transforming-growth-factor-alpha and Gastritis

Our purpose was to study the effect of Helicobacter pylori (HP) on mucosal protein fractional synthesis (MPFS) and growth factor expression. 14C-leucine incorporation, and TGF-alpha, beta-FGF, and EGF-receptor levels were assessed in gastric and duodenal mucosa in 20 patients with HP-associated gastritis and repeated after treatment of the gastritis, with or without eradication of the organism. At entry, MPFS in the fundus, antrum, and duodenum was 43.1, 38.2, and 28.3%/day, respectively. Following HP eradication, fundal and antral rates fell to 28.1 and 21.4%/day (P < 0.05), whereas the duodenum was unchanged. MPFS in the patient subset not eradicated remained similar to entry values (35.9, 31.6, and 25.4%/day). Expression of TGF-alpha, beta-FGF, and EGF receptors was unchanged. Eradication of HP results in reduction of gastric, but not duodenal, MPFS and has no effect on the growth factors measured. Increased MPFS associated with HP gastritis may relate to the potential for neoplastic transformation.

Topics: Adult; Anti-Bacterial Agents; Anti-Ulcer Agents; Chronic Disease; Duodenum; ErbB Receptors; Fibroblast Growth Factors; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Leucine; Radioactive Tracers; Transforming Growth Factor alpha

Inflammation induced by Helicobacter pylori infection related to gastric carcinogenesis. In this study, we have investigated the anti-inflammatory effect and its mechanism of kaempferol in the inflammatory response caused by H. pylori infection in vitro. We found that kaempferol reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-8) and production of IL-8 in AGS cells. In addition, kaempferol suppressed translocation of cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) of H. pylori to AGS cells. It was due to decreased transcription of type IV secretion system (T4SS) components involved in CagA injection and secretion system subunit protein A (SecA) of type V secretion system (T5SS) involved in VacA secretion by kaempferol. In conclusion, kaempferol shows the anti-inflammatory effect by suppressing the translocation of CagA and VacA proteins and leading to the down-regulation of pro-inflammatory cytokines. Abbreviations: CagA: cytotoxin-associated gene A; VacA: vacuolating cytotoxin A; T4SS: type IV secretion systems; SecA: secretion system subunit protein A; T5SS: type V secretion system.

Topics: Anti-Inflammatory Agents; Antigens, Bacterial; Bacterial Proteins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-8; Kaempferols; Protein Transport; 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

Previous studies have indicated that increased expression of TGFalpha and cyclin E are correlated with the oncogenesis and progress of cancer; however, their expression patterns in gastric precancerous lesions have been not clear yet. In addition, the association between expression of TGFalpha and cyclin E has not been reported. This study was designed to investigate the expression of TGFalpha and cyclin E in chronic superficial gastritis (CSG), gastric precancerous lesions, and gastric carcinoma (GCA), and analyze the association of TGFalpha and cyclin E expression, and the relationship between their expression and different development stages of oncogenesis of GCA.. The expression of TGFalpha and cyclin E in CSG, intestinal metaphases (IM), atypical hyperplasia (AH), and GCA were examined using immunohistochemical staining. The association of TGFalpha and cyclin E expression was also statistically analyzed.. The expression rates of TGFalpha and cyclin E were 15.1%, 53.6%, 51.7%, 61.7%, and 7.5%, 28.6%, 37.9%, 42.6% in tissue samples of CSG, IM, AH and GCA, respectively. The positive expression rates of TGFalpha and cyclin E were higher in IM, AH, GCA than in CSG; the difference was significant (each P< 0.05). In addition, the positive expression rates of TGFalpha and cyclin E were higher in low differential adenocarcinoma (TGFalpha 81.0%, cyclin E 57.1%) than in mediate to high differential one (TGFalpha 41.7%, cyclin E 16.7%) (P< 0.05,for both TGFalpha and cyclin E). It is also revealed that the expression of TGFalpha and cyclin E were closely associated (P< 0.001 for the tissue of gastric chronic inflammation, and P=0.005 for gastric carcinoma, respectively).. In the tissues of CSG, IM, AH, and GCA, the expression rates of TGFalpha and cyclin E are increased gradually with the severity of the pathological lesions and the malignancy of GCA. In addition, the expression of TGFalpha and cyclin E were obviously associated.

