epidermal-growth-factor and Stomach-Ulcer

Spices and herbal remedies have been used since ancient times to treat a variety of disorders. It has been experimentally demonstrated that spices, herbs, and their extracts possess antimicrobial, anti-inflammatory, antirheumatic, lipid-lowering, hepatoprotective, nephroprotective, antimutagenic and anticancer activities, besides their gastroprotective and anti-ulcer activities. Despite a number of reports on the toxicity of herbs and spices, they are generally accepted as safer alternatives to conventional therapy against gastric ulcers. To this end, it is also believed, that excessive consumption of spices may favor the pathogenesis of gastric and duodenal ulcer and some studies have substantiated this common perception. Based on various in vivo experiments and clinical studies, on the effects of spices and herbs on gastric ulcers, it has indeed been shown that certain spices do possess remarkable anti-ulcer properties mediated by antisecretory, cytoprotective, antioxidant, and anti-Helicobacter pylori effects and mechanisms regulated by nitric oxide, prostaglandins, non-protein sulfhydryl molecules and epidermal growth factor expression. Accordingly, their consumption may attenuate and help prevent peptic ulcer disease. In the present review, the beneficial effects of spices and herbal nutritive components on the gastric mucosa are discussed against the paradigm of their deleterious potential.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Clinical Trials as Topic; Epidermal Growth Factor; Helicobacter pylori; Humans; Nitric Oxide; Phytotherapy; Plant Extracts; Spices; Stomach; Stomach Ulcer; Xenobiotics

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, tissue repair, and ulcer healing. Epidermal growth factor (EGF) inhibits acid secretion, protects gastric mucosa against injury, mediates mucosal adaptation, and accelerates gastroduodenal ulcer healing. EGF exerts its actions by binding to its receptor (EGF-R), which is a transmembrane protein tyrosine kinase. Binding of EGF to its receptor triggers receptor dimerization and autophosphorylation, recruitment of kinase substrates (signaling enzyme adapter proteins with an SH2 domain, Grb2 adapter protein, and Grb2-SOS complex). These events lead to Ras (GTP-binding protein) phosphorylation and activation of the Ras/Raf/MAP kinase pathway, in turn leading to phosphorylation of regulatory proteins and transcription factors and culminating in cell proliferation. Other pathways potentially activated by EGF include the phosphatidylinositol pathway (leading to activation of protein kinase C and an increase in cytosolic calcium) and the JAK/STAT signaling pathway. While EGF-induced signaling events have been extensively studied in various cell systems, predominantly neoplastic and/or transformed cells, the relevance of those findings to gastric mucosal injury repair or ulcer healing is as yet not fully elucidated. This paper is intended to provide an overview of signaling pathways triggered by EGF-R activation and on this background to summarize current knowledge pertaining to involvement of EGF-R signaling pathways in gastric mucosal repair and ulcer healing.

Topics: Animals; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Humans; Protein-Tyrosine Kinases; Signal Transduction; Stomach Ulcer

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

Ulcer healing, i.e. the reconstruction of the mucosal architecture, is an active process of filling the mucosal defect with proliferating and migrating epithelial cells and connective tissue.. This article represents a summary of histologic and ultrastructural assessment of the cellular events occurring during healing of experimental gastric ulcer.. Mucosa adjacent to the ulcer crater forms a 'healing' zone. The gastric glands in this zone dilate and the epithelial cells lining these glands de-differentiate, express epidermal growth factor receptor, and proliferate. The latter is the result of local activation of genes encoding for EGF and its receptors. At the ulcer margin, proliferating and dividing epithelial cells migrate onto the granulation tissue to cover (re-epithelialize) the ulcer and bud into granulation tissue to reconstruct glandular structures within the ulcer scar. Re-epithelialization and reconstruction of epithelial structures is under control of epidermal growth factor (EGF) and related peptides which are produced locally by regenerating cells. Under control of fibroblast growth factors, granulation connective tissue grows extensively supplying (a) microvessels for restoration of the microvascular network and (b) connective tissue cells for restoration of the lamina propria within the mucosal scar. The final outcome of the healing process reflects a dynamic interaction between the epithelial component for the 'healing' zone at the ulcer margin and the connective tissue component (including microvessels) originating from the granulation tissue. Depending on these interactions, mucosal scar can be of good quality (restoration close to normal) or poor quality. While a number of pharmacologic agents affect gastric ulcer healing, it is unknown whether these drugs affect the quality of mucosal architecture reconstruction. In previous studies, we demonstrated that sucralfate exerts a trophic effect on gastric mucosa and, compared with omeprazole, improves the quality of restored mucosal structures within the scar of healed gastric ulcers. In the most recent studies, we demonstrated that treatment with sucralfate activates genes for EGF, bFGF, and their receptors, significantly increasing (vs placebo and omeprazole) expression of EGF and its receptor in ulcerated gastric mucosa.. Thus, the superior quality of ulcer healing by sucralfate (versus omeprazole) is most likely based on its capacity to induce and stimulate expression of EGF, bFGF, and their receptors.

Topics: Animals; Anti-Ulcer Agents; Epidermal Growth Factor; ErbB Receptors; Fibroblast Growth Factors; Gastric Mucosa; Granulation Tissue; Neovascularization, Physiologic; Omeprazole; Stomach Ulcer; Sucralfate

The maintenance of the integrity of the gastrointestinal mucosa and the repair of acute and chronic mucosal lesions are under the influence of various growth factors, especially epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha). EGF originates mainly from salivary glands, whereas TGF-alpha is released locally in the gastric mucosa, particularly when the mucosa is exposed to topical irritants. EGF and TGF-alpha have similar spectra of biological activity, which include the stimulation of the restitution and proliferation of mucosal cells, gastroprotection, vasodilatation, gastric adaptation to noxious substances, healing of acute and chronic lesions and inhibition of gastric acid secretion. Accumulation of EGF in the ulcer area as a result of excessive production by ulcer-associated new cell lineages contributes together with overexpression of EGF receptors in the ulcer area to the migration of cells from the ulcer margin and formation of granulation tissue and microvessels (angiogenesis) during the ulcer healing process.

Topics: Animals; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Granulation Tissue; Humans; Neovascularization, Physiologic; Stomach Ulcer; Transforming Growth Factor alpha; Wound Healing

Important role is attributed to the growth factors in the development, growth, and restitution after injury of the gastrointestinal tract. The common feature of growth factors is their ability to stimulate the growth and mitosis of quiescent cells in a nutritionally complete medium which in itself is not sufficient to initiate cell division. Epidermal growth factor prevents efficiently the experimentally induced acute gastric mucosal lesions induced by aspirin, absolute ethanol, HCl, NaCl, immobilization, and immersion and it accelerates the healing of acetic acid-induced chronic gastric and cysteamine-induced chronic duodenal ulcers. It proved to be also useful in the treatment of human gastric ulcers. Fibroblast growth factor possesses similar gastroprotective and chronic ulcer-healing properties. Its effects is much more potent than that of epidermal growth factor and that of H2-receptor blockers. The "trefoil"-peptides constitute the latest family of growth factors which are supposed to be involved in the regeneration of the normal and the ulcerated gastrointestinal mucosa. Polyamines are non-peptide growth promoting compounds present in all eukaryotic cells; their gastroprotective and ulcer-healing properties have also been published. The use of some growth factors as regenerative and angiogenic therapy could open a new, alternative way in the future management of peptic ulcer disease.

Topics: Animals; Aspirin; Chronic Disease; Duodenal Ulcer; Epidermal Growth Factor; Ethanol; Fibroblast Growth Factors; Gastric Mucosa; Humans; Polyamines; Rats; Stomach Ulcer

Topics: Animals; Cell Division; Epidermal Growth Factor; Gastric Mucosa; Humans; Stomach Ulcer

The gastroprotective and ulcer-healing properties of prostaglandins, especially in gastric ulcers induced by non-steroidal anti-inflammatory drugs, are well established. Ulcer healing is an active process of filling the mucosal defect with migrating and proliferating epithelial cells combined with angiogenesis in granulation tissue at the ulcer bed. Growth factors, especially epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) are crucial in the regulation of the reconstruction of damaged mucosal structures.. In this double-blind, randomized, prospective study 40 patients with gastric ulcer were treated with nocloprost, a stable prostaglandin E2 derivative, or with ranitidine. All subjects underwent endoscopy before and after 4 and 8 weeks of anti-ulcer therapy. During endoscopy mucosal biopsies were performed for determination of EGF content in gastric mucosa at the ulcer margin and in the intact mucosa. Additionally, EGF output in saliva and its plasma concentrations were determined in all subjects before and during the treatment.. The gastric ulcer healing rate after 4 weeks was significantly higher in patients treated with nocloprost than in those treated with ranitidine (63% versus 39%, respectively). At initial examination the EGF content in the gastric mucosa obtained from the ulcer edge was significantly higher than that in the intact mucosa. There was a significant increase in the EGF content in both the ulcer margin and the intact mucosa in subjects treated with nocloprost but not in patients under treatment with ranitidine. Similarly, patients treated with nocloprost had significantly higher EGF output in saliva and higher EGF concentration in plasma throughout the anti-ulcer therapy.. Nocloprost is superior to ranitidine in the treatment of chronic gastric ulcers, and these effects could be due, at least in part, to higher expression and mucosal content of EGF in the ulcer area.

Topics: Adult; Anti-Ulcer Agents; Double-Blind Method; Drug Administration Schedule; Epidermal Growth Factor; Female; Gastric Mucosa; Humans; Male; Middle Aged; Prospective Studies; Prostaglandins F, Synthetic; Ranitidine; Stomach Ulcer; Time Factors; Wound Healing

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

We introduced a double-blind controlled clinical study to compare intravenous human epidermal growth factor (hEGF) to cetraxate hydrochloride (CH), an antiulcer drug, for their healing effect on gastric ulcers. We also prospected an oral use of EGF on the basis of our experimental evidence. In the clinical trial, the rate of ulcer healing within 8 weeks was 77.9% (67/86) in patients receiving 6 micrograms EGF intravenously twice a week, being significantly greater than 51.7% (45/87) in those given CH. Taking together all aspects assessed including the healing rate, pain relief, blood examination and adverse reactions, we judged the hEGF to be a useful and safe anticuler drug. In rats, 50 micrograms/kg mouse EGF (mEGF) and 2% hydroxypropyl cellulose (HPC) or 1.0 g/kg sucralfate given by gastric intubation significantly raised the residual mEGF levels in both gastric luminal content (HPC: x 30; sucralfate: x 300 as high as those in EGF alone) and tissue (HPC: x 60; sucralfate: x 100). In addition, the combined treatments significantly promoted healing of rat gastric ulcers whereas each agent alone had no significant effect as compared with control (saline). This indicated the beneficial effect on ulcers of oral administration of EGF with agents allowing it to remain at high levels in the stomach, whereas most reports suggested less effect of oral EGF on healing of gastroduodenal ulcers. Subsequent to the clinical study, evaluation of oral use of EGF may be expected as the next step in the treatment of ulcers. The experimental evidence above would possibly be a guide for such trial.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Ulcer Agents; Double-Blind Method; Epidermal Growth Factor; Female; Humans; Injections, Intravenous; Male; Middle Aged; Stomach Ulcer; Tranexamic Acid

The aim of our study was to investigate the healing effect of propionyl-L-carnitine (PLC) on chronic gastric ulcers and its underlying mechanisms. This study included rats with gastric ulcers induced by applying serosal glacial acetic acid. These rats were then given either saline (vehicle) or PLC at doses of 60 and 120 mg/kg, administered orally 3 days after ulcer induction for 14 consecutive days. Our study found that treatment with PLC resulted in a reduction of the gastric ulcer area, a faster rate of ulcer healing, and stimulated mucosal restoration. Additionally, the treatment with PLC reduced the number of Iba-1+ M1 macrophages while increasing the number of galectin-3+ M2 macrophages, as well as desmin+ microvessels, and α-SMA+ myofibroblasts in the gastric ulcer bed. The mRNA expression of COX-2, eNOS, TGF-β1, VEGFA, and EGF in the ulcerated gastric mucosa was greater in the PLC-treated groups compared with the vehicle-treated rats. In conclusion, these findings suggest that PLC treatment may accelerate gastric ulcer healing by stimulating mucosal reconstruction, macrophage polarization, angiogenesis, and fibroblast proliferation, as well as fibroblast-myofibroblast transition. This process is associated with the upregulation of TGF-β1, VEGFA, and EGF, as well as modulation of the cyclooxygenase/nitric oxide synthase systems.

Topics: Acetic Acid; Animals; Cyclooxygenase 2; Epidermal Growth Factor; Rats; Rats, Wistar; Stomach Ulcer; Transforming Growth Factor beta1; Ulcer

To assess the efficacy of Erzhu Yiren Decoction in treating gastric ulcer of spleen deficiency and dampness-heat and its effect on serum NO, EGF, and PGE2 levels.. A retrospective study was conducted among 64 patients with gastric ulcers of spleen deficiency and dampness heat admitted to our hospital from September 2019 to May 2020, and they were divided at a ratio of 1 : 1 into an observation group (rabeprazole sodium enteric-coated capsules plus Erzhu Yiren Decoction) and a control group (rabeprazole sodium enteric-coated capsules) based on different treatment methods. The clinical symptom scores, the effective rate of ulcer healing under gastroscopy, the quality of ulcer healing (QOUH), serum nitric oxide (NO), endothelial growth factor (EGF), and prostaglandin E2 (PGE2) levels were compared between the two groups.. The clinical symptom scores of the observation group after treatment were significantly lower than those of the control group (. Erzhu Yiren Decoction can relieve the clinical symptoms of patients with gastric ulcers of spleen deficiency and dampness heat; improve the serum NO, EGF, and PGE2 levels; optimize the mucosal maturity; and enhance the overall efficacy, which merits clinical promotion.

