcer disease was confirmed by endoscopy. The stimulated salivary output and secretory epidermal growth factor level were measured.. Compared with non-xerostomic counterparts, xerostomic patients manifested a higher occurrence of peptic ulcer disease (31% vs. 12%, P = 0.001), lower stimulated salivary output (9.3 +/- 4.1 vs. 22.9 +/- 5.9 mL/15 min, P < 0.001) and lower stimulated salivary epidermal growth factor output (1.40 +/- 0.77 vs. 3.00 +/- 0.96 ng/min, P < 0.001). Multivariate analysis disclosed that an older age (> or = 60 years) (odds ratio, 4.71; P < 0.001), xerostomia with stimulated salivary output of < or =1 mL/min (odds ratio, 7.54; P = 0.014) and the use of non-steroidal anti-inflammatory drugs (odds ratio, 5.76; P = 0.031) were the risk factors leading to peptic ulcer disease. In addition, xerostomic connective tissue disease patients receiving non-steroidal anti-inflammatory drugs manifested an extremely high risk of development of peptic ulcer disease (odds ratio, 19.78; P < 0.001).. Ageing, the use of non-steroidal anti-inflammatory drugs and poor salivary function are potential risk factors for the development of peptic ulcer disease in patients with connective tissue disease. If these xerostomic subjects consume non-steroidal anti-inflammatory drugs, they will encounter an extremely high peptic ulcer disease risk.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Connective Tissue Diseases; Dyspepsia; Epidermal Growth Factor; Female; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Peptic Ulcer; Regression Analysis; Risk Factors; Xerostomia

Helicobacter pylori (Hp) infection causes duodenal ulcers, delays the healing of such ulcers, and is associated with ulcer recurrence. The pathogenic mechanisms involved in Hp-induced duodenal mucosal injury and delay in ulcer healing remain unclear. In this study we sought to investigate the possible pathogenic actions of Hp infection and vacuolating cytotoxin (Vac A) on duodenal epithelial wound healing, using an in vitro wound model consisting of excisionally scraped or eroded IEC-6 duodenal monolayers. Two isogenic strains of Hp were used: wild-type strain 60190, producing Vac A; and an isogenic mutant strain, 60190-v1, that lacks the gene to produce the cytotoxin. The addition of Vac A-positive or Vac A-negative Hp (50:1 ratio of bacterial to epithelial cells) to the eroded or "wounded" IEC-6 monolayers resulted in significant inhibition of wound reepithelialization. The Vac A-positive Hp produced significantly greater inhibition than did the Vac A-negative Hp (70% and 35% inhibition, respectively; P <.001). Additionally, the bacterial supernatant containing Vac A (but not the supernatant lacking the cytotoxin) caused significant inhibition of IEC-6 wound reepithelialization in the absence of Hp infection, indicating that Vac A has an independent inhibitory action on wound reepithelialization. The Vac A inhibition of IEC-6 reepithelialization correlated with down-regulation of actin stress fibers in the migrating cells. Epidermal growth factor (EGF) stimulated IEC-6 wound reepithelialization with a corresponding increase in the formation of actin stress fiber. Vac A-positive bacterial supernatant (but not Vac A-negative supernatant) prevented the EGF-stimulated increase in IEC-6 actin stress fiber formation and wound reepithelialization. These findings demonstrate that Hp infection inhibits the process of duodenal epithelial wound healing. Hp inhibition of duodenal wound healing may therefore be an important pathogenic factor contributing to duodenal mucosal injury and delay in ulcer healing in vivo.

Topics: Actins; Animals; Bacterial Proteins; Cell Division; Cell Line; Down-Regulation; Duodenal Ulcer; Epidermal Growth Factor; Helicobacter Infections; Helicobacter pylori; Intestinal Mucosa; Rats; Wound Healing

Epidermal growth factor (EGF) receptor ligands (EGFRL) including transforming growth factor alpha (TGF-alpha), amphiregulin, and heparin binding-EGF (HB-EGF) are involved in gastric mucosal repair in chronic gastritis. Their mRNA expression has been shown to be upregulated after Helicobacter pylori (H.p.)-eradication but little is known about this gene expression in atrophic gastritis. The purpose of our study was to investigate EGFRL mRNA expression in gastric mucosa of patients with atrophic gastritis before and after H.p.-eradication.. Antral mucosal biopsies were obtained during endoscopy in 10 H.p. positive patients with atrophic gastritis and in 10 H.p. negative controls with intact mucosa. Total RNA of antral biopsies was extracted and RT-PCR was performed, the PCR-products being measured densitometrically. Values were compared with mRNA expressions in H.p. negative antral mucosa (n=10).. Gastric biopsies revealed mRNA expression for TGF-alpha, amphiregulin and HB-EGF, both in H.p. positive atrophic antritis and in H.p. negative healthy mucosa. The mRNA expression of TGF-alpha in atrophic gastritis was significantly upregulated after H.p.-eradication, whereas that of amphiregulin did not change after this eradication. Expression of HB-EGF mRNA was higher in H.p.-infection than after H.p.-eradication or in H.p. negative healthy subjects.. H.p. positive atrophic gastritis is associated with differential mRNA expression of EGF receptor ligands. H.p.-eradication in this entity leads to unequal changes of these growth factor expressions compared to chronic active gastritis without atrophy.