Topics: Adolescent; Adult; Aged; Chronic Disease; Cyclin E; Female; Gastritis; Humans; Immunohistochemistry; Male; Middle Aged; Precancerous Conditions; Stomach Neoplasms; Transforming Growth Factor alpha

A prominent pathological feature of murine autoimmune gastritis is a pronounced mucosal hypertrophy. Here, we examined factors that may be responsible for inducing this hypertrophy. Because gastrin is known to be both an inducer of gastric mucosal cell proliferation and is elevated in autoimmune gastritis, mice deficient in gastrin were thymectomised at day 3 and assessed for autoimmune gastritis. Gastrin-deficient mice showed all the characteristic features of murine autoimmune gastritis, including gastric unit hypertrophy due to hyperproliferation and accumulation of immature epithelial cells, decreases in the number of zymogenic and parietal cells, and autoantibodies to the gastric H+/K+-ATPase. Hence, gastrin is not required for either the establishment of chronic gastritis or development of the typical pathological features of this disease. We also examined mRNA levels of a number of gastric mucosal growth factors in RNA samples from mice with hypertrophic autoimmune gastritis. Members of the Reg family, RegIIIbeta and RegIIIgamma, were greatly elevated in mice with hypertrophic gastritis, whereas RegI and amphiregulin (an EGF receptor ligand) were more modestly and/or inconsistently induced. These data demonstrate that induction of gastric mitogenic factors, such as members of the Reg family, can be achieved in inflammatory situations by gastrin-independent pathways. Members of the Reg family, in particular RegIIIbeta and RegIIIgamma, are good candidates to be involved in inducing the mucosal hyperproliferation in autoimmune gastritis. These findings are likely to be of relevance to other gastric inflammatory conditions.

Topics: Amphiregulin; Animals; Autoantibodies; Autoimmune Diseases; Chronic Disease; EGF Family of Proteins; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Gastrins; Gastritis; Gene Expression; Glycoproteins; Growth Substances; H(+)-K(+)-Exchanging ATPase; Heparin-binding EGF-like Growth Factor; Hypertrophy; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Proteins; RNA, Messenger; Transforming Growth Factor alpha

The mechanisms by which transforming growth factor-a (TGP-alpha) protects the stomach against mucosal injury are incompletely understood. The aim of this study was to examine the roles of sensory neurons, sensory neuropeptides and prostaglandins in TGFalpha gastroprotection against ethanol. Fasted rats received TGF-alpha (50 microg/kg, intraperitoneally) prior to orogastric ethanol (75% v/v, 1 ml). Gastric injury was quantitated 30 min after ethanol. Involvement of sensory neurons and the sensory neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP), were examined by capsaicin deafferentation and specific receptor antagonist infusion, respectively. Indomethacin (10 mg, intragastrically) was used to determine the role of prostaglandins in TGF-alpha-mediated gastroprotection. TGF-alpha significantly diminished ethanol-induced gastric lesion area to 5.7 +/- 0.8 mm2 vs 41.1 +/- 5.2 mm2 (p < 0.001). Sensory denervation and CGRP-receptor blockade abolished the TGF-alpha protective effect. In contrast, SP antagonist and indomethacin did not alter TGF-alpha gastroprotection. In conclusion, TGF-alpha-mediated gastroprotection involves sensory neuron activation and CGRP release and this protective effect did not involve substance P or prostaglandin generation.

Topics: Analysis of Variance; Animals; Calcitonin Gene-Related Peptide; Capsaicin; Disease Models, Animal; Ethanol; Gastric Mucosa; Gastritis; Indomethacin; Injections, Intraperitoneal; Male; Neurons, Afferent; Neuropeptides; Probability; Prostaglandins; Radionuclide Imaging; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Sensitivity and Specificity; Stomach; Substance P; 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

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

1. Epidermal growth factor and the related peptide transforming growth factor alpha have been implicated in the stimulation of gastric mucosal proliferation. We assessed the immunohistochemical distribution of these peptides and their receptor, epidermal growth factor receptor, in mucosa from the antrum and body of the stomach from 28 patients. Twenty-three of the 56 biopsies were histologically normal (12 antrum and 11 body), whereas the other 33 showed varying degrees of inflammation. 2. Epidermal growth factor, transforming growth factor alpha and epidermal growth factor receptor had maximal density of distribution on the apical surfaces of the superficial epithelial cells, but were also expressed to a lesser extent on neck and body cells of the glandular tissue (P less than 0.05). We also demonstrated that epidermal growth factor expression was greater in the epithelial cells of inflamed mucosa than in those of normal mucosa (P less than 0.05). 3. We assessed mucosal proliferation by the Ki-67 labelling index. Ki-67-positive cells were found predominantly in the neck area of the glands and were more frequent in glandular antral tissue than in body glandular tissue (P less than 0.05). Expression of epidermal growth factor receptor in the neck and isthmus cells had a significant correlation with the Ki-67 labelling index (P less than 0.05). 4. We conclude that epidermal growth factor and epidermal growth factor receptor may be important in the adaptation of gastric mucosa to inflammation.

Topics: Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Gastritis; Humans; Leukocyte Count; Lymphocytes; Mitosis; Transforming Growth Factor alpha