Topics: Capsules; Dinoprostone; Epidermal Growth Factor; Hot Temperature; Humans; Rabeprazole; Retrospective Studies; Spleen; Stomach Ulcer; Ulcer

Gastric ulcer (GU) is a peptic disease with high morbidity and mortality rates affecting approximately 4% of the population throughout the world. Current therapies for GU are limited by the high relapse incidence and side effects. Therefore, novel effective antiulcer drugs are urgently needed. Ginsenosides have shown good anti-GU effects, and the major intestinal bacterial metabolite of ginsenosides, protopanaxatriol (PPT), is believed to be the active component. In this study, we evaluated the anti-GU effect of PPT in rats in an acetic acid-induced GU model. High (H-PPT) and medium (M-PPT) doses of PPT (20.0 and 10.0 mg/mg/day) significantly reduced the ulcer area and the ET-1, IL-6, EGF, SOD, MDA and TNF-α levels in serum were regulated by PPT in a dose-dependent manner. We also investigated the mechanisms of anti-GU activity of PPT based on metabolomics coupled with network pharmacology strategy. The result was that 16 biomarkers, 3 targets and 3 metabolomic pathways were identified as playing a vital role in the treatment of GU with PPT and were further validated by molecular docking. In this study, we have demonstrated that the integrated analysis of metabolomics and network pharmacology is an effective strategy for deciphering the complicated mechanisms of natural compounds.

Topics: Acetic Acid; Animals; Biomarkers; Epidermal Growth Factor; Ginsenosides; Interleukin-6; Metabolomics; Molecular Docking Simulation; Network Pharmacology; Rats; Stomach Ulcer; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Peptic ulcer episodes cause damage to the stomach and intestine, with inflammatory cell infiltration and oxidative stress as the main players. In this study, we investigated the potential of anthocyanidin malvidin for preventive and curative peptic ulcer treatment. The anthocyanidin effects were examined in gastric ulcer mouse models induced by ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion (IR), acetic acid and duodenal ulcer induced by polypharmacy. Expression levels of oxidative and inflammatory genes were measured to investigate the mechanism of anthocyanin activity. At a dose of 5 mg·kg

Topics: Acetic Acid; Animals; Anthocyanins; Antioxidants; Biomarkers; Cyclooxygenase 1; Disease Models, Animal; Duodenum; Epidermal Growth Factor; Ethanol; Gastric Mucosa; Gene Expression Regulation; Indomethacin; Inflammation; Male; Matrix Metalloproteinase 9; Mice; Oxidative Stress; Peptic Ulcer; Polypharmacy; Protective Agents; Reperfusion Injury; Stomach Ulcer; Tight Junctions; Wound Healing

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Topics: Duodenal Ulcer; Epidermal Growth Factor; Gastrins; Gastrointestinal Hemorrhage; Humans; Stomach Ulcer

Our previous studies indicated that the triterpenes from the fruits of Chaenomeles speciosa (Sweet) Nakai (TCS) owned effectively therapeutic effects on gastric ulcer patients and animals, but its mechanisms have not been fully understood. The current study was to further investigate its protective effect on indomethacin (IND)-damaged RGM-1 cells and rats, as well as its mechanisms involved.. The gastroprotection of TCS was evaluated with IND-induced gastric lesions model in RGM-1 cells and rats. In vitro, the proliferation, migration, mitochondrial viability and apoptosis were assessed. In vivo, ulcer index, ulcer inhibition rate, gastric juice acidity, gastric wall mucus (GWM) and histopathology of gastric mucosa were detected. The gastroprotective effects of TCS through the TFF1-mediated EGF/EGFR and apoptotic pathways were measured by qRT-PCR and Western blot assays.. The results demonstrated that TCS had gastroprotective function, which was related to the amelioration in promoting IND-damaged RGM-1 cell proliferation and migration, hoisting gastric juice acidity and GWM, improving ulcer index and ulcer inhibition rate, attenuating the haemorrhage, oedema, epithelial cell loss and inflammatory cell infiltration of gastric mucosa, upregulating PCNA, Bcl-2, Bcl-xl mRNA and TFF1, EGF, p-EGFR, p-Src, pro-caspase-3, pro-caspase-9 protein expressions, mitochondrial viability, mitochondrial cytochrome c concentration and p-EGFR/EGFR, p-Src/Src, Bcl-2/Bax, Bcl-xl/Bad ratioes, downregulating Bax, Bad, Apaf-1 mRNA and cleaved-caspase-3, cleaved-caspase-9, cleaved PARP-1 protein expressions and cytosol cytochrome c concentration.. Our present study demonstrated that TCS's gastroprotective effect was closely connected with boosting TFF1 expression, activating TFF1-mediated EGF/EGFR pathway, thus restraining mitochondrial-dependent apoptosis, which provided new insights into interpreting its underlying mechanism and promised to act as a candidate drug to treat gastric mucosal injury.

Topics: Animals; Apoptosis; Caspase 3; Cell Line; Cell Movement; Cell Proliferation; Cell Survival; Epidermal Growth Factor; ErbB Receptors; Fruit; Gastric Mucosa; Indomethacin; Mitochondria; Rats; Rats, Sprague-Dawley; Rosaceae; Stomach Ulcer; Trefoil Factor-1; Triterpenes

The β-glucan H6PC20 (Mw: 2390 kDa) and α-heteropolysaccharide HPB-3 (Mw: 15 kDa) were purified from the fruiting body of Hericium erinaceus according to the previous methods. Their gastroprotective activities and corresponding structure-activity relationship were studied in the ethanol-induced gastric ulcer model of rats. After intragastric administrated with H6PC20 and HPB-3 for 14 days, macroscopic and histological evaluation of gastric mucosa was improved significantly. The defense and repair factors (EGF, bFGF and PGE

Topics: Animals; Biomarkers; Biopsy; Chemical Phenomena; Cytokines; Disease Models, Animal; Epidermal Growth Factor; Ethanol; Fungal Polysaccharides; Gastric Mucosa; Hericium; Immunohistochemistry; Male; Protective Agents; Rats; Stomach Ulcer

 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

The present study investigated the potent therapeutic effects of Ruscogenin, main steroid sapogenin of traditional Chinese plant called 'Ophiopogon japonicas', on chronic ulcer model established with acetic acid in rats.. 24 rats were attenuated to the sham (2 ml/kg/day isotonic solution), control (untreated ulcer) and treatment (3 ml/kg/day ruscogenin) groups. After treatment for 2 weeks, gastric tissues were collected and prepared for light microscopic (H&E), immunohistochemical (Collagen I, III and IV) and biochemical analysis [Epidermal growth factor (EGF), Prostaglandin E2 (PGE2), Tumor Necrosis Factor alpha (TNF-α), Interleukin 6 and 8 (IL-6 and IL-8), Lipid Peroxidase (LPO), Myeloperoxidase (MPO), Glutathione (GSH) and Glutathione Peroxidase (GSH-Px)] and transmission electron microscopy (TEM).. Macroscopic scoring showed that the ulceration area of ruscogenin-treated group decreased compared with control group. Immunohistochemical analysis revealed ruscogenin ameliorated and restored the levels of Collagen I and IV to the levels of sham group. Tissue levels of EGF and PGE2 enhanced significantly in untreated ulcer group while were higher in treated ulcer group than the control group. TNF-α, IL-6, IL-8, LPO, MPO levels increased significantly in control group whereas decreased in treated rats after ruscogenin treatment. However, levels of GSH and GSH-Px increased significantly in treatment group. TEM showed chief cells and parietal cells of ulcer group having degenerated organelles while ruscogenin group had normal ultrastructure of cells.. There are potent anti-inflammatory and anti-oxidant effects of ruscogenin on gastric ulcer and may be successfully used as a safe and therapeutic agent in treatment of peptic ulcer.

Topics: Animals; Chronic Disease; Collagen; Cytokines; Dinoprostone; Disease Models, Animal; Epidermal Growth Factor; Female; Microscopy, Electron, Transmission; Ophiopogon; Parietal Cells, Gastric; Peroxidases; Phytotherapy; Rats, Sprague-Dawley; Spirostans; Stomach Ulcer; Tumor Necrosis Factor-alpha

Hydrotalcite plays an important role in the therapy of gastric ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), but little is known about the mechanism. We designed two experiments to study the preventive and curative effects of hydrotalcite on NSAIDs-related gastric injury in rats and to investigate the relationship between the protective and curative mechanism of hydrotalcite and the secretion of epidermal growth factor (EGF)/prostaglandin E2 (PGE2).. Two experiments were separately designed to evaluate the preventive and curative effects of hydrotalcite. A total of 25 male rats and 25 female rats were randomly divided into five groups (vehicle group, model group, omeprazole group, hydrotalcite group, and ranitidine group) in each experiment. Rats were treated with indomethacin by gavage to build the model of acute gastric mucosal injury. The concentrations of EGF and PGE2 in blood specimens and mucosal injury indexes by gross inspection were measured and an immunohistochemical technique was also employed to test the levels of EGF, cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2) in gastric mucosa.. Comparing with model group in both preventive and curative experiments, hydrotalcite decreased the gastric injury in the mucosa of stomach significantly (7±4.5 vs. 16±11.25, 1.5±2 vs. 2.5±6;. Hydrotalcite promotes gastric protection and healing via several mechanisms, including increased levels of PGE2 in blood serum, activation of EGF, and antagonising the inhibition of cyclooxygenase (COX) caused by NSAIDs.

Topics: Aluminum Hydroxide; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Epidermal Growth Factor; Female; Gastric Mucosa; Indomethacin; Magnesium Hydroxide; Male; Membrane Proteins; Omeprazole; Ranitidine; Rats; Rats, Wistar; Stomach; Stomach Ulcer

The gastroprotective activity of Hericium erinaceus polysaccharide was investigated in rats. The antioxidant activities were also evaluated. Pre-treatment of polysaccharide could reduce ethanol-induced gastric mucosal lesion and pylorus ligation-induced gastric ulcer. The polysaccharide exhibited scavenging activities of 1, 1-diphenyl-2-picryl-hydrozyl and hydroxyl radicals, and ferrous ion-chelating ability. In the pylorus ligation-induced model, gastric secretions (volume of gastric juice, gastric acid, pepsin and mucus) of ulcer rats administrated with polysaccharide were regulated. Levels of tumor necrosis factor-α and interleukins-1β in serum, and myeloperoxidase activity of gastric tissue were reduced, while antioxidant status of gastric tissue was improved. Defensive factors (nitric oxide, prostaglandin E2, epidermal growth factor) in gastric tissue were increased. These results indicate that Hericium erinaceus polysaccharide possess gastroprotective activity, and the possible mechanisms are related to its regulations of gastric secretions, improvements of anti-inflammatory and antioxidant status, as well as increments of defensive factors releases.

Topics: Animals; Antioxidants; Dinoprostone; Epidermal Growth Factor; Ethanol; Gastric Mucosa; Interleukin-1beta; Nitric Oxide; Polysaccharides; Pylorus; Rats; Stomach Ulcer; Tumor Necrosis Factor-alpha

Carbon monoxide (CO), a gaseous mediator produced by haem oxygenases (HOs), has been shown to prevent stress-, ethanol-, aspirin- and alendronate-induced gastric damage; however, its role in gastric ulcer healing has not been fully elucidated. We investigated whether CO released from tricarbonyldichlororuthenium (II) dimer (CORM-2) can affect gastric ulcer healing and determined the mechanisms involved in this healing action.. CO released from CORM-2 or endogenously produced by the HO1/Nrf2 pathway accelerates gastric ulcer healing via an increase in GBF, an up-regulation in EGF expression and down-regulation of the inflammatory response.

Topics: Acetic Acid; Animals; Carbon Monoxide; Cyclooxygenase 2; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Heme Oxygenase (Decyclizing); Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-1beta; Male; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Organometallic Compounds; Rats, Wistar; Regional Blood Flow; Stomach; Stomach Ulcer; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

The rhizome of Atractylodes lancea (AL, Compositae, Chinese name: Cangzhu; Japanese name: Sou-ju-tsu) has been used traditionally for the treatment of various diseases such as digestive disorders, rheumatic diseases, and influenza in China, Korea and Japan. The crude AL and AL bran-processed are both listed in the Chinese Pharmacopoeia. However, the differences between the effects of the crude and AL bran-processed on gastric ulcer were poorly understood, and the mechanisms for the treatment of gastric ulcer were not clear. This study aimed at comparing the anti-ulcer effects between the crude AL and AL processed in acetic acid induced model in rats and evaluating the mechanisms of action involved in the anti-ulcer properties of AL.. The model of gastric ulcer was imitated by acetic acid in rats, and AL was gavaged. The serum and gastric tissues were collected. The levels of epidermal growth factor (EGF), trefoil factor2 (TFF2), tumor necrosis factor-α (TNF-α), interleukin 6, 8 (IL-6, 8) and prostaglandin E2 (PGE2) in serum and gastric tissues were determined by the double-antibody sandwich enzyme-linked immunosorbent assay (ELISA), and the mRNA expressions of EGF, TFF2, TNF-α, and IL-8 in stomach were analyzed by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Meanwhile, histopathological changes were evaluated by hematoxylin and eosin (HE) stain. The protein expressions of EGF, TFF2, TNF-α, and IL-8 were examined by immunohistochemistry in stomach.. The results demonstrated that the damage of gastric tissue was obviously alleviated and the productions of TNF-α, IL-8, IL-6, and PGE2 and the mRNA expressions of TNF-α, and IL-8 were notably inhibited. Furthermore, the productions of EGF and TFF2 and the mRNA expressions of EGF and TFF2 were significantly stimulated by both crude AL and AL processed in a dose-dependent manner. Compared with the crude AL, the processed AL was more effective.. The AL processed had more satisfactory effects in treatment of gastric-ulcer than the crude AL. The anti-ulcer effects of AL could be attributed to the anti-inflammatory properties via down-regulating TNF-α, IL-8, IL-6 and PGE2 and to the gastroprotective effects via up-regulating EGF and TFF2.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Atractylodes; Dietary Fiber; Dinoprostone; Disease Models, Animal; Drugs, Chinese Herbal; Epidermal Growth Factor; Female; Interleukin-6; Interleukin-8; Male; Peptides; Powders; Rats; Stomach Ulcer; Trefoil Factor-2; Tumor Necrosis Factor-alpha