Topics: Amphiregulin; Base Sequence; DNA Primers; EGF Family of Proteins; Epidermal Growth Factor; ErbB Receptors; Gastritis, Atrophic; Glycoproteins; Growth Substances; Helicobacter Infections; Helicobacter pylori; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor alpha

Epidermal growth factor (EGF) and TGF-alpha play a central role in maintaining gastric mucosal integrity. Little is known about the regulative role of the four other widely expressed epidermal growth factor receptor ligands, heparin-binding EGF, amphiregulin, betacellulin and cripto in the gastric mucosa.. Nineteen patients with Helicobacter pylori-positive gastritis and 32 healthy controls were investigated. Mucosal mRNA expression of EGF receptor ligands was determined by quantitative PCR before and after H. pylori eradication. PCR products were analyzed by soft laser scanning densitometry. Moreover, the effect of chronic active gastritis on EGF receptor expression was assessed by [125I] EGF receptor autoradiography. Immunohistochemistry was performed for TGF-alpha to localize growth factor expression.. Antral and oxyntic biopsies showed strong mRNA expressions for TGF-alpha, amphiregulin and heparin binding EGF, but not for EGF, cripto and betacellulin. mRNA expression was significantly reduced down to 50% in H. pylori infection, significantly lower compared to normal gastric mucosa, and increased after eradication therapy. Moreover, chronic gastritis was associated with decreased antral EGF receptor binding compared to healthy controls, possibly reflecting reduced autoinduction. Immunohistochemical analyses localized TGF-alpha in the cytoplasma of gastric epithelial cells and revealed its increased expression after H. pylori eradication.. The data presented suggest that amphiregulin, heparin binding EGF and TGF-alpha are important EGF receptor ligands in the gastric mucosa. H. pylori infection apparently suppresses their mRNA as well as receptor expression that is reversed by H. pylori eradication. This deficiency of the gastroprotective EGF system may contribute to the gastric pathogenicity of H. pylori infection.

Topics: Adult; Amphiregulin; Betacellulin; EGF Family of Proteins; Epidermal Growth Factor; ErbB Receptors; Female; Gastric Mucosa; Gastritis; Glycoproteins; GPI-Linked Proteins; Growth Substances; Helicobacter Infections; Helicobacter pylori; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Male; Membrane Glycoproteins; Neoplasm Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor alpha

Helicobacteria pylori infection of gastroduodenal mucosa is strongly associated with gastritis and peptic ulcer disease. The aims of the present study were to compare the gastroduodenal mucosal levels of epidermal growth factor (EGF) and its receptor (EGFR) among H. pylori-negative controls and H. pylori infected patients with chronic active gastritis or gastroduodenal ulcer before and after H. pylori eradication.. The protein levels of EGF in mucosal tissues and saliva were determined by a solid-phase enzyme-linked immunosorbent assay (ELISA). Repeat transcription-polymerase chain reaction and the following polymerase chain reaction ELISA were employed to examine the mucosal EGFR mRNA expression.. Mucosal injury and H. pylori infection increased EGF protein levels and EGFR mRNA expression in the antral mucosa. The concentration of EGF in saliva was not affected by mucosal damage or H. pylori infection. Successful H. pylori eradication normalized the EGFR mRNA back to its basal level 6 weeks after treatment. However, after unsuccessful eradication their high levels in the antrum persisted. All patients experienced ulcer healing after drug treatment, regardless of H. pylori eradication.. Mucosal damage increased the expression of EGF protein and EGFR mRNA in the gastric mucosa. H. pylori could induce the expression of EGFR but not the EGF in the antral mucosa. The expression of EGFR could be a contributing factor for ulcer healing in patients with H. pylori infection.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Chronic Disease; Duodenal Ulcer; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; ErbB Receptors; Female; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Polymerase Chain Reaction