Gastric bleeding is one of the irritant problems in ulcer patients. In this study, we evaluated hemostatic action of ulcer-coating powder (EGF-endospray) on gastric ulcer animal models. EGF-endospray, containing epidermal growth factor, is designed to be applied through an endoscope. Hemostatic action of the EGF-endospray was evaluated on gastric hemorrhage models of rabbits and micro-pigs. The EGF-endospray was directly applied onto a mucosal resection (MR)-induced gastric bleeding focus in a rabbit model. In a porcine model, the EGF-endospray was applied once via an endoscopy to a bleeding lesion created by endoscopic submucosal dissection. The bleeding focus was then observed via an endoscope. In the rabbit model, EGF-endospray treatment significantly shortened mean bleeding time in comparison with other treatments (104.3 vs 548.0 vs 393.2 s for the EGF-endospray, the non-treated control and the epinephrine injection, respectively). In the micro-pig model, EGF-endospray showed immediate hemostatic action and prolonged covering of the bleeding focus for over 72 h. Histology proved mucosal thickness was more efficiently recovered in all EGF-endospray treated animals. The results of the present study suggest that the EGF-endospray is a promising hemostatic agent for GI bleeding.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Epidermal Growth Factor; Female; Gastric Mucosa; Hemorrhage; Hemostasis; Hemostatics; Hydrogels; Models, Animal; Mucous Membrane; Powders; Rabbits; Stomach Ulcer; Swine; Swine, Miniature

Gastrointestinal endoscopy is a standard diagnostic tool for gastrointestinal ulcers and cancer. In this study, we have developed recombinant human epidermal growth factor-containing ulcer-coating polymeric sol-gel for endoscopic application. Chitosan and pluronic F127 were employed for their thermoresponsive and bioadhesive properties. At temperatures below 21, polymeric sol-gel remains liquid during endoscopic application and transforms to gel at body temperature after application on ulcers. In an in vitro cellular wounding assay, recombinant human epidermal growth factor sol-gel significantly enhanced the cell migration and decreased the wounding area (68%) compared to nontreated, recombinant human epidermal growth factor solution, and sol-gel without recombinant human epidermal growth factor (42, 49, and 32 % decreased at day 1). The in vivo ulcer-healing study was performed in an acetic acid-induced gastric ulcer rat model and proved that our recombinant human epidermal growth factor endoscopic sol-gel facilitated the ulcer-healing process more efficiently than the other treatments. Ulcer sizes in the recombinant human epidermal growth factor sol-gel group were decreased 2.9- and 2.1-fold compared with those in the nontreated group on days 1 and 3 after ulceration, respectively. The mucosal thickness in the recombinant human epidermal growth factor sol-gel group was significantly increased compared to that in the nontreated group (3.2- and 6.9-fold on days 1 and 3 after ulceration, respectively). In a gastric retention study, recombinant human epidermal growth factor sol-gel stayed on the gastric mucosa more than 2 h after application. The present study suggests that recombinant human epidermal growth factor sol-gel is a prospective candidate for treating gastric ulcers via endoscopic application.

Topics: Cell Line; Endoscopy; Epidermal Growth Factor; Gastrointestinal Hemorrhage; Gels; Humans; Recombinant Proteins; Stomach Ulcer

Angiogenesis is essential for gastric ulcer healing. Recent results suggest that vascular endothelial growth factor receptor 1 (VEGFR1), which binds to VEGF, promotes angiogenesis. In the present study, we investigated the role of VEGFR1 signaling in gastric ulcer healing and angiogenesis.. Gastric ulcers were induced by serosal application of 100 % acetic acid in wild-type (WT) and tyrosine kinase-deficient VEGFR1 mice (VEGFR1 TK(-/-)). Bone marrow transplantation into irradiated WT mice was carried out using bone marrow cells isolated from WT and VEGFR1 TK(-/-) mice.. Ulcer healing was delayed in VEGFR1 TK(-/-) mice compared to WT mice and this was accompanied by decreased angiogenesis, as evidenced by reduced mRNA levels of CD31 and decreased microvessel density. Recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) was suppressed and epidermal growth factor (EGF) expression in ulcer granulation tissue was attenuated. Treatment of WT mice with neutralizing antibodies against VEGF or CXCR4 also delayed ulcer healing. In WT mice transplanted with bone marrow cells from VEGFR1 TK(-/-) mice, ulcer healing and angiogenesis were suppressed, and this was associated with reduced recruitment of bone marrow cells to ulcer granulation tissue. VEGFR1 TK(-/-) bone marrow chimeras also exhibited downregulation of EGF expression on CXCR4(+)VEGFR1(+) cells recruited from the bone marrow into ulcer lesions.. VEGFR1-mediated signaling plays a critical role in gastric ulcer healing and angiogenesis through enhanced EGF expression on VEGFR1(+)CXCR4(+) cells recruited from the bone marrow into ulcer granulation tissue.

Topics: Animals; Bone Marrow Cells; Bone Marrow Transplantation; Disease Models, Animal; Epidermal Growth Factor; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Physiologic; Receptors, CXCR4; Signal Transduction; Stomach Ulcer; Up-Regulation; Vascular Endothelial Growth Factor Receptor-1

To study the efficacy and mechanism of Weiyangning pills against experimental gastric ulcer.. The gastric ulcer model were established by acetic acid, water-immersion stress, aspirin induction, pyloric ligation in rats, in order to observe the effect of Weiyangning pills against experimental gastric ulcer and study its effect on the content of nitric oxide (NO) and epidermal growth factor (EGF), gastric mucosal blood flow, the content of PGE2, gastric secretion, gastric acid content and the activity of pepsin.. Weiyangning pills markedly reduced index of gastric ulcers of various types, increased the content of NO, EGF, PGE2 and gastric mucosal blood flow, inhibited gastric secretion and gastric acid content, and decreased the activity of pepsin.. Weiyangning pills has a significant effect against experimental gastric ulcer, which is related to the reduction of gastric mucosa damage factors (gastric acid and pepsin) and the increase in gastric mucosa's function as a barrier and its recovery effects, such as NO, EGF, PGE2 and gastric mucosal blood flow.

Topics: Acetic Acid; Animals; Aspirin; Dinoprostone; Drugs, Chinese Herbal; Epidermal Growth Factor; Female; Gastric Acid; Ligation; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Stomach Ulcer

Rhizophora mangle, the red mangrove, has long been known as a traditional antiulcer medicine. The present work evaluated the mechanisms of action involved in the anti-ulcer properties of the Rhizophora mangle bark extracts.. Gastroprotection of Rhizophora mangle was evaluated in rodent experimental models (ethanol). To elucidate the mechanisms of action the antisecretory action and involvement of NO, SH, mucus and PGE(2) were evaluated. The acetic acid-induced gastric ulcer model, Western blotting assay (COX-1, COX-2 and EGF) and immunohistochemical localization of HSP-70, PCNA and COX-2 were also used to evaluate the Rhizophora mangle healing properties.. Results showed that Rhizophora mangle bark crude extract (CE), as well as ethyl acetate (EtOAc) and butanolic fractions (BuOH) provided significant gastroprotection at all the tested doses. Thereby, the following protocols were performed using the lowest dose capable of producing the most effective gastroprotection, which was the BuOH 0.5mg/kg (P<0.001). Several mechanisms are involved in the antiulcer activity of Rhizophora mangle, such as, participation of NO, SH and mucus. The enhancement of PGE(2) levels and the upregulation of COX-2 and EGF seem to be directly linked to the antisecretory, cytoprotective and healing effects of BuOH. HSP-70 and PCNA are also involved in this cicatrisation process. No sign of toxicity was observed in this study, considering the analyzed parameters.. Our study reinforces its traditional medicinal use. Considering that the current therapies are based on the use of antisecretory or cytoprotective drugs, the Rhizophora mangle arises as a promising alternative antiulcer therapy.

Topics: Acetic Acid; Animals; Anti-Ulcer Agents; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Epidermal Growth Factor; Ethanol; Female; Gastric Acid; Gastric Mucosa; Male; Medicine, Traditional; Membrane Proteins; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phytotherapy; Plant Bark; Plant Extracts; Rats; Rats, Wistar; Rhizophoraceae; Stomach Ulcer; Sulfhydryl Compounds

Clopidogrel is not safe enough for the gastric mucosa in patients with high risk of peptic ulcer. This study aimed to explore if clopidogrel delays gastric ulcer healing and elucidate the involved mechanisms. Gastric ulcer was induced in rats and the ulcer size, mucosal epithelial cell proliferation of the ulcer margin, expression of growth factors [epidermal growth factor (EGF), basic fibroblast growth factor] and their receptors, and signal transduction pathways for cell proliferation were measured and compared between the clopidogrel-treated group and untreated controls. For the in vitro part, rat gastric mucosal epithelial cell line (RGM-1 cells) was used to establish EGF receptor over-expressed cells. Cell proliferation and molecular change under EGF treatment (10ng/ml) with and without clopidogrel (10(-6)M) were demonstrated. Ulcer size was significantly larger in the clopidogrel-treated group compared to the control and mucosal epithelial cell proliferation of the ulcer margin was significantly decreased in the clopidogrel-treated group (P<0.05). Clopidogrel (2mg and 10mg/kg/day) significantly decreased ulcer-induced gastric epithelial cell proliferation and ulcer-stimulated expressions of EGF receptor and phosphorylated extracellular signal-regulated kinase (PERK) at the ulcer margin (P<0.05). Clopidogrel (10(-6)M) also inhibited EGF-stimulated EGF receptor, PERK expression, and cell proliferation in RGM-1 cells (P<0.05), and caused much less inhibition of EGF-stimulated cell proliferation in EGF receptor over-expressed RGM-1 cells than in RGM-1 cells (22% vs. 32% reduction). In conclusion, clopidogrel delays gastric ulcer healing in rats via inhibiting gastric epithelial cell proliferation, at least by inhibition of the EGF receptor-ERK signal transduction pathway.

Topics: Animals; Cell Line; Cell Proliferation; Clopidogrel; Epidermal Growth Factor; Epithelial Cells; ErbB Receptors; Gastric Mucosa; Gene Expression Regulation; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stomach Ulcer; Ticlopidine; Time Factors; Wound Healing

To study the antiulcer effects and the mechanism of Veronicastrum axillare (Sieb. et Zucc) Yamazaki (VAY) on ethanol induced gastric ulcer rats.. Totally 48 healthy SD rats were randomly divided into 6 groups, i.e., the normal group, the model group, the ranitidine group, the high dose VAY group, the medium dose VAY group, and the low dose VAY group, 8 in each group. Rats in the normal group and the model group were administered with normal saline respectively. Rats in the ranitidine group were administered with 0.18% ranitidine suspension (at the daily dose of 0.027 g/kg) by gastrogavage. Those in the high dose VAY group, the medium dose VAY group, and the low dose VAY group were administered with VAY at the daily dose of 2.8 g/kg, 1.4 g/kg, and 0.7 g/kg by gastrogavage, once daily for 14 consecutive days. The gastric ulcer model was established using absolute ethanol after the last gastrogavage. The ulcer index and the ulcer inhibitory rate were compared. The concentrations of malonyldialdehyde (MDA), nitric oxide (NO), epidermal growth factor (EGF), and the activity of superoxide dismutase (SOD) in the serum and the homogenate of the gastric mucosa tissue were detected.. Compared with the model group, the gastric ulcer index in the rest groups obviously decreased (P < 0.01). The ulcer index was dose-dependent with VAY (P < 0.01), with the highest gastric ulcer index shown in the high dose VAY group (P < 0.01). Compared with the normal group, the concentrations of MDA and NO significantly increased in the serum and the gastric mucosa tissue, the activity of SOD and the EGF content in the gastric mucosa tissue of rats in the model group significantly decreased (P < 0.01). Compared with the model group, the MDA concentrations in the serum and the gastric mucosa tissue decreased, the serum NO content increased, the NO content in the gastric mucosa tissue decreased, the serum SOD activity increased, the EGF content in the gastric mucosa tissue increased in the rest groups, all showing statistical difference (P < 0.05, P < 0.01).. The water extract of VAY had significant effects on ethanol induced gastric ulcer. Its mechanisms might lie in reducing the generation of free radicals, promoting the oxygen free radical clearance, restraining lipid peroxidation, regulating and controlling the in vivo contents of NO and EGF.

Topics: Animals; Anti-Ulcer Agents; Epidermal Growth Factor; Ethanol; Male; Malondialdehyde; Plant Extracts; Plantago; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Superoxide Dismutase

To observe the effects and mechanisms of Pongamia pinnata root flavonoids (PRF) on the experimental gastric ulcer induced by acetic acid and to study the mechanism of PRF on the quality of ulcer healing.. The models were established by acetic acid erosion, the quality of ulcer healing of PRF on the model of gastric ulcer were observed. The contents of epidermal growth factor (EGF) in serum were determined by radioimmunoassay. The expression of EGF and transforming growth factor-alpha (TGF-alpha) were detected by immunohistochemistry (SP).. PRF significantly inhibited ulcerative formation induced by acetic acid (P < 0.05, P < 0.01). PRF could significantly increase the EGF and TGF-alpha (P < 0.05, P < 0.01) expression of para-ulcer mucosa tissue and improve the EGF contents in blood serum (P < 0.05, P < 0.01).. PRF increases the contents of EGF in serum and the expression of EGF and TGF-alpha in the tissue around gastric ulcer which might be one of possible mechanisms that PRF improves quality of ulcer healing.