Hypergastrinemia occurs frequently in association with acid suppression and Helicobacter infection, but its role in the progression to gastric atrophy and gastric cancer has not been well defined.. The effects of hypergastrinemia, and possible synergy with Helicobacter felis infection, were investigated in insulin-gastrin (INS-GAS) transgenic mice.. INS-GAS mice initially showed mild hypergastrinemia, increased maximal gastric acid secretion, and increased parietal cell number but later progressed to decreased parietal cell number and hypochlorhydria. Development of gastric atrophy was associated with increased expression of growth factors, heparin-binding epidermal growth factor and transforming growth factor alpha. At 20 months of age, INS-GAS mice showed no evidence of increased enterochromaffin-like cell number, but instead exhibited gastric metaplasia, dysplasia, carcinoma in situ, and gastric cancer with vascular invasion. Invasive gastric carcinoma was observed in 6 of 8 INS-GAS mice that were >20 months old. Helicobacter felis infection of INS-GAS mice led to accelerated (< or = 8 mo) development of intramucosal carcinoma (85%), with submucosal invasion (54%) and intravascular invasion (46%; P < or = 0.05).. These findings support the unexpected conclusion that chronic hypergastrinemia in mice can synergize with Helicobacter infection and contribute to eventual parietal cell loss and progression to gastric cancer.

Topics: Animals; Cell Count; Epidermal Growth Factor; Epithelial Cells; Gastric Acid; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Heparin; Heparin-binding EGF-like Growth Factor; Hyperplasia; Hypertrophy; Intercellular Signaling Peptides and Proteins; Metaplasia; Mice; Mice, Transgenic; Stomach Neoplasms; Transforming Growth Factor alpha

We studied the expression of cell cycle regulators and growth factor-receptor systems in gastric carcinoma in young adults and tried to clarify the specific alterations associated with H. pylori. We studied 33 young patients (18-29 years old, mean age 26.4) with gastric carcinoma. The patients were classified into two groups according to the degree of atrophic gastritis. Then we examined the expression of p53, cripto, cyclin-E, c-met, c-erbB2 and TGF-alpha immunohistochemically and compared the results between the two groups. The results were compared with 66 sex-, tumor histology-, and depth-matched elder controls (36-86 years old, mean age 64.0). H. pylori was judged by Giemsa staining. Seventeen patients had atrophic changes in the corpus (Group A), while 16 showed superficial gastritis or normal mucosa (Group S). All 17 patients of Group A showed H. pylori infection, while the 3 of the 16 members of Group S did not have H. pylori. p53 overexpression was observed more frequently in Group S (88%) than in Group A (41%, p<0.05). In the 3 patients without H. pylori infection, all carcinoma specimens showed p53 overexpression. Overexpression of cyclin-E was detected in 4 patients from Group S. On the other hand, cripto was observed more frequently in Group A than in Group S. No obvious differences were observed in c-erbB2, TGF-alpha and c-met expression. Overall, p53 overexpression was detected more frequently in younger than in older patients, whereas cripto expression was less detected. These results suggest that p53 and cyclin-E may act in an H. pylori-independent or -adjunctive manner for gastric carcinogenesis. Cripto expression might be correlated tightly with H. pylori infection.

Topics: Adolescent; Adult; Cell Cycle Proteins; Cyclin E; Epidermal Growth Factor; Female; GPI-Linked Proteins; Growth Substances; Helicobacter Infections; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Male; Membrane Glycoproteins; Neoplasm Proteins; Proto-Oncogene Proteins c-met; Receptor, ErbB-2; Receptors, Growth Factor; Stomach Neoplasms; Transforming Growth Factor alpha; Tumor Suppressor Protein p53

Helicobacter pylori (H. pylori) infection has been linked to gastric cancer. The factors that promote carcinogenesis remain unknown. Epidermal growth factor (EGF) has been shown to be a potent epithelial mitogen and oncoprotein when sustained over expression occurs. Our aim was to compare gastric mucosal levels of EGF and its receptor (EGFR) among controls, H. pylori infected subjects, and subjects following H. pylori eradication using quantitative flow cytometric analysis.. Patients referred for evaluation of dyspepsia underwent EGD and six antral biopsies were performed (two each for rapid urease testing (RUT), histopathology, and flow cytometry). Controls were those found to be H. pylori negative while subjects had confirmed infection. The study patients were treated, then had repeat EGD with biopsies.. There were 17 controls and 28 cases. Mean EGF and EGFR values were 2.69 and 2.46 for controls and 4.67 and 4.64 for subjects. Subjects' mean EGF was 73% higher (p = .035) and EGFR was 88% higher (p = 0.029) than controls. After treatment, the subjects' mean values declined 55% (p = 0.0001) for EGF and 40% (p = 0.002) for EGFR. Three subjects had persistent infection and showed no change in their EGF/EGFR levels. No difference was found among factor levels with respect to endoscopic findings.. Both EGF and EGFR from gastric antral biopsies are increased nearly 2-fold in infection with H. pylori. Infection eradication reduces levels of both factors to those of controls. One major pathogenic mechanism for gastric mucosal hyperproliferation and possibly carcinogenesis related to H. pylori may be the over expression of EGF and increased receptor density of EGFR on gastric mucosal cells.