Topics: Acetic Acid; Animals; Epidermal Growth Factor; Female; Flavonoids; Gastric Mucosa; Male; Millettia; Plant Roots; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Transforming Growth Factor alpha

Gastric ulcers and related complications associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, represent a major global health problem. In the present study, we investigate the immunological activity of fucoidan against aspirin-induced gastric mucosal damage in rats. Thirty-six rats were randomly divided into the following, normal (Carboxy methyl cellulose 0.05 %), aspirin (Asp-400mg/kg) treated, fucoidan alone (Fu-0.02 g/kg, daily for 14 days) and Fu+Asp. Cytokines, total nitrite and nitrate (NOx) analysis and tissue localization of Cyclooxygenase 1, 2 and epidermal growth factor receptor (EGFR) were done using Elisa and immunohistochemistry respectively. Histopathology of gastric tissue, collagen deposition was performed using Hematoxylin and Eosin and Masson's trichrome were performed. Treatment of rats with a single dose of aspirin (400mg/kg, orally) led to significant alterations in the levels of total nitrite and nitrate (NOx), interleukins (IL-4, 6, 10, 12), tumor necrosis factor (TNF-α), and interferon gamma (IFN-γ). Notably, collagen deposition in glandular tissue and localization of cyclooxygenase 1, 2, and epidermal growth factor were considerably affected in aspirin-treated rats. These severities were prevented to a significant extent in rats pretreated with fucoidan (0.02 g/kg/day for two weeks orally). Our findings collectively indicate that the gastro-protective effect of fucoidan against aspirin-induced ulceration in rats is mediated through its immunomodulatory properties.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Aspirin; Collagen; Cyclooxygenase 1; Cyclooxygenase 2; Cytokines; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Gastric Mucosa; Immunohistochemistry; Immunologic Factors; Nitric Oxide; Polysaccharides; Rats; Rats, Wistar; Stomach Ulcer

Hyptis Jacq. (Lamiaceae) is being used in traditional medicine to treat fever, inflammation and gastric disturbances. Hyptis spicigera Lam. is a native plant distributed across the central region of Brazil. The essential oil extracted from this plant is used in folk medicine as antipyretic.. The effects of the essential oil obtained from the aerial parts of Hyptis spicigera (OEH) were evaluated for their gastroprotective and healing activities.. OEH chemical composition was analyzed by gas chromatography-mass spectrometry (GC-MS). The gastroprotective action of the OEH was evaluated in rodent experimental models (ethanol and NSAID). To elucidate mechanisms of action, the antisecretory action and involvements of NO, SH, mucus and PGE2 were evaluated. The acetic acid-induced gastric ulcer model and Western Blot assay (COX-2 and EGF) were also used to evaluate the OEH healing capacity.. GC-MS analysis of OEH indicated three monoterpenes as major compounds: alpha-pinene (50.8%), cineole (20.3%) and beta-pinene (18.3%) and, at the dose of 100 mg/Kg, p.o., OEH provided effective gastroprotection against lesions induced by absolute ethanol (97%) and NSAID (84%) in rats. OEH do not interfere with H+ secretion in gastric mucosa and its gastric protection does not depend on nitric oxide (NO) and sulfhydryl compounds (SH). The gastroprotective action of OEH occurs due to an increase in the gastric mucus production (28%) induced by PGE2 levels. Furthermore, OEH demonstrated a great healing capacity with 87% of reduction in ulcerative lesion area. It accelerated the healing of acetic acid-induced gastric lesions due to an increase in COX-2 (75%) and EGF (115%) expression in gastric mucosa. No sign of toxicity was observed in this study, considering the analyzed parameters.. All these results suggest the efficacy and safety of Hyptis spicigera in combating and healing gastric ulcer. Considering the results, it is suggested that the OEH could probably be a good therapeutic agent for the development of new phytotherapeutic medicine for the treatment of gastric ulcer.

Topics: Acetic Acid; Animals; Anti-Ulcer Agents; Bicyclic Monoterpenes; Brazil; Bridged Bicyclo Compounds; Cyclohexanols; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Epidermal Growth Factor; Ethanol; Eucalyptol; Gastric Mucosa; Hyptis; Male; Monoterpenes; Mucus; Oils, Volatile; Phytotherapy; Plant Extracts; Rats; Rats, Inbred Strains; Stomach Ulcer

Earlier we had shown that on the 3 (rd) day of its administration to mice, indomethacin (18 mg kg (-1), P. O.) produced maximum stomach ulceration with a damage score of 3.46, which was reduced by a 3-day treatment with the methanol extract of Myristica malabarica (40 mg kg (-1), P. O.) and omeprazole (3 mg kg (-1), P. O.) to 0.95 and 0.82, respectively. Presently, we investigated the possible role of the test samples in modulating PG synthesis and angiogenesis for their healing action. The ulceration was found to be associated with suppression of PGE (2), VEGF and vWF VIII, and an increase in EGF and endostatin levels. Treatment with the plant extract reversed all these parameters accounting for its healing activity. However, despite providing similar healing, omeprazole did not alter these parameters.

Topics: Angiogenesis Inducing Agents; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Dinoprostone; Endostatins; Epidermal Growth Factor; Fruit; Gastric Mucosa; Indomethacin; Male; Mice; Myristicaceae; Neovascularization, Physiologic; Omeprazole; Oxytocics; Phytotherapy; Plant Extracts; Stomach Ulcer; Vascular Endothelial Growth Factor A; von Willebrand Factor

Hormonal fluctuations are known to predispose ulceration of the upper gastrointestinal tract, but to date no comparative study of their effects on the healing of pre-existing ulcers in the oral cavity and stomach has been made. We studied the effects of depletion of testosterone and of EGF on the healing of acetic acid-induced ulcers using rats having undergone bilateral orchidectomy and/or salivectomy respectively. We measured alterations in gastric acid secretion and blood flow at ulcer margins, as well as plasma levels of testosterone, gastrin and the proinflammatory cytokines IL-1 beta and TNF-alpha. Testosterone (0.01-10 mg/kg/day i. m.) dose-dependently delayed oral and gastric ulcer healing. When applied in an optimal dose of 1 mg/kg/day, this hormone significantly raised gastric acid secretion and plasma IL-1 beta and TNF-alpha levels. Attenuation of plasma testosterone levels via bilateral orchidectomy inhibited gastric acid secretion and accelerated the healing of oral and gastric ulcers, while increasing plasma gastrin levels and these effects were reversed by testosterone. Salivectomy raised plasma testosterone levels, and delayed oral and gastric ulcer healing. Treatment of salivectomised animals with testosterone further inhibited ulcer healing, and this effect was counteracted by EGF. We propose that testosterone delays ulcer healing via a fall in blood flow at the ulcer margin, a rise in plasma levels of IL-1 beta and TNF-alpha and, in the case of gastric ulcers, an increase in gastric acid secretion. EGF released from the salivary glands plays an important role in limitation of the deleterious effects of testosterone on ulcer healing.

Topics: Animals; Chemokines; Dose-Response Relationship, Drug; Epidermal Growth Factor; Gastric Juice; Gastric Mucosa; Gastrins; Injections, Intramuscular; Interleukin-1beta; Male; Orchiectomy; Photomicrography; Rats; Rats, Wistar; Regional Blood Flow; Stomach Ulcer; Testosterone; Time Factors; Tongue; Tongue Diseases; Treatment Outcome; Tumor Necrosis Factor-alpha; Wound Healing

To evaluate the plant phenolics, malabaricone B (mal B) and malabaricone C (mal C) in healing stomach ulcer by modulating angiogenesis.. Male Swiss albino mice, ulcerated with indomethacin (18 mg/kg, p. o., single dose) were treated up to 7 days with different doses of mal B or mal C. The healing capacities of the drugs and their effects on the angiogenic parameters were assessed.. Maximum ulceration, observed on the 3rd day after indomethacin administration was effectively healed by mal B and mal C (each 10 mg/kg, p. o. x 3 days), the latter showing equivalent potency (~78% p < 0.001) as that of Omez (3 mg/kg, p. o. x 3 days) and misoprostol (10 mug/kg, p. o. x 3 days). Compared to the untreated mice, those treated with mal B or mal C respectively for 3 days increased the mucosal EGF level (139 and 178%, p < 0.001), the serum VEGF level (56%, p < 0.01 and 95%, p < 0.001) and microvessels formation (37%, p < 0.05 and 62%, p < 0.01), while reducing the serum endostatin level (37%, p < 0.05 and 61%, p < 0.01). The relative healing capacities of mal B and mal C correlated well with their respective abilities to modulate the angiogenic factors. The healing by Omez and misoprostol was not due to improved angiogenesis.. The drugs, mal B and mal C could effectively heal indomethacin-induced stomach ulceration in mice by promoting angiogenesis.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Cell Proliferation; Dose-Response Relationship, Drug; Endostatins; Epidermal Growth Factor; Gastric Mucosa; Granulation Tissue; Indomethacin; Male; Mice; Misoprostol; Neovascularization, Physiologic; Omeprazole; Regional Blood Flow; Resorcinols; Stomach Ulcer; Vascular Endothelial Growth Factor A; von Willebrand Factor

The present study was undertaken to evaluate the potential of the rhizomes of the Indian medicinal plant, Picrorhiza kurroa in healing indomethacin-induced acute stomach ulceration in mice and examine its capacity to modulate oxidative stress and the levels of prostaglandin (PGE2) and EGF during the process.. Male swiss albino mice, ulcerated with indomethacin (18 mg/kg, p. o., single dose) were treated up to 7 days with different doses of the methanol extract of P. kurroa rhizomes (designated as PK). The healing capacity of the most effective dose of PK (20 mg/kg, p. o. x 3 d) was compared with that of omeprazole (Omez) (3 mg/kg, p. o. x 3 d). The effects of the drug-treatment for one and three days on the biochemical parameters were assessed by comparing the results with that of untreated mice of the 1st and 3rd day of ulceration. The stomach tissues of the mice were used for the biochemical analysis.. The macroscopic indices revealed maximum ulceration on the 3rd day after indomethacin administration, which was effectively healed by PK. Under the optimized treatment regime, PK and Omez reduced the ulcer indices by 45.1% (P < 0.01), and 76.3% respectively (P < 0.001), compared to the untreated ulcerated mice. Compared to the ulcerated untreated mice, those treated with PK for 3 days showed decreased the levels of thiobarbituric acid reactive substances (TBARS) (32.7%, P < 0.05) and protein carbonyl (37.7%, P < 0.001), and increased mucin (42.2%, P < 0.01), mucosal PGE2 (21.4%, P < 0.05), and expressions of COX-1 and 2 (26.9% and 18.5%, P < 0.05), EGF (149.0%, P < 0.001) and VEGF (56.9%, P < 0.01). Omez reduced the TBARS (29.4%, P < 0.05), and protein carbonyl (38.9%, P < 0.001), and increased mucin (38.3%, P < 0.01), without altering the other parameters significantly.. PK (20 mg/kg, p. o. x 3 days) could effectively heal indomethacin-induced stomach ulceration in mice by reducing oxidative stress, and promoting mucin secretion, prostaglandin synthesis and augmenting expressions of cyclooxygenase enzymes and growth factors.

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Dinoprostone; Dose-Response Relationship, Drug; Epidermal Growth Factor; Gastric Mucosa; Indomethacin; Male; Mice; Oxidative Stress; Phytotherapy; Picrorhiza; Plant Extracts; Rhizome; Stomach; Stomach Ulcer; Thiobarbituric Acid Reactive Substances

The aim of this study was to investigate the effects of sea buckthorn procyanidins (SBPC) on healing of acetic acid-induced lesions in the rat stomach and its possible mechanism. The sea buckthorn procyanidins (SBPC) were extracted with 60% alcohol/H2O from sea buckthorn bark and purified by macropore adsorption resin column, with a purity of >96%. The chemical character of SBPC was analyzed by reverse phase high-performance liquid chromatography/mass spectrometry (HPLC/MS). Chronic gastric ulceration was induced by injecting acetic acid into the subserosa of stomach. Different concentrations of SBPC were orally administrated to gastric ulcers rats. After treatment 7d and 14d, rats were sacrificed respectively. The healing of the acetic acid induced ulcerations was measured by ulcer index (UI). The level of epidermal growth factor (EGF) in plasma was determined; the expression of epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) around ulcer was detected by immunohistochemical method. SBPC was found to reduce the size of the ulcers at day 7 and 14 in a dose-dependent manner. Compared with the control, the UI of SBPC group was significantly lower (p< 0.01) and the level of EGF in the plasma of SBPC group increased significantly (p< 0.01), meanwhile the expression of EGFR and PCNA around ulcer in high-dose SBPC stomach were enhanced (p< 0.05). The results implied that SBPC plays an important role in healing of acetic acid-induced gastric lesions possibly by the acceleration of the mucosal repair.

Topics: Animals; Dose-Response Relationship, Drug; Epidermal Growth Factor; ErbB Receptors; Hippophae; Immunohistochemistry; Male; Proanthocyanidins; Proliferating Cell Nuclear Antigen; Random Allocation; Rats; Rats, Wistar; Specific Pathogen-Free Organisms; Stomach; Stomach Ulcer; Time Factors; Wound Healing

To study the effect and mechanism of mexican tea herb and pilular adina herb (abbreviated to MP) on concrescence of gastric mucosa in experimental gastric ulcer rats by observing the changes of epidermal growth factor (EGF), nitrogen monoxidum (NO) and expression of epidermal growth factor receptor (EGFR).. The rat ulcer model was established by 100% glacial acetic injection into the subserosa. The ulcer index (UI) was measured by sliding caliper. The levels of NO and EGF in tissue and serum were measured by the nitrate reductase method and enzyme-linked immunosorbent assay, respectively. The expression of EGFR in the mucosa around the ulcer was detected by the immunohistochemical assay and microimage analysis system.. (1) Compared with the model group, UI of MP groups (10, 15 and 20 mg.kg(-1).d(-1)) and ranitidine group was lower (P<0.05 or P<0.01), the levels of NO and EGF in the tissue and serum were higher (P<0.05), the thickness of regenerated mucous membrane increased, and the width loss of lamina muscularis mucosa decreased (all P<0.05). (2) The expression of EGFR is weakly positive in gastric mucosa cells in the normal group, mainly in the cytoplasm and cytomembrane. In the model group, the expression of EGFR was mainly in epithelial cells in cervical part and basilar part of gastric gland around the ulcer margin, and the number of cells with EGFR weakly positive expression was more than that in the normal group. Compared with that in the normal and model groups, the number of cells with EGFR positive in MP groups and ranitidine group increased (all P<0.05), with weakly positive expression.. MP can protect gastric mucosa, cure gastric ulcer, restrain the secretion of gastric acid, and boost multiplication, differentiation, migration and repair of the endothelial cell by promoting the secretion of NO and EGF, and increasing the expression of EGFR of gastric mucosa epithelial cells.

Topics: Animals; Drugs, Chinese Herbal; Epidermal Growth Factor; ErbB Receptors; Female; Gastric Mucosa; Immunohistochemistry; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley; Regeneration; Stomach Ulcer; Tea

The epidermal growth factor (EGF) has been shown to promote the proliferation of various types of cells, to maintain the physiological function of the mucosa of the digestive tract, and to promote the healing of the gastric and duodenal ulcers. It has been expressed in many types of bacteria and yeasts. In this article, a bio-reactor was constructed, namely, the human EGF (hEGF) transgenic mini-tomato. On the basis of hEGF gene sequence, a tomato codon preference hEGF gene was chemically synthesized, and it was constructed into the plant expression vector pCAMBIA2300. The transgenic tomato plants containing gene hEGF were obtained through Agrobacterium-mediated transformation. The expression product was determined by radioimmunoassay (RIA) and showed a yield of 3.48 +/- 1.01 ng/g fresh fruits. The intragastric gavage (ig) administration of the rhEGF-containing juice of the transgenic tomato (equivalent to 24 ng rhEGF per mouse a day) for 15 days could significantly protect mice against the alcohol-induced ulceration. The ulcer index, expressed as a degree of the stomach lesion, decreased from 42.20 +/- 18.13 to 16.25 +/- 9.57.