Topics: Adult; Antacids; Anti-Bacterial Agents; Anti-Ulcer Agents; Biopsy; Bismuth; Chronic Disease; Drug Therapy, Combination; Epidermal Growth Factor; ErbB Receptors; Female; Flow Cytometry; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Omeprazole; Organometallic Compounds; Prospective Studies; Salicylates

Epidermal growth (EGF) and transforming growth factor alpha (TGFalpha) are potent gastric secretory inhibitors, mitogens, and mucosal protectors, but the impact of Helicobacter pylori infection on their mucosal expression and luminal release has not been clarified.. In this study, gene and immunoreactive and immunohistochemical expressions of EGF and TGFalpha were assessed in the gastric mucosa of 15 H. pylori-negative healthy normals, in 22 H. pylori-positive duodenal ulcer patients (DU) and in 24 H. pylori-positive non-ulcer dyspepsia patients (NUD). All studies in DU and NUD patients were repeated after 2 weeks of triple therapy (amoxicillin + clarithromycin + omeprazole) and 4 weeks and 2 years later.. Immunohistochemical expression of EGF and TGFalpha in H. pylori-positive DU and NUD was significantly higher than in H. pylori-negative normals, and this increase persisted at 2 and 4 weeks after therapy but normalized 2 years later. EGF mRNA was detected in the gastric mucosa of H. pylori-positive DU before and at 2 and 4 weeks after H. pylori eradication, but it was not found 2 years after the eradication of H. pylori or in gastric mucosa of H. pylori-negative control subjects. TGFalpha mRNA was detected in the gastric mucosa independently of H. pylori status, with the stronger expression observed in the gastric mucosa of H. pylori-positive DU and NUD before eradication than after this procedure. Plasma gastrin, which was significantly increased in H. pylori-positive DU, normalized already after 2 weeks of triple therapy. The eradication rate as determined by histology after triple therapy reached 86.3% in DU patients and 90.5% in NUD patients. Two years after the eradication the H. pylori reinfection rate was 4.5% among DU patients and 4.2% among NUD. Treatment of DU patients with triple therapy resulted in complete ulcer healing.. 1) Chronic H. pylori infection and resulting antral gastritis are associated with increased plasma gastrin and increased mucosal cell proliferation, probably due to enhanced expression of EGF and TGFalpha, and 2) the H. pylori eradication results in a decrease in plasma gastrin, but the increase in gastric TGFalpha and EGF content is sustained, suggesting that they may be involved in ulcer healing.

Topics: Adult; Cell Division; Duodenal Ulcer; Dyspepsia; Epidermal Growth Factor; Female; Gastric Mucosa; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Male; Middle Aged; Polymerase Chain Reaction; Proliferating Cell Nuclear Antigen; Radioimmunoassay; Transforming Growth Factor alpha

Acute exposure to Helicobacter pylori causes cell damage and impairs the processes of cell migration and proliferation in cultured gastric mucosal cells in vitro. EGF-related growth factors play a major role in protecting gastric mucosa against injury, and are involved in the process of gastric mucosal healing. We therefore studied the acute effect of H. pylori on expression of EGF-related growth factors and the proliferative response to these factors in gastric mucosal cells (MKN 28) derived from gastric adenocarcinoma. Exposure of MKN 28 cells to H. pylori suspensions or broth culture filtrates upregulated mRNA expression of amphiregulin (AR) and heparin-binding EGF-like growth factor (HB-EGF), but not TGFalpha. This effect was specifically related to H. pylori since it was not observed with E. coli, and was independent of VacA, CagA, PicA, PicB, or ammonia. Moreover, H. pylori broth culture filtrates stimulated extracellular release of AR and HB-EGF protein by MKN 28 cells. AR and HB-EGF dose-dependently and significantly stimulated proliferation of MKN 28 cells in the absence of H. pylori filtrate, but had no effect in the presence of H. pylori broth culture filtrates. Inhibition of AR- or HB-EGF- induced stimulation of cell growth was not mediated by downregulation of the EGF receptor since EGF receptor protein levels, EGF binding affinity, number of specific binding sites for EGF, or HB-EGF- or AR-dependent tyrosine phosphorylation of the EGF receptor were not significantly altered by incubation with H. pylori broth culture filtrates. Increased expression of AR and HB-EGF were mediated by an H. pylori factor > 12 kD in size, whereas antiproliferative effects were mediated by both VacA and a factor < 12 kD in size. We conclude that H. pylori increases mucosal generation of EGF-related peptides, but in this acute experimental model, this event is not able to counteract the inhibitory effect of H. pylori on cell growth. The inhibitory effect of H. pylori on the reparative events mediated by EGF-related growth factors might play a role in the pathogenesis of H. pylori-induced gastroduodenal injury.

Topics: Adenocarcinoma; Amphiregulin; Cell Division; Cell Line; EGF Family of Proteins; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Gastritis; Glycoproteins; Growth Substances; Helicobacter Infections; Helicobacter pylori; Heparin; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Peptic Ulcer; Recombinant Proteins; RNA, Messenger; Stomach Neoplasms; Transforming Growth Factor alpha; Up-Regulation; Virulence

The relationship between the expression of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) and that of their receptor (EGF-R) in the Helicobacter pylori-infected gastric mucosa has not been completely elucidated. The aim of this study was to examine the interplay between H. pylori colonization and gastric mucosal growth factor content.. By means of a solid-phase enzyme-linked immunosorbent assay EGF, TGF-alpha, and EGF-R levels and interleukin-1beta (IL-1beta) content, which is considered a marker of chronic inflammation, were evaluated in the antral mucosa of 24 H. pylori-positive patients before and 8 weeks after eradication therapy.. After therapy H. pylori was eradicated in 19 patients. The eradication was accompanied by a significant decrease in IL-1beta content and an increase in EGF and TGF-alpha levels. On the other hand, in the five patients in whom the bacterium was not eradicated EGF, TGF-alpha, and EGF-R levels were quite similar to those assayed before therapy, whereas IL-1beta content was still high.. These results suggest that H. pylori exerts an inhibitory effect on the mucosal expression of EGF and TGF-alpha, which are likely involved in the gastric mucosa repair process.

Topics: Adult; Anti-Bacterial Agents; Anti-Ulcer Agents; Dyspepsia; Epidermal Growth Factor; ErbB Receptors; Female; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Interleukin-1; Male; Middle Aged; Transforming Growth Factor alpha

Helicobacter hepaticus is a new bacterial species that is homologous to Helicobacter pylori, a human gastric carcinogen. H. hepaticus causes chronic active hepatitis, with progression to hepatocellular tumors. We hypothesized that chronic up-regulation of epidermal growth factor (EGF), transforming growth factor-alpha, and nuclear oncogenes (cyclin D1 and c-Myc), all known to transform by overexpression, might contribute to tumorigenesis. Livers from mice that were 6-18 months old were analyzed, including nonneoplastic and preneoplastic tissues and tumors, along with age-matched controls, by immunohistochemistry and immunoblotting. EGF and transforming growth factor-alpha were increased at the earliest stage, with a further increase in EGF in tumors. Cyclin D1, cyclin-dependent kinase 4, and c-Myc were strongly increased in all infected livers, with even greater increases in tumors. An increase in cyclin D1/cyclin-dependent kinase 4 complex was also demonstrated in tumors, and its functionality was confirmed by an increase in the hyperphosphorylated:hypophosphorylated retinoblastoma protein ratio. Our findings suggest a possible cooperation of growth factors, cell cycle proteins, and transcription factors during the development of H. hepaticus-associated liver tumors and may have relevance to human cancers associated with bacterial, viral, or parasitic infections.

Topics: Animals; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Epidermal Growth Factor; Helicobacter Infections; Hepatitis, Animal; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred A; Neoplasm Proteins; Phosphorylation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-myc; Retinoblastoma Protein; Transforming Growth Factor alpha

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF alpha) are potent gastric acid inhibitors and stimuli of mucosal growth and protection but their involvement in Helicobacter pylori associated duodenal ulcer has been little examined.. To assess gastric acid secretion, plasma gastrin concentrations, mucosal content of EGF and TGF alpha, and mucosal expression of these peptides and their receptor (EGFr) as well as salivary and gastric luminal release of EGF under basal conditions and after pentagastrin stimulation in 10 healthy subjects and in 25 H pylori positive patients with duodenal ulcer before and after two weeks of triple anti-H pylori therapy and four weeks after the termination of this therapy.. Pentagastrin stimulation caused a significant increase in salivary and gastric release of EGF both in healthy controls and patients with duodenal ulcers but in the patients, the eradication of H pylori resulted in several fold higher gastric luminal (but not salivary) EGF release than before the anti-H pylori therapy. Mucosal contents of immunoreactive EGF and TGF alpha and mucosal expression of EGF, TGF alpha, and EGFr in H pylori positive patients with duodenal ulcer were significantly higher than those in healthy H pylori negative controls and this increase persisted after eradication of H pylori. Basal plasma gastrin was significantly reduced after two weeks of triple therapy and four weeks after the H pylori eradication all ulcers were completely healed.. (1) H pylori infection in patients with duodenal ulcer was accompanied by enhanced plasma gastrin and increased mucosal content and expression of TGF alpha, EGF, and EGFr; (2) H pylori eradication resulted in ulcer healing, reduction in plasma gastrin, and enhancement of gastric (but not salivary) luminal release of EGF, particularly after pentagastrin stimulation; and (3) enhanced mucosal content and expression of TGF alpha, EGF, and EGFr and increased luminal release of EGF may contribute to ulcer healing after eradication of H pylori.