Topics: Animals; Base Sequence; Beverages; Epidermal Growth Factor; Ethanol; Female; Fruit; Gene Expression; Genetic Vectors; Humans; Male; Mice; Molecular Sequence Data; Peptic Ulcer; Plants, Genetically Modified; Polymerase Chain Reaction; Radioimmunoassay; Sequence Analysis, DNA; Solanum lycopersicum; Stomach; Stomach Ulcer

To discuss the protective effect of electroacupuncture at the Foot-Yangming Meridian on gastric mucosal lesion, somatostatin (SS) and the expression of SS receptor genes (SSR(1)mRNA ) in rabbits with gastric ulcer and to further explore the relative specificity of meridians and viscera at gene expression level.. Forty rabbits were randomly divided into control group (A), gastric ulcer model group (B), Foot-Yangming Meridian group (C), Foot-Shaoyang Meridian group (D) and Foot-Taiyang Meridian group (E). The gastric ulcer model was prepared by infusing alcohol into stomach. Groups C-E were treated with electro-acupuncture at points along the above meridians using meridian stimulating instruments for 7 d respectively. By the end of treatment, the index of gastric ulcer was determined, the amount of epidermal growth factor(EGF) and somatostatin was measured by radioimmunoassay (RIA). SS-R(1)mRNA expression in gastric mucosa was determined by RT-PCR.. The value of EGF in model group was obviously lower (73.6+/-14.8 vs 91.3+/-14.9 pg/mL, P<0.01) than that in control group. The index of gastric ulcer, content of SS and expression of SSR1mRNA in gastric mucosa were significantly higher than those in control group (24.88+/-6.29 vs 8.50+/-2.98 scores, P<0.01; 2978.6+/-587.6 vs 1852.4+/-361.7 mIU/mL, P<0.01; 2.56+/-0.25 vs 1.04+/-0.36, P<0.01). The value of EGF in Foot-Yangming Meridian group was higher than that in model group (92.2+/-6.7 vs 73.6+/-14.8 pg/mL, P<0.01). The index of gastric ulcer, content of SS and expression of SS-R(1)mRNA in gastric mucosa were significantly lower than those in control group (10.88+/-3.23 vs 24.88+/-6.29 scores, P<0.01; 1800.2+/-488 vs 2978.6+/-587.6 mIU/mL, P<0.01; 1.07+/-0.08 vs 2.56+/-0.25 mIU/mL, P<0.01). Compared to the model group, the content of SS and expression of SSR1mRNA in gastric mucosa in Foot-Shaoyang Meridian group decreased (2441.0+/-488.vs 2978.6+/-587.6 mIU/mL, P<0.05;1.73+/-0.16 vs 2.56+/-0.25 mIU/mL, P<0.01). But the above parameters in Foot-Taiyang Meridian group did not improve and were significantly different from those in Foot-Yangming Meridian group (P<0.05).. Electro-acupuncture at Foot-Yangming Meridian can protect gastric mucosa against injury. The mechanism may be related to the regulation of brain-gut peptides and the expression of SSR(1)mRNA.

Topics: Acupuncture Points; Animals; Disease Models, Animal; Electroacupuncture; Epidermal Growth Factor; Female; Gastric Mucosa; Gene Expression Regulation; Male; Rabbits; Radioimmunoassay; Receptors, Somatostatin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatostatin; Stomach; Stomach Ulcer

To investigate the protective mechanisms of Weikang (WK) decoction on gastric mucosae.. Ninety rats were randomly divided into nine groups of 10 each, namely group, model group, group with large WK dosage, group with medium WK dosage, group with small WK dosage, group with herbs of jianpiyiqi (strengthening the spleen and replenishing qi), group with herbs of yangxuehuoxue (invigorating the circulation of and nourishing the blood), group with herbs of qingrejiedu (clearing away the heat-evils and toxic materials), group with colloidal bismuth pectin (CBP) capsules. According to the method adopted by Yang Xuesong, except normal control group, chronic gastric ulcer was induced with 100% acetic acid. On the sixth day after moldmaking, WK decoction was administered, respectively at doses of 20, 10 and 5 g/kg to rats of the WK groups, or the groups with herbs of jianpiyiqi, yangxuehuoxue and qingrejiedu, 10 mL/kg was separately administered to each group every day. For the group with CBP capsules, medicine was dissolved with water and doses 15 times of human therapeutic dose were administered (10 mL/kg solution containing 0.35% CBP). Rats of other groups were fed with physiological saline (10 mL/kg every day). Administration lasted for 16 d. Rats were killed on d 22 after mold making to observe changes of gastric mucosa. The mucus thickness of gastric mucosa surface was measured. Levels of epidermal growth factor (EGF) in gastric juice, nitric oxide (NO) in gastric tissue, endothelin (ET) in plasma, superoxide dismutase (SOD) in plasma, malondialdehyde (MDA) in plasma and prostaglandin I(2) (PGI(2)) were examined.. Compared with control group, ulceration was found in gastric mucosa of model group rats. The mucus thickness of gastric mucosa surface, the levels of EGF, NO, 6-K-PGF(1)alpha and SOD decreased significantly in the model group (EGF: 0.818+/-0.18 vs 2.168+/-0.375, NO: 0.213+/-0.049 vs 0.601+/-0.081, 6-K-PGF(1)alpha: 59.7+/-6.3 vs 96.6+/-8.30, SOD: 128.6+/-15.0 vs 196.6+/-35.3, P<0.01), the levels of ET (179.96+/-37.40 vs 46.64+/-21.20, P<0.01) and MDA (48.2+/-4.5 vs 15.7+/-4.8, P<0.01) increased. Compared with model group, the thickness of regenerative mucosa increased, glandular arrangement was in order, and cystic dilative glands decreased, while the mucus thickness of gastric mucosa surface increased (20 g/kg WK: 51.3+/-2.9 vs 23.2+/-8.4, 10 g/kg WK: 43.3+/-2.9 vs 23.2+/-8.4, 5 g/kg WK: 36.1+/-7.2 vs 23.2+/-8.4, jianpiyiqi: 35.4+/-5.6 vs 23.2+/-8.4, yangxuehuoxue: 33.1+/-8.9 vs 23.2+/-8.4, qingrejiedu: 31.0+/-8.0 vs 23.2+/-8.4 and CBP: 38.2+/-3.5 vs 23.2+/-8.4, P<0.05-0.01). The levels of EGF (20 g/kg WK: 1.364+/-0.12 vs 0.818+/-0.18, 10 g/kg WK: 1.359+/-0.24 vs 0.818+/-0.18, 5 g/kg WK: 1.245+/-0.31 vs 0.818+/-0.18, jianpiyiqi: 1.025+/- 0.45 vs 0.818+/-0.18, yangxuehuoxue: 1.03+/-0.29 vs 0.818+/-0.18, qingrejiedu: 1.02+/-0.47 vs 0.818+/-0.18 and CBP: 1.237+/-0.20 vs 0.818+/-0.18, P<0.05-0.01), NO (20 g/kg WK: 0.480+/-0.026 vs 0.213+/-0.049, 10 g/kg WK: 0.390+/-0.055 vs 0.213+/-0.049, 5 g/kg WK: 0.394+/-0.026 vs 0.213+/-0.049, jianpiyiqi: 0.393+/-0.123 vs 0.213+/-0.049, yangxuehuoxue: 0.463+/-0.077 vs 0.213+/-0.049, qingrejiedu: 0.382+/-0.082 vs 0.213+/-0.049 and CBP: 0.395+/-0.053 vs 0.213+/-0.049, P<0.05-0.01), 6-K-PGF(1)alpha (20 g/kg WK: 86.8+/-7.6 vs 59.7+/-6.3, 10 g/kg WK: 77.9+/-7.0 vs 59.7+/-6.3, 5 g/kg WK: 70.0+/-5.4 vs 59.7+/-6.3, jianpiyiqi: 73.5+/-12.2 vs 59.7+/-6.3, yangxuehuoxue: 65.1+/-5.3 vs 59.7+/-6.3, qingrejiedu: 76.9+/-14.6 vs 59.7+/-6.3, and CBP: 93.7+/-10.7 vs 59.7+/-6.3, P<0.05-0.01) and SOD (20 g/kg WK: 186.4+/-19.9 vs 128.6+/-15.0, 10 g/kg WK: 168.2+/-21.7 vs 128.6+/-15.0, 5 g/kg WK: 155.6+/-21.6 vs 128.6+/-15.0, jianpiyiqi: 168.0+/-85.3 vs 128.6+/-15.0, yangxuehuoxue: 165.0+/-34.0 vs 128.6+/-15.0, qingrejiedu: 168.2+/-24.9 vs 128.6+/-15.0, and CBP: 156.3+/-18.1 vs 128.6+/-15.0, P<0.05-0.01) significantly increased. The levels of ET (20 g/kg WK: 81.30+/-17.20 vs 179.96+/-37.40, 10 g/kg WK: 83.40+/-25.90 vs 179.96+/-37.40, 5 g/kg WK: 93.87+/-20.70 vs 179.96+/-37.40, jianpiyiqi: 130.67+/-43.66 vs 179.96+/-37.40, yangxuehuoxue: 115.8. WK decoction and separated recipes have significantly protective effect on ethanol-induced gastric mucosal injury. They can increase the content of EGF in gastric juice, PGI(2) SOD in plasma and NO in gastric tissues, thicken the mucus on the gastric mucosa, and decrease the impairing factor MDA, ET in plasma.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Drugs, Chinese Herbal; Endothelins; Epidermal Growth Factor; Female; Gastric Juice; Gastric Mucosa; Male; Malondialdehyde; Nitric Oxide; Rats; Rats, Wistar; Stomach Ulcer; Superoxide Dismutase

The purpose of the present study was to prepare multivesicular liposomes with a high drug loading capacity and to investigate its potential applicability in the oral delivery of a peptide, human epidermal growth factor (rhEGF). The multivesicular liposomes containing rhEGF was prepared by a two-step water-in-oil-in-water double emulsification process. The loading efficiency was increased as rhEGF concentration increased from 1 to 5 mg/mL, reaching approximately 60 % at 5 mg/mL. Approximately 47% and 35% of rhEGF was released from the multivesicular liposomes within 6 h in simulated intra-gastric fluid (pH 1.2) and intra-intestinal fluid (pH 7.4), respectively. rhEGF-loaded multivesicular liposomes markedly suppressed the enzymatic degradation of the peptide in an incubation with the Caco-2 cell homogenate. However, the transport of rhEGF from the multivesicular liposomes to the basolateral side of Caco-2 cells was two times lower than that of the rhEGF in aqueous solution. The gastric ulcer healing effect of rhEGF-loaded multivesicular liposomes was significantly enhanced compared with that of rhEGF in aqueous solution; the healing effect of the liposomes was comparable to that of the cimetidine in rats. Collectively, these results indicate that rhEGF-loaded multivesicular liposomes may be used as a new strategy for the development of an oral delivery system in the treatment of peptic ulcer diseases.

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Biological Availability; Caco-2 Cells; Disease Models, Animal; Drug Delivery Systems; Drug Stability; Epidermal Growth Factor; Ethanol; Gastric Mucosa; Humans; Hydrogen-Ion Concentration; Liposomes; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Stomach Ulcer; Time Factors

In this study, dexamethasone-induced gastric lesions were studied in rats that had undergone sialoadenectomy. The ultrastructural changes developed during the study were detected by electron microscopically, while blood serum and stomach epidermal growth factor (EGF) concentrations were measured by RIA. The result of the study showed that gastric lesions were correlated with gastric mucus secretion and both serum and mucosa EGF levels. After the administration of dexamethasone, it was found that sialoadenectomy significantly (p<0.01) raised the incidence of stomach lesions (p<0.01), and a significant increase in mucus secretion was also found. Additionally, the serum and gastric mucosal EGF levels fell after sialoadenectomy when compared to normal rats. The most important gastric mucosal changes were observed in rats treated with dexamethasone and those both sialoadenectomised and treated with dexamethasone.

Topics: Animals; Anti-Inflammatory Agents; Dexamethasone; Epidermal Growth Factor; Gastric Mucosa; Mucus; Rats; Rats, Sprague-Dawley; Salivary Glands; Stomach Ulcer

To explore the regularity of multi-meridians controlling a same viscus (MMCSV).. The rabbit gastric ulcer model was established by ethanol intragastric instillation. Fifty-six rabbits were randomly divided into normal group, model group (MG), model plus acupuncture at Foot Yangming Meridian group (YMG), model plus acupuncture at Foot Taiyin Meridian group (TYG), model plus acupuncture at Foot Shaoyang Meridian group (SYG), model plus acupuncture at Foot Jueyin Meridian group (JYG), model plus acupuncture at Foot Taiyang Meridian group (TYMG), with eight rabbits in each group. Gastric mucosal nitric oxide (NO) and nitric oxide synthase (NOS) were assayed by the nitric acid reductase method, and prostaglandin E2 (PGE2) and epidermal growth factor (EGF) were measured by radioimmunoassay. The comprehensive effects were analyzed by weighing method.. Compared to MG, SYG, JYG and TYMG, the rabbits gastric mucosal injury index (GMII) reduced very significantly in YMG (P<0.01). Compared to MG, the GMII also reduced significantly in TYG (P<0.05). NO, NOS, PGE2 and EGF increased very significantly in YMG (P<0.01). The EGF in YMG also increased significantly than that in TYG compared to those in MG, SYG, JYG and TYMG (P<0.05). The PGE2 and EGF also increased very significantly in TYG than those in MG, JYG and TYMG (P<0.01). While compared to SYG, the NOS increased significantly in TYG (P<0.05). NOS was the highest in YMG (P<0.01), and was higher in TYG than in MG (P<0.01).. MMCSV is common. The Foot Yangming Meridian is most closely related to the stomach, followed by Foot Taiyin Meridian, Foot Shaoyang Meridian and Foot Jueyin Meridian. Foot Taiyang Meridian has no correlation with the stomach.