Topics: Duodenal Ulcer; Epidermal Growth Factor; ErbB Receptors; Follow-Up Studies; Gastric Mucosa; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Pentagastrin; Saliva; Transforming Growth Factor alpha

Helicobacter pylori (H. pylori) infection of gastric mucosa is strongly associated with gastritis and peptic ulcer disease. However, the mechanisms of the ulcerogenic action of H. pylori and/or the interference of H. pylori with ulcer healing are unknown. Through binding to its receptor, epidermal growth factor (EGF) accelerates cells migration and triggers epithelial cell proliferation which are both important for the healing of gastroduodenal ulcers. H. pylori seems to interfere with ulcer healing, but the cellular and molecular targets and mechanisms of these actions have not been elucidated. In the present study, we tested the effect of H. pylori culture supernatant (dialyzed to remove molecules smaller than 10 kD) on EGF binding to its receptor and on the proliferative response of human gastric Kato III cells to EGF. H. pylori culture supernatant significantly reduced specific binding of EGF to its receptor and reduced EGF-stimulated gastric cell proliferation. Since ulcer healing requires epithelial cell proliferation and cell migration (re-epithelialization), which are both triggered by EGF binding to its receptor, the alteration in these mechanisms by H. pylori product may be the basis of H. pylori-induced interference with ulcer healing.

Topics: Biopsy; Cell Division; Cell Movement; Cells, Cultured; Culture Media; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Stomach Ulcer; Wound Healing

Previous study showed that duodenal ulcer (DU) patients infected with Helicobacter pylori (H. pylori) have increased basal and pentagastrin- or GRP-induced gastric acid secretion and that these disturbances reversed fully after eradication of H. pylori. This study was designed to compare the gastric acid secretory profile, plasma gastrin levels and growth factors (EGF and TGF alpha) expression in gastric mucosa in DU patients with those in atrophic gastritis patients before and six months after verified eradication of H. pylori. In DU patients, basal and stimulated (GRP and pentagastrin) gastric acid secretion was significantly higher than in healthy controls. Six months following the eradication of H. pylori with triple therapy (omeprazole+clarithromycin+amoxicillin), this secretion returned to normal value. In contrast, in patients with atrophic gastritis, such eradication of H. pylori resulted in a significant increase in basal and pentagastrin- and GRP-stimulated acid secretion. Mucosal expression of immunoreactive EGF and TGF alpha was significantly enhanced in H. pylori positive DU and atrophic gastritis patients but this elevation disappeared or was markedly decreased 6 months upon the eradication of H. pylori. We conclude that 1) H. pylori infection is accompanied both in DU and atrophic gastritis patients by an enhanced plasma gastrin and increased mucosal expression of EGF and TGF alpha, 2) basal and GRP-induced acid secretion is significantly elevated in DU, whereas that in atrophic gastritis patients is greatly reduced, and 3) the H. pylori eradication restores gastric acid and plasma gastrin release as well as the mucosal expression of growth factors in DU and atrophic gastritis.

Topics: Adult; Duodenal Ulcer; Epidermal Growth Factor; Gastric Acid; Gastric Mucosa; Gastrin-Releasing Peptide; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Male; Transforming Growth Factor alpha

Epidemiological studies have consistently shown an association between infection of Helicobacter pylori (Hp) and duodenal ulcer (DU) and gastric cancer. The mechanism of the ulcerogenic effect of Hp has been related to excessive gastrin release, gastric acid hypersecretion and gastric metaplasia in duodenum. The implication of Hp in gastric carcinogenesis has not been explained. In this study, mucosal expression of EGF and TGF alpha and luminal release of EGF as well as basal and pentagastrin-stimulated acid secretion and plasma gastrin levels have been determined in healthy subjects, gastric carcinoma and DU patients. It was found that Hp positive DU patients show excessive gastrin release and gastric acid secretion combined with increased expression and luminal release of EGF and TGF alpha. These changes returned to normal values two years after the eradication of Hp. Gastric cancer patients also showed increased expression of EGF and TGF alpha and highly increased plasma gastrin but their gastric acid secretion was markedly reduced possibly due to atrophy of oxyntic mucosa. This study indicates that overexpression of growth factors in gastric mucosa may be implicated in the pathogenesis of both duodenal ulcer and gastric cancer and that Hp positive hypochlorhydric and hypergastrinemic patients may be predisposed to development of gastric cancer.

Topics: Adult; Aged; Carcinoma; Duodenal Ulcer; Epidermal Growth Factor; Gastric Acid; Gastric Juice; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Immunochemistry; Middle Aged; Pentagastrin; Stomach Neoplasms; Transforming Growth Factor alpha

In 10 patients with Helicobacter pylori (HP) positive chronic gastritis, gastric mucosal content of interleukin (IL)-1 beta, IL-8, Transforming Growth Factor (TGF)-beta 1, Epidermal Growth Factor (EGF) and Polyamines (putrescine, spermine and spermidine) was evaluated before and after eradicating treatment. Histologically, in all patients eradication of HP was accompanied by a marked reduction of the inflammatory infiltrate. At the same time, at the end of the therapeutical regimen, elevated levels of IL-1 beta, IL-8, TGF-beta 1, putrescine and spermidine/spermine ratio significantly dropped, while EGF mucosal content, significantly increased. Results are discussed in terms of the reciprocal role of inflammatory cytokines, growth factors and polyamines in the evolution of the HP-associated chronic gastritis.

Topics: Cytokines; Epidermal Growth Factor; Gastric Mucosa; Gastritis, Atrophic; Helicobacter Infections; Helicobacter pylori; Humans; Polyamines

Epidermal growth factor (EGF) is secreted by salivary and Brunner's glands and shows a potent inhibitory effect on gastric acid and stimulatory influence on mucosal growth and protection but little is known about the effect of the Helicobacter pylori (Hp) infection on the release of EGF. In this study the salivary and gastric concentrations of EGF have been measured and gastric mucosal expression of EGF has been determined in 25 Hp positive duodenal ulcer (DU) patients before and after the eradication of Hp (using triple therapy with omeprazole, 20 mg bd, amoxycillin, 500 mg qd and metronidazole, 500 mg bd for 2 weeks) and in 10 healthy controls under basal conditions and following pentagastrin (2 micrograms/kg-h) stimulation. Basal salivary and gastric concentrations of EGF were similar and no significant difference was found between DU patients and healthy controls. Pentagastrin infusion (2 micrograms/kg-h) caused a significant increase in EGF release into saliva and gastric juice both in healthy controls and DU patients but in DU patients the Hp eradication resulted in several folds higher basal and pentagastrin-induced gastric EGF content than that before the anti-Hp therapy, whereas such Hp eradication had no significant influence on basal and pentagastrin-induced salivary EGF. Antral mucosal expression of EGF in Hp-positive DU patients was significantly higher than that in healthy Hp-negative controls and this elevation persisted after eradication of Hp. Basal and pentagastrin-induced gastric acid outputs in Hp-positive DU patients were significantly higher than in healthy controls and they were slightly reduced after the triple therapy. In all DU patients, 4 weeks after termination of anti-Hp therapy, a complete ulcer healing occurred. We conclude that (1) the stomach is capable of secreting large amounts of EGF and pentagastrin appears to be a potent stimulus of salivary and gastric EGF release; (2) the Hp infection reduces the release of gastric EGF and the eradication of Hp results in the augmentation of basal and pentagastrin-induced EGF release into the stomach but not into the saliva and (3) since the eradication of Hp infection in DU patients resulted in DU healing and this was accompanied by an increase in EGF release, we conclude that EGF plays a crucial role in the DU healing process.

Topics: Duodenal Ulcer; Epidermal Growth Factor; Gastric Acid; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Pentagastrin; Saliva

Epidermal growth factor (EGF), pivotal in mucosal protection, is partly degraded proteolytically at low pH in the gastric milieu; gastric acid secretion, on the other hand, remains influenced by H. pylori colonization. The aim of this study, therefore, was to evaluate the impact of low pH and H. pylori colonization status on immunoreactive EGF and the other member of EGF-family, immunoreactive transforming growth factor-alpha (TGF-alpha). Eighteen patients with nonulcer dyspepsia (NUD) colonized by H. pylori and 55 NUD patients without H. pylori colonization were investigated. Gastric juice samples were aspirated at the beginning of the endoscopy procedure and immediately placed on ice, and their pH was recorded. The measurement of immunoreactive EGF and TGF-alpha was performed using commercially available radioimmunoassays (RIAs) after adjustment of pH to neutral using an assay buffer. Statistical analysis was performed using sigma-Stat for Windows. The concentration of immunoreactive EGF in patients with NUD colonized by H. pylori was 80% lower (P < 0.02) than in those without H. pylori and in both groups immunoreactive EGF was significantly lower when the pH of gastric juice was below 4.0. The concentration of immunoreactive EGF in H. pylori(+) and H. pylori(-) patients was similar when the pH of aspirated gastric juice was above 4.0. However, with gastric juice pH < 4.0, the EGF concentration was 64% lower in H. pylori(+) patients than H. pylori(-) patients (P < 0.05). In general, the concentration of immunoreactive TGF-alpha in gastric juice was unaffected by H. pylori colonization or pH of gastric juice. It is concluded that: (1) significantly lower immunoreactive EGF concentrations in patients with pH below 4.0 indicate that immunoreactive EGF but not immunoreactive TGF-alpha is affected by an acidic gastric milieu; (2) the further reduction of gastric juice immunoreactive EGF at pH below 4.0 in patients colonized by H. pylori suggests that this microorganism may elaborate factors that accelerate its proteolytic degradation or inhibit its rate of synthesis and/or secretion; and (3) this diminished content of immunoreactive EGF at low pH, especially in patients colonized by H. pylori, may facilitate the development and/or progression of mucosal damage.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Epidermal Growth Factor; Female; Gastric Acidity Determination; Gastric Juice; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Transforming Growth Factor alpha