Topics: Acupuncture; Animals; Dinoprostone; Epidermal Growth Factor; Gastric Mucosa; Nitric Oxide; Nitric Oxide Synthase; Rabbits; Stomach Ulcer

We investigated the antiulcerogenic activity of pyrrolizidine alkaloids (PAs) integerrimine, retrorsine, senecionine, usaramine and seneciplhylline, an alkaloidal extract obtained from Senecio brasiliensis. The PA extract demonstrated significantly activity in both, acute and chronic gastric ulcers on rats. The effects of PA extract were dose dependent. The mechanisms implicated on this activity were evaluated by determination of gastrin plasma levels in rats subjected to the acute treatment with PA extract and by expression of mRNA of Epidermal Growth Factor (EGF) after chronic treatment with this extract. The results showed that the PA extract increased both the levels of gastrin and the expression of EGF on these animals. Moreover, the histological examinations showed a reduction of exfoliation of superficial cells, hemorrhages and blood cell infiltration. We concluded that the PAs showed an important and qualitative antiulcerogenic activity mediated by increase in gastrin secretion and mRNA expression of EGF.

Topics: Animals; Dose-Response Relationship, Drug; Epidermal Growth Factor; Gastrins; Male; Mice; Plant Extracts; Pyrrolizidine Alkaloids; Rats; Senecio; Stomach Ulcer

To study the therapeutic mechanism of weitongning (WTN) in treating peptic ulcer.. Rat model of chronic gastric ulcer induced by glacial acetic acid was used to observe the effect of WTN on the curative quality, thickness of regenerated mucous membrane, epidermal growth factor (EGF) and nitric oxide (NO) contents in scar tissue around the gastric ulcer.. The thickness of regenerated mucous membrane, EGF and NO contents in peri-ulcer scar tissue were higher in the model rats after WTN treatment than that in the untreated model rats (P<0.01 or P<0.05).. WTN could elevate the quality of ulcer curing, to raise the EGF and NO contents in peri-ulcer scar tissue might be one of its mechanisms for preventing relapse of peptic ulcer.

Topics: Animals; Anti-Ulcer Agents; Drugs, Chinese Herbal; Epidermal Growth Factor; Female; Gastric Mucosa; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley; Stomach Ulcer

To observe the effect of Chinese drugs of Jianpi Huayu (JPHY, strengthening Pi and dissolving stasis) on healing quality of gastric ulcer and its mechanism.. The gastric ulcer model was established by subserous injection of ethanoic acid in rats. Rats were randomly divided into 4 groups, the blank group, the model group, the ranitidine (RT) group and the JPHY group. Quantity of regenerative mucosa of healed gastric ulcer was determined using HE stain, epidermal growth factor (EGF) content in serum and stomach mucosa was detected by RIA and epidermal growth factor receptor (EGFR) protein expression was determined by immunohistochemistry.. Thickness of regenerated mucosa in the CHM group was higher than that in the model group and the RT group (P<0.05 or P<0.01); EGF content in mucosa in the JPHY group and the RT group was higher than that in the model group (P<0.01) and EGFR protein expression in the JPHY group was higher than that in the model group (P<0.05).. JPHY could improve the proliferation of epithelial cells, inhibit gastric acid, improve microcirculation of gastric mucosa through the mediation of EGFR, so as to elevate the healing quality of gastric ulcer, display its anti-ulcer action.

Topics: Acetic Acid; Animals; Anti-Ulcer Agents; Drugs, Chinese Herbal; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Male; Random Allocation; Rats; Rats, Wistar; Stomach Ulcer

The present study was to investigate the feasibility of oral delivery of recombinant human epidermal growth factor (rhEGF). Polyethylene glycol (PEG)-coated liposomes containing rhEGF was prepared and evaluated for their stability and permeability in Caco-2 cells. In the animal study, we also determined plasma concentration and gastric ulcer healing effect after oral administration of rhEGF liposomes or the solution. Encapsulation of rhEGF into liposomes, suppressed the degradation in Caco-2 cell homogenate compared with the solution. The flux of rhEGF from dipalmitoylphosphatidylcholine (DPPC) liposome across Caco-2 cell monolayer from the apical to basolateral side was three times greater than that from phosphatidylcholine (PC) liposome or the solution. After oral administration of rhEGF liposomes or the solution in rats, the area under the concentration-time curve (AUC) of rhEGF increased 1.7- and 2.5-fold for PC and DPPC liposomes, respectively. The gastric ulcer healing effect was significantly increased in DPPC liposome compared with PC liposome and the solution. The enhanced curative ratio of rhEGF encapsulated into DPPC liposome may be due to the resistance to enzyme degradation, higher permeability and increased plasma AUC. Therefore, PEG-coated liposomes containing rhEGF could be used as an oral delivery formulation with enhanced encapsulation efficiency.

Topics: Acute Disease; Administration, Oral; Animals; Area Under Curve; Biological Transport; Caco-2 Cells; Cell Membrane Permeability; Drug Compounding; Drug Delivery Systems; Drug Stability; Epidermal Growth Factor; Epithelial Cells; Feasibility Studies; Gastric Mucosa; Humans; Liposomes; Male; Particle Size; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Stomach Ulcer; Time Factors

The effects of intragastric (i.g.) administration of microemulsion formulation of epidermal growth factor (EGF) on the healing of acute gastric ulcers induced by cold-restraint stress in rats was studied and compared with intraperitoneal (i.p.) administration of solutions. In the microemulsion formulation (W/O), labrafil M 1944 CS was the oil phase. Arlacel 186 and Brij 35 were used as the surfactants. Absolute alcohol and distilled water were used as the co-surfactant and the aqueous phase, respectively. Acute gastric lesions were induced by cold-restraint stress for 4 h in the refrigerator (4.0+/-0.5 degrees C). EGF was administered at a dose of 6 microg/kg per day intraperitoneally and intraperitoneally for 7 days. Basal gastric acid secretion (microequiv. H+/30 min), ulcer score (mm(2)) and tissue mucus levels (microg/g tissue) were measured. Basal gastric secretion was significantly reduced after the administration of EGF microemulsion (ME+EGF) (P<0.05). There was no significant decrease in basal gastric acid secretion following i.p (IPEGF) and i.g (IG-EGF) of EGF administrations of solutions compared to their control groups (P>0.05). The results indicate that the highest reduction in the basal acid secretion was seen after the administration of a microemulsion of EGF formulation. The mean ulcer score was reduced by i.g treatment with the microemulsion dosage form of EGF in 7 days from 15.9+/-1.4 to 1.16+/-0.45 mm(2) and was almost completely healed in four of the animals. The results demonstrate that the ulcer score was significantly reduced in i.p. (IPEGF) solution (P<0.005), i.g (IG-EGF) solution (P<0.01) and i.g. microemulsion (ME+EGF) (P<0.01) treated groups compared to untreated group. In IG-EGF, ME+EGF treated groups, mucus levels increased significantly compared to their control groups(P<0.05 and P<0.01). In contrast, there was no significant change in the mucus levels following i.p. EGF administration (P>0.05).

Topics: Animals; Chemistry, Pharmaceutical; Drug Carriers; Emulsions; Epidermal Growth Factor; Female; Gastric Mucosa; Microspheres; Rats; Rats, Wistar; Stomach Ulcer; Stress, Physiological

We investigated the role of epidermal growth factor (EGF) microemulsion (ME) formulation on stress ulcer healing and the levels of gastric mucosal malondialdehyde (MDA) and glutathione (GSH).. Forty-eight female Wistar rats were divided into five groups according to the treatments given. Ten rats were given intragastric (i.g.) serum physiologic (SP) for 7 days; ten rats were given i.g. ME for 7 days; ten rats were given i.g. EGF in SP 6 microg/kg per day for 7 days; ten rats were given i.g. ME + EGF (Sigma E-7755) 6 microg/kg per day for 7 days; and eight rats were exposed to cold and immobilization stress or no stress (NS), and not given any treatment, as controls. The mean ulcerated area, and the MDA and GSH levels of the gastric mucosa were measured.. The mean ulcerated area of the ME+EGF treatment group was significantly less than that of the ME- and EGF-treated groups and the control groups. The gastric MDA levels were also found to be significantly lower in the ME+EGF treated group than in the ME-treated group or the control groups. However, there were no significant changes in the gastric GSH levels among all the groups. The gastric MDA levels were positively correlated with the ulcerated area.. The ME formulation of EGF at the dose given in this study was more effective than EGF alone on the healing of stress ulceration of the gastric mucosa.

Topics: Animals; Epidermal Growth Factor; Female; Gastric Mucosa; Glutathione; Malondialdehyde; Rats; Rats, Wistar; Stomach Ulcer

Gastrin, PGs, and growth factors have important roles in maintaining gastrointestinal mucosal integrity. Cyclooxygenases (COX-1 and COX-2) are the key enzymes involved in PG synthesis. This study aimed to clarify the mechanisms of gastric mucosal protection by gastrin. Fasted rats were administered subcutaneous gastrin 17 with or without gastrin receptor antagonist YM022 pretreatment. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and COX-2 expression were examined using Western blot analysis. Another series of experiments investigated 1) PGE(2) levels in gastric mucosa, 2) the protective action of gastrin against gastric damage by acidified ethanol, 3) the effects of a specific HB-EGF-neutralizing antibody on gastrin-induced COX-2 expression, and 4) the effects of a specific COX-2 inhibitor NS-398 on PGE(2) synthesis and the mucosal protection afforded by gastrin. Gastrin dose-dependently increased HB-EGF, COX-2 expression, and PGE(2) levels and reduced gastric damage. However, pretreatment with YM022 dose-dependently abolished such effects of gastrin. A specific HB-EGF- neutralizing antibody and an EGF receptor inhibitor decreased gastrin-induced COX-2 expression. NS-398 blocked gastrin-induced PGE(2) synthesis and mucosal protection. In conclusion, this study demonstrates that gastrin enhances gastric mucosal integrity through COX-2, which is partially mediated by HB-EGF, and PGE(2) upregulation in rats.

Topics: Animals; Antibodies; Blotting, Western; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Epidermal Growth Factor; Ethanol; Gastric Mucosa; Gastrins; Heparin-binding EGF-like Growth Factor; Hepatocyte Growth Factor; Hydrogen-Ion Concentration; Immunoenzyme Techniques; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Isoenzymes; Male; Membrane Proteins; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Sulfonamides

A crude extract from Angelica sinensis (ASCE), which mainly consists of polysaccharides, prevents ethanol- or indomethacin-induced gastric mucosal damage and promotes ulcer healing. The aim of this study was to test the hypothesis that ASCE has a direct stimulating effect on gastric epithelial cells for wound healing. We found that ASCE significantly promoted the migration of epithelial cells over an artificial wound on the surface of an RGM-1 monolayer. The extract also stimulated DNA synthesis in a dose-dependent manner and concomitantly increased EGF mRNA expression. Co-incubation of ASCE with anti-EGF antibody reduced the speed of migration and the DNA synthesis, which however were still higher than the control without ASCE. These results strongly suggest that ASCE has a direct wound healing effect on gastric mucosa, and this is acting partially through an EGF-mediated pathway.

Topics: Animals; Antibodies; Cell Culture Techniques; Cell Division; Cell Movement; Dose-Response Relationship, Drug; Epidermal Growth Factor; Epithelial Cells; Gastric Mucosa; Gastrointestinal Agents; Plant Extracts; Plant Roots; Plants, Medicinal; Polysaccharides; RNA, Messenger; Stomach Ulcer; Thymidine; Wound Healing

Biodegradable microspheres containing recombinant human epidermal growth factor (rhEGF) were prepared using poly(L-lactic acid) by a solvent evaporation method based on multiple w/o/w emulsion. Encapsulation efficiency and initial release were influenced by the amount of polymer, inner water phase volume and osmotic pressure difference between inner water phase and outer water phase. The effect of osmotic pressure difference between inner water phase and outer water phase in w/o/w emulsion on particle size, porosity and in vitro release of rhEGF from microspheres were also studied. Microspheres prepared with the optimized osmotic pressure, polymer amount and inner water volume produced 21% initial release on the first day with 92% encapsulation efficiency. The blood concentration of rhEGF was maintained at constant levels for 9-11 days after a single subcutaneous (s.c.) administration of rhEGF microspheres. The gastric ulcer healing effect of a single s.c. administration of rhEGF microspheres was increased 1.44-fold compared with twice a day s.c. administration of rhEGF saline solution after 11 days. The enhanced curative ratio of rhEGF loaded microspheres may be due to the optimized osmotic pressure, high encapsulation efficiency and sustained release pattern.

Topics: Animals; Chronic Disease; Epidermal Growth Factor; Lactic Acid; Male; Microscopy, Electron, Scanning; Microspheres; Osmotic Pressure; Particle Size; Polyesters; Polymers; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Stomach Ulcer

Cigarette smoking is associated with peptic ulcer diseases. Smokers have lower levels of salivary epidermal growth factor (EGF) than nonsmokers. We investigated whether reduction of EGF is involved in the delay of gastric ulcer healing by cigarette smoking. Rats with acetic acid-induced ulcers were exposed to cigarette smoke (0, 2, or 4% vol/vol) 1 day after ulcer induction. EGF level was elevated 1 day after ulcer induction in salivary glands and serum, and 4 days after ulcer induction in the gastric mucosa. However, cigarette smoke depressed these beneficial effects and EGF mRNA expression in salivary glands and gastric mucosa. Cigarette smoke delayed gastric ulcer healing and reduced cell proliferation, angiogenesis, and mucus synthesis. Exogenous EGF (10 and 20 microg/kg i.v.) before smoke exposure reversed the adverse effects of cigarette smoke, whereas vascular endothelial growth factor level and nitric oxide synthase activity were unaffected. It is concluded that the detrimental effect of cigarette smoke on ulcer healing is a consequence of reduction of angiogenesis, cell proliferation, and mucus secretion through the depressive action on EGF biosynthesis and its mRNA expression in salivary glands and gastric mucosa.