Helicobacter pylori is the cause of chronic (type B) gastritis, duodenal ulceration (DU), and gastric ulceration (GU). Smoking is associated with delayed ulcer healing. Epidermal growth factor (EGF) is produced in the salivary and Brunner's glands of the upper gastrointestinal tract, inhibits gastric acid secretion, and is a powerful mitogen.. We sought to determine gastric luminal EGF (GL-EGF) in smokers and patients with Hp-associated DU and the effects of Hp eradication. Our aim was to determine GL-EGF in patients with GU and the effect of ulcer healing and to measure serum EGF in patients with Hp gastritis with or without DU disease.. GL-EGF was reduced in smokers compared to controls (p = .008). Subjects with HP gastritis had reduced GL-EGF compared to controls (p = .0002). There was no difference in GL-EGF between Hp-positive subjects who had DU and those with chronic gastritis alone. Eradication of Hp from those patients with DU had no effect on the low levels of GL-EGF. There was no difference between GL-EGF in Hp gastritis alone and in Hp-associated active GU. GL-EGF fell after ulcer healing (p = .04), a difference confirmed by analysis of paired samples from patients before and after ulcer healing (p = .03). There was no difference in serum EGF between controls and subjects with Hp infection. There was no difference in serum EGF in subjects with DU associated and non-ulcer-associated gastritis.. Subjects with Hp gastritis, or those who smoke, had low concentrations of GL-EGF regardless of whether DU was present. Eradication of Hp did not return the concentrations of GL-EGF to normal in DU subjects. Individuals and Hp gastritis and inactive GU had low levels of GL-EGF compared to non-ulcer Hp infection. The relative increase in GL-EGF that occurred with ulceration of the gastric mucosa may have resulted from the development of an ulcer-associated cell lineage. Serum EGF did not play a role in the pathogenesis of Hp gastritis or of associated DU ulcer disease.

Topics: Adult; Aged; Biopsy; Duodenal Ulcer; Epidermal Growth Factor; Female; Gastric Acid; Gastric Juice; Gastric Mucosa; Gastritis; Gastrointestinal Contents; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Parietal Cells, Gastric; Peptic Ulcer; Smoking

The level of epidermal growth factor (EGF) was measured in the basal and maximally stimulated gastric juice of 20 control subjects and 20 patients each with duodenal ulcer and non-ulcer dyspepsia. Basal gastric juice was analysed for ammonia and urea concentrations, and the [ammonia]3/[urea] ratio was used to show Helicobacter pylori status, as was the [13C]urea breath test in nine controls. There was complete concordance in the nine controls between the two methods for determining H. pylori status. Twenty-five subjects were H. pylori positive (seven with duodenal ulcer, nine with non-ulcer dyspepsia, nine controls) and 35 H. pylori negative (13, 11 and 11 respectively). In H. pylori-positive subjects, the median EGF concentrations in the stimulated secretion of patients with duodenal ulcer and without (non-ulcer dyspepsia and controls combined) were 46.7 and 18.0 ng/ml (P < 0.001), and in H. pylori-negative subjects were 40.0 and 26.5 ng/ml respectively (P < 0.01). There was no difference in EGF concentration between controls and subjects with non-ulcer dyspepsia irrespective of H. pylori status. Lack of EGF is unlikely to be a cause of duodenal ulcer. The increased EGF concentration in patients with ulcer bore no relationship to the H. pylori status of the individual. If this bacterium causes duodenal ulcer, it is not via a reduction in EGF concentration.

Topics: Breath Tests; Duodenal Ulcer; Dyspepsia; Epidermal Growth Factor; Gastric Juice; Helicobacter Infections; Helicobacter pylori; Humans

Topics: Epidermal Growth Factor; Helicobacter Infections; Helicobacter pylori; Humans; Stomach Neoplasms