Topics: Animals; Endothelial Growth Factors; Epidermal Growth Factor; Gastric Mucosa; Lymphokines; Male; Mucus; Neovascularization, Physiologic; Nitric Oxide Synthase; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; RNA, Messenger; Salivary Glands; Smoking; Stomach Ulcer; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Wound Healing

Experimental gastric ulcers are rapidly colonized by various bacteria, resulting in significantly impaired healing. Epidermal growth factor (EGF) is capable of preventing bacterial colonization of the healthy intestinal mucosa. In this study, we examined the possibility that EGF accelerates gastric ulcer healing by reducing bacterial colonization of the ulcer. Gastric ulcers were induced by serosal application of acetic acid. The effect of daily administration of EGF on ulcer healing and bacterial colonization was assessed and compared with the effect of daily treatment with broad-spectrum antibiotics. EGF administration reduced colonization levels and accelerated ulcer healing as effectively as the antibiotic treatment. EGF was without effect on acid secretion or neutrophil infiltration into the ulcer. Bacterial growth was not inhibited in the presence of EGF in vitro. These results demonstrate that EGF reduces bacterial colonization during an established infection of a compromised mucosal surface. This effect may contribute to the ability of EGF to accelerate gastric ulcer healing. This effect is acid independent and not due to an anti-inflammatory effect or to direct bactericidal actions.

Topics: Administration, Oral; Animals; Bacteria; Colony Count, Microbial; Epidermal Growth Factor; Gastric Acid; Male; Microscopy, Electron; Peroxidase; Rats; Rats, Wistar; Stomach Ulcer; Wound Healing

Accumulating evidence indicates that capsaicin sensitive afferent fibers play a pivotal role not only in gastroprotection but also in ulcer healing. Denervation of capsaicin sensitive afferent fibers exerts an adverse action on these effects. However, whether such an action is mediated through a depression on epidermal growth factor (EGF) is undefined. In this study, the effects of denervation of sensory neurons with capsaicin (100 mg/kg, s.c.) on acetic acid-induced chronic gastric ulcers and their relationship with the EGF expression in salivary glands, serum and gastric mucosa were investigated. Capsaicin significantly increased ulcer size, decreased gastric mucosal cell proliferation at the ulcer margin, angiogenesis in the granulation tissue and also gastric mucus content. Ulcer induction by itself dramatically elevated EGF levels in salivary glands and serum on day 1 and 4, and also in the gastric mucosa on day 4. However, capsaicin completely abolished these effects. It is concluded that stimulation of EGF expression in salivary glands and serum may be one of the mechanisms by which capsaicin sensitive nerves contribute to the gastroprotective and ulcer healing actions in the stomach.

Topics: Animals; Capsaicin; Cell Division; Epidermal Growth Factor; Gastric Mucosa; Granulation Tissue; Male; Mucus; Neovascularization, Physiologic; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Salivary Glands; Stomach Ulcer

The healing effect of heparin on gastric ulcer and its underlying mechanisms were studied. The influences of protamine on these effects were also investigated. Gastric ulcer was induced by acetic acid in rats. Heparin (100-1000 U/kg i.v.) was given once daily for 4 or 7 days. Ulcer area was measured; gastric mucosal regeneration, proliferation, and angiogenesis were determined by histological or immunohistochemical methods. Gastric mucosal basic fibroblast growth factor (bFGF) level was assessed by an enzyme-linked immunosorbent assay, and the mucosal epidermal growth factor (EGF) level and nitric oxide synthase (NOS) activity were measured by radioimmunoassay. The anticoagulant action of heparin was determined by the duration of bleeding time. The results showed that heparin given for 4 or 7 days significantly accelerated gastric ulcer healing in a dose-dependent manner. The three doses of heparin significantly stimulated mucosal regeneration and proliferation as well as angiogenesis but not the contraction of ulcer base. Similar effects were observed in gastric mucosal bFGF and EGF levels and constitutive NOS activity. Protamine not only abolished the anticoagulant action of heparin but also significantly potentiated its effects on ulcer healing, gastric mucosal proliferation, angiogenesis, and constitutive NOS activity. These findings indicate that heparin can accelerate gastric ulcer healing, which is associated with mucosal regeneration, proliferation, and angiogenesis. These actions are likely to be stimulated by bFGF, EGF, and constitutive NOS activity in the gastric mucosa. Protamine potentiates the ulcer-healing effect of heparin, which is probably acting through constitutive NOS activation.

Topics: Acetates; Animals; Anti-Ulcer Agents; Anticoagulants; Blood Coagulation; Cell Division; Epidermal Growth Factor; Epithelial Cells; Fibroblast Growth Factor 2; Gastric Mucosa; Heparin; Heparin Antagonists; Male; Neovascularization, Physiologic; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Protamines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Protamine sulphate has been reported to stimulate nitric oxide production from blood vessels, which is a pivotal factor for gastric ulcer healing. Our preliminary study also showed that protamine sulphate potentiated the ulcer healing effect of heparin.. Male SD rats with acetic acid-induced gastric ulcers were given protamine sulphate (40-80 mg/kg, s.c.) twice daily for 4 or 7 days. L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), an inhibitor of nitric oxide synthase (NOS), was given s.c. prior to protamine sulphate (80 mg/kg) treatment. Ulcer healing, angiogenesis, mucosal histological changes, NOS activity and growth factors were determined.. Protamine sulphate dose-dependently accelerated gastric ulcer healing, which was accompanied by a significant increase in angiogenesis, mucosal regeneration and constitutive NOS activity. Inhibition of gastric secretion was observed. Epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), tumour necrosis factor-alpha (TNF-alpha) or inducible NOS activity was also affected. L-NAME completely blocked the beneficial effects of protamine sulphate.. Protamine sulphate accelerates gastric ulcer healing through a mucosal nitric oxide-dependent and possibly also the EGF-and bFGF-associated pathways, which are followed by an increase of angiogenesis and mucosal regeneration. Acid inhibition contributes in part to the ulcer healing action of protamine sulphate.

Topics: Animals; Cell Division; Enzyme Activation; Epidermal Growth Factor; Fibroblast Growth Factor 2; Gastric Mucosa; Heparin Antagonists; Male; Neovascularization, Pathologic; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Protamines; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Tumor Necrosis Factor-alpha

Fibroblasts (FIB) play an important role in the wound-healing process. It is not known whether human skin and gastric FIB show different responses to regulatory compounds. In this study, we have examined the collagen production by these FIB after different stimuli. In vitro release of collagen into the medium by steady-state confluent human FIB cultures was assessed over a 24-hour period by 3H-proline incorporation into collageneous protein. Serum and epidermal growth factor increased collagen secretion in both types of FIB, but gastric FIB produced less collagen than skin FIB. Prostaglandin E1 inhibited collagen production in both types of FIB, but nonsteroidal anti-inflammatory drugs and interleukin-1beta, a cytokine involved in the wound-healing process, had opposite effects on gastric and skin FIB. The effects of lipoxygenase metabolites on collagen secretion was small, but different in both types of FIB. We conclude that, when compared to skin FIB, human gastric FIB produce less collagen and show pronounced different responses to different agents, which might be relevant to explain (in part) their clinical effects on ulcer healing. These data provide new insights into the wound-healing process.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Collagen; Epidermal Growth Factor; Fibroblasts; Humans; Interleukin-1; Leukotriene C4; Prostaglandins; Stomach Ulcer; Wound Healing

Polyamines such as spermine or putrescine, resulting from increased activity of ornithine decarboxylase (ODC), are known for gastroprotective and mucosal growth promoting effects but little information is available about their role in the acceleration of the healing of stress-induced gastric lesions by epidermal growth factor (EGF). In this study, rats with intact or suppressed ODC activity by alpha-difluoromethylornithine (DFMO, 400 mg/kg i.p.) were subjected to 3.5 h of water immersion and restraint stress (WRS) without or with intragastric (i.g.) administration of spermine and putrescine or with subcutaneous (s.c.) injection of EGF. At 0, 2, 6, 12 and 24 h after stress, rats were killed and the number of gastric lesions was counted, gastric blood flow (GBF) was recorded by the H2-gas clearance technique, the gene expression of ODC mRNA using reverse-transcriptase polymerase chain reaction (RT-PCR) and the ODC activity in this mucosa were determined in oxyntic mucosa. Stress produced gastric lesions combined with decreased GBF (by approximately 43%), but at 2, 6, 12 and 24 h after stress, these lesions and the fall in GBF were gradually attenuated. Healing of stress lesions was accompanied by strong stimulation of ODC mRNA expression and by an immediate increase in enzyme activity, with a peak occurring about 6 h after stress. Pretreatment with DFMO or salivectomy (which resulted in a marked fall in luminal EGF levels and mucosal DNA synthesis) delayed significantly the healing of stress lesions. EGF or spermine significantly accelerated the ulcer healing and raised the GBF. Suppression of endogenous generation of prostaglandins (PGs) with indomethacin (5 mg/kg i.p.) almost completely reversed the EGF- and spermine-induced acceleration of the healing of stress lesions and the accompanying rise in GBF. DFMO significantly reduced the enhancement in healing and the rise in the GBF induced by EGF, but failed to influence those induced by exogenous spermine. The acceleration of the healing induced by spermine or EGF and accompanying hyperemia were not affected by salivectomy. We conclude that (1) upregulation of the ODC transcript, increased ODC activity and polyamines play an important role in mucosal recovery from stress lesions due to acceleration of mucosal repair and an increase in gastric microcirculation, (2) increased ODC activity and resulting excessive polyamine release appear to act as primary mediators of EGF-induced acceleration of healing of st

Topics: Animals; Anti-Ulcer Agents; Eflornithine; Enzyme Inhibitors; Epidermal Growth Factor; Gastric Mucosa; Indomethacin; Male; Ornithine Decarboxylase; Putrescine; Rats; Rats, Wistar; RNA, Messenger; Salivary Glands; Spermine; Stomach Ulcer; Stress, Psychological; Wound Healing

Rebamipide (Mucosta) is a novel mucosal protective and ulcer-healing drug. Clinical and experimental data indicate that it accelerates ulcer healing and improves the quality of the scar. Since epidermal growth factor (EGF) and its receptor (EGF-R) play important roles in mucosal protection and ulcer healing, we studied whether rebamipide treatment affects expression of EGF and EGF-R in normal and ulcerated gastric mucosa in rats. Forty-eight male rats without or with gastric ulcers (induced by acetic acid) received intragastrically either placebo or rebamipide, 40 mg twice daily, for 14 days. Ulcer size was measured under a dissecting microscope; mucosal sections were stained with H&E or immunostained with specific antibodies against EGF and EGF-R. The distribution and intensity of fluorescence signal was quantified using a video image system. Rebamipide significantly accelerated ulcer healing, produced a significant increase in EGF and EGF-R expression in normal gastric mucosa (both P < 0.001), and increased expression of EGF and EGF-R in regenerating glands of the ulcer scar. Since EGF and its receptor are crucial for epithelial cell proliferation, re-epithelialization, and gland reconstruction, the above actions of rebamipide may provide a new mechanism for its ulcer healing action.

Topics: Alanine; Animals; Anti-Ulcer Agents; Disease Models, Animal; Epidermal Growth Factor; ErbB Receptors; Fluorescent Antibody Technique; Gene Expression Regulation; Male; Quinolones; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Polyamines such as spermine or putrescine, resulting from increased activity of ornithine decarboxylase (ODC), are known for gastroprotective and mucosal growth-promoting effects. EGF exhibits similar effects, but little is known about the involvement of polyamines in acceleration of the healing of stress-induced gastric lesions by epidermal growth factor (EGF). In this study, rats with intact or suppressed ODC activity by alpha-difluoromethy-ornithine (DFMO, 400 mg/kg i.p.) were subjected to 3.5 h of water immersion and restraint stress (WRS) without or with addition of spermine or EGF. At 0, 2, 6, 12, or 24 h after stress, rats were sacrificed. The number of gastric lesions was determined and gastric blood flow (GBF) was recorded by the H2 gas clearance technique. Stress produced gastric lesions (mean number 18+/-2 per stomach) and decreased GBF (by approximately 43%), but at 2, 6, 12, and 24 h after stress, these lesions and the decrease in GBF were gradually attenuated. Pretreatment with DFMO or removal of an endogenous source of EGF by salivectomy resulted in a marked decrease in mucosal DNA synthesis and significantly delayed the healing of stress lesions. EGF or spermine significantly accelerated ulcer healing and increased the GBF in rats with intact or removed salivary glands. DFMO significantly reduced the enhancement of healing and the increase in GBF induced by EGF, but failed to influence those induced by exogenous spermine. We conclude that polyamines play an important role in mucosal recovery from stress lesions due to acceleration of mucosal repair and increase in gastric microcirculation and that increased ODC activity and resulting excessive polyamine release appear to act as primary mediators of EGF-induced acceleration of the healing of stress lesions.

Topics: Animals; Eflornithine; Enzyme Inhibitors; Epidermal Growth Factor; Gastric Mucosa; Male; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Putrescine; Rats; Rats, Wistar; Spermine; Stomach Ulcer; Stress, Physiological

MS-818 is a novel synthetic pyrimidine compound that stimulates nerve regeneration and promotes synthesis of various growth factors and differentiation of astrocytes. Effects of MS-818 on gastric epithelial cells were assessed using a wound repair model with primary cultured gastric epithelial cells from rabbits. A round wound with a constant cell-free area was created and the process of restoration was monitored by measuring wound size every 12 h. Cell proliferation was monitored by sequential staining with BrdU. As previously reported, EGF (10 ng/ml) accelerated wound repair by promoting cell migration and proliferation. Although MS-818 alone had no effects, MS-818 (10-100 microM) enhanced EGF-induced acceleration of gastric epithelial restoration, including cell migration and proliferation. Although the detailed mechanism of action of this agent is still unclear, MS-818 might have favorable effects on in vivo gastric mucosal repair.

Topics: Animals; Cell Division; Cell Movement; Cells, Cultured; Drug Synergism; Epidermal Growth Factor; Gastric Mucosa; Male; Neuroprotective Agents; Pyrimidines; Rabbits; Stomach Ulcer; Wound Healing

Growth factors such as epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) have been shown to share common receptor (EGFR) and to accelerate ulcer healing due to stimulation of cell proliferation, but the time sequence of expression of EGF and TGF alpha during ulcer healing has not been investigated. In this study the rate of cell proliferation and the gastric secretion and gene expression of mRNA for EGF and TGF alpha were determined during ulcer healing.. Gastric ulcers were induced in 150 Wistar rats by serosal application of 100% acetic acid (ulcer area, 14 mm2). Some of these animals were also equipped with a gastric fistula for the assessment of gastric secretion during ulcer healing. The animals were killed 0, 2, 4, 6, or 8 days after ulcer induction, and the ulcer area was determined. The mucosal sections with gastric ulcer were immunostained for proliferating cell nuclear antigen (PCNA) and for immunoexpression of EGF, TGF alpha, and EGFR. The expression of mRNA EGF and mRNA TGF alpha was also determined in the ulcer margin by reverse transcriptase (RT) polymerase chain reaction (PCR) using specific primers.. Two, 4, 6, and 8 days after ulcer induction the gastric ulcer area was gradually reduced from the initial size (day 0) by 47%, 70%, 80%, and 87%, respectively, and this was accompanied by an increase in PCNA with its maximum on day 4. The gastric acid and pepsin secretion was significantly reduced by 75% and 79%, respectively, on day 2 after ulcer induction but then the secretion tended to return to normal value by day 8. The expression of EGF, TGF alpha, and EGFR was negligible on day 0 but increased significantly during the healing, reaching maximum on day 4. Expression of EGF mRNA was detected on days 2, 4, and 6, and that of TGF alpha mRNA on days 2, 4, 6, and 8 after ulcer induction, with the most intense signals for both transcripts observed on day 2.. 1) The enhancement in cell proliferation during ulcer healing may be mediated by increased release of EGF and TGF alpha; 2) the expression of EGF and TGF alpha mRNA precedes the overexpression of these growth factors at the ulcer margin during ulcer healing; and 3) the overexpression of growth factors coincides with the inhibition of gastric secretion and increased blood flow at the ulcer margin, indicating that these factors affect gastric secretion and blood flow in the course of ulcer healing.

Topics: Animals; Cell Division; Epidermal Growth Factor; ErbB Receptors; Female; Gastric Acid; Gastrins; Gene Expression; Immunohistochemistry; Male; Rats; Rats, Wistar; Regional Blood Flow; RNA, Messenger; Stomach; Stomach Ulcer; Time Factors; Transforming Growth Factor alpha; Wound Healing

Expression of members of the epidermal growth factor family, including epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), amphiregulin (AR), and Cripto, as well as their putative receptor, epidermal growth factor receptor (EGFR), was studied immunohistochemically in human gastric mucosa to evaluate their possible roles in cell proliferation of normal and regenerative gastric mucosa. We also examined the correlation betwen cell proliferation and EGFR by double immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and EGFR. In normal gastric mucosa, TGF-alpha, Cripto, and AR immunoreactivities were observed in the surface epithelial and parietal cells of gastric fundic glands, respectively. EGF immunoreactivity was not observed in any of normal mucosa examined. EGFR immunoreactivity was detected on foveolar cells in proliferative zones and in parietal cells. Double immunostaining revealed that EGFR immunoreactivity was distributed much more widely than PCNA immunoreactivity. PCNA positive epithelial cells adjacent to gastric ulcer margin expressed relatively intense EGFR but did not express any of the growth factors examined. On the other hand, relatively intense immunoreactivity of both TGF-alpha and Cripto was detected in PCNA-negative regenerative epithelium located distant from gastric ulcer margin. Relative immunoreactivity of AR in regenerative gastric epithelium associated with ulcer was not different from that in normal gastric mucosa. TGF-alpha, AR, and Cripto are considered to play important roles in normal gastric mucosal proliferation, and TGF-alpha and Cripto may be involved in ulcer healing, possibly via a paracrine mechanism.

Topics: Amphiregulin; Cell Division; EGF Family of Proteins; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Glycoproteins; GPI-Linked Proteins; Growth Substances; Humans; Immunoenzyme Techniques; Intercellular Signaling Peptides and Proteins; Membrane Glycoproteins; Neoplasm Proteins; Parietal Cells, Gastric; Proliferating Cell Nuclear Antigen; Stomach Ulcer; Transforming Growth Factor alpha; Wound Healing

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

Epidermal growth factor (EGF) is a potent mitogen implicated in gastroprotection and ulcer healing, but its possible interaction with nitric oxide (NO) and sensory nerves on healing after acute gastric damage has not been assessed. We examined the effects of topical application of a small dose (0.5 mg/kg) of capsaicin to stimulate sensory nerves and a larger parenteral dose of capsaicin (125 mg/kg s.c.) to deactivate these neurons or the effect of systemic administration of NG-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg i.v.) to suppress NO synthase on healing of gastric lesions induced by 3.5 h of water immersion and restraint stress (WRS) in rats without or with EGF administration. Rats were sacrificed at 0, 6, 12, or 24 h after WRS and the gastric blood flow (GBF) was measured by the H2 gas clearance technique. Exposure to WRS produced many gastric lesions, with a marked decrease in GBF, but at 12 h these lesions started to heal and the lesion number was reduced by 75% after 24 h. This was accompanied by progressive increase in the GBF and an increase in expression of EGF mRNA in gastric mucosa, as detected by RT-PCR. Pretreatment with L-NAME or functional ablation of sensory nerves by capsaicin significantly delayed the healing of WRS lesions and accompanying hyperemia. In contrast, pretreatment with EGF (100 micrograms/kg s.c.) or glyceryl trinitrate (10 mg/kg i.g.), a donor of NO, or stimulation of sensory nerves by topical capsaicin significantly enhanced the healing of these lesions and increased the GBF. The acceleration of the healing and accompanying hyperemia induced by EGF at 12 h after WRS were completely reversed in rats pretreated with L-NAME or in those with capsaicin denervation. Addition of L-arginine but not D-arginine to L-NAME restored the healing of stress lesions and gastric hyperemia induced by this peptide. Removal of salivary glands, which reduced luminal content of EGF and DNA synthesis by about fourfold compared to rats with intact glands, produced a significant delay in healing, and this was further aggravated by capsaicin denervation. We conclude that EGF, sensory nerves, and NO play an important role in the healing of gastric mucosa from lesions induced by stress and that sensory nerves and NO appear to interact with EGF in the mechanism of mucosal recovery from stress lesions.

Topics: Animals; Capsaicin; Enzyme Inhibitors; Epidermal Growth Factor; Gastric Mucosa; Immersion; Male; Neurons, Afferent; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; Salivary Glands; Stomach Ulcer; Stress, Physiological; Wound Healing

This study examined the relationship between healing of acetic acid-induced chronic gastric ulcer and connexin formation. In addition, the effect of anti-ulcer drugs on ulcer healing and the presence of connexin was investigated. In a rat model, acetic acid-induced gastric ulcers were healed without administration of drugs after 14 days. Appearance of an electrophoretic connexin 32 band was observed 7 days after ulcer induction. Administration of cimetidine (3 mg/day) promoted ulcer healing, i.e., ulcers were healed 12 days after ulcer induction, 2 days earlier than the control. The appearance of a connexin 32 band in electrophoresis was observed on the fourth day after ulcer induction. Administration of cimetidine at a higher dose further promoted ulcer healing and the connexin 32 band was more strongly visible. After administration of i.p. 2 nM EGF, acetic acid-induced gastric ulcers were healed 12 days after ulcer induction and the appearance of connexin 32 was observed on the fourth day after induction. These results indicate that connexin 32 is related to the healing of acetic acid-induced gastric ulcers.

Topics: Acetic Acid; Animals; Anti-Ulcer Agents; Chronic Disease; Cimetidine; Connexins; Epidermal Growth Factor; Gap Junction beta-1 Protein; Gastric Mucosa; Male; Rats; Rats, Wistar; Stomach Ulcer; Time Factors

AS101 as a new immunomodulator has been shown to induce production of a variety of cytokines such as interleukin-1, interleukin-2, colony-stimulating factor, interferon-gamma and tumor necrosis factor, and demonstrate a potential chemo-protection from chemotherapy induced immunosuppression and hematopoietic toxicity in tumor bearing mice and cancer patients on phase I and II clinical trials. This study was designed to verify whether AS101 exerts a cytoprotective effect in rats and mice with gastric lesions induced by intragastric (i.g.) instilling of 0.6N hydrochloride (HCl). AS101 given intraperitoniously (i.p) 2h before a HCl administration markedly prevented HCl-induced gastric lesions both in rats and mice. It also accelerated the ulcer repair when given i.p. 1h after a HCl treatment. Indomethacin (IND), a cyclo-oxygenase inhibitor, given i.p. at a non-ulcerogenic dose of 5mg/kg 1h before AS101 administration, abolished its protective effect. Mechanistic analysis showed that the gastric cytoprotective property of AS101 appears to be mediated through the induction of prostaglandin E2 (PGE2) and epidermal growth factor (EGF), of which, both prevent the gastric mucosa from HCl ulceration while EGF also contributes to the promotion of ulcer repair. This study adds another cytoprotective property to the known immunomodulating role of AS101.

Topics: Adjuvants, Immunologic; Animals; Dinoprostone; Dose-Response Relationship, Drug; Epidermal Growth Factor; Ethylenes; Female; Gastric Mucosa; Hydrochloric Acid; Indomethacin; Injections, Intraperitoneal; Intubation, Gastrointestinal; Male; Mice; Mice, Inbred BALB C; Rats; Rats, Sprague-Dawley; Stomach Ulcer

A model of gastric ulceration in the rat has been used to determine the expression of four messenger RNAs (mRNAs) encoding peptides considered to play active parts in the healing response. The trefoil peptides, rat spasmolytic polypeptide (rSP) and rat intestinal trefoil factor (rITF), along with epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) were the molecules studied. Ulceration was caused under anaesthesia by brief application of a liquid nitrogen-filled cryoprobe to the gastric serosal surface and RNA expression was monitored over the next 10 days. Each mRNA was quantified by ribonuclease protection assay, and mRNAs encoding rSP and rITF were localized within tissue sections by hybridization in situ with 35S antisense riboprobes. Ulceration induced the very rapid expression of first rSP and then rITF mRNA, whereas the mRNAs encoding EGF and TGF alpha increased at later times, with maxima recorded at 3 and 6 days, respectively. Hybridization in situ detected extensive rSP mRNA expression in the regenerative epithelia. The pronounced, but temporally different patterns of mRNA induction after ulceration suggest that the trefoil peptides may fulfil different and more immediate roles than the more 'traditional' healing proteins EGF and TGF alpha.

Topics: Animals; Cold Temperature; Epidermal Growth Factor; Gastric Mucosa; Gene Expression; Growth Substances; Immunoenzyme Techniques; Male; Mucins; Muscle Proteins; Neuropeptides; Peptide Biosynthesis; Peptides; Rats; Rats, Wistar; RNA, Messenger; Stomach Ulcer; Transforming Growth Factor alpha; Trefoil Factor-2; Trefoil Factor-3; Wound Healing

Indomethacin induces gastric ulcerations and decreases cell proliferation in the gastric ulcer margin. Since epithelial cell proliferation is under control of epidermal growth factor (EGF), we studied whether indomethacin may affect specific binding of [125I]-EGF to its receptors in cultured human gastric KATO III cells. To assess effects of EGF, indomethacin and their combination on cell proliferation, KATO III cells were incubated for 24 h with either (a) vehicle (b) indomethacin (doses from 10(-5) to 10(-3) M), EGF (doses 0.01, 0.05 or 0.1 microgram/ml) or (d) a combination of b and c, and the bromodeoxyuridine labeling index was determined. Indomethacin in a dose which did not affect cell viability significantly (by 21.5%) decreased [125I]-EGF binding to the KATO III cells and decreased the bromodeoxyuridine labeling index. Epidermal growth factor significantly increased cell proliferation and increased the labeling index from 28.9 +/- 0.6% in the vehicle group to 36.2 +/- 0.5%. Co-treatment with indomethacin significantly reduced the proliferative response of KATO III cells to EGF. In conclusion, indomethacin, in a dose which does not affect cell viability, decreased binding of EGF to cultured gastric KATO III cells and decreased their proliferative response to EGF.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cell Division; Cell Survival; Cells, Cultured; Epidermal Growth Factor; Humans; Indomethacin; Stomach Ulcer

The anti-ulcer effects of bifidobacteria, lactobacilli and streptococci were examined using the acetic acid-induced gastric ulcer and ethanol-induced erosion models in rats. Bifidobacterium breve YIT4014 and 4043, and Bifidobacterium bifidum YIT4007 were administered orally, and anti-ulcer effects were confirmed for not only these organisms but also their polysaccharide fractions (PSFs). The major component of these anti-ulcer polysaccharides was rhamnose. In particular, polysaccharides in which the rhamnose content exceeded 60% were more effective in healing gastric ulcers. After administration of the PSF from B. bifidum YIT4007, the levels of epidermal growth factor and basic fibroblast growth factor increased in gastric tissues. Similar results were observed for the culture supernatant of gastric epithelial cells cultured with PSF. Furthermore, the production of 6-ketoprostaglandin F1 alpha by macrophages was also enhanced by PSF. These results indicated that these bacteria and their polysaccharides induced host repair and protective systems in the gastric ulcer model.

Topics: 6-Ketoprostaglandin F1 alpha; Acetates; Animals; Anti-Ulcer Agents; Bifidobacterium; Cell Wall; Epidermal Growth Factor; Ethanol; Gastric Mucosa; Macrophages; Male; Polysaccharides, Bacterial; Rats; Rats, Sprague-Dawley; Stomach Ulcer

1. The interaction between endogenous nitric oxide (NO) and factors from the rat submandibular salivary gland such as epidermal growth factor (EGF) on gastric mucosal integrity in the rat has been investigated. 2. Bolus administration of the NO synthase inhibitor, NG nitro-L-arginine methyl ester (L-NAME; 6.25-50 mg kg-1, i.v.) to animals treated intraluminally with 0.15 N HCl resulted in a significant increase in the area of mucosal haemorrhagic damage at doses 12.5 and 50 mg kg-1. Concurrent administration of indomethacin (5 mg kg-1, i.v.) resulted in a significant haemorrhagic mucosal damage in response to L-NAME (12.5-50 mg kg-1). Administration of the highest dose of L-NAME resulted in an increase in histological damage to the rat gastric mucosa. 3. When compared to control animals, the extent of damage produced by L-NAME or L-NAME in combination with indomethacin was significantly exacerbated in rats which had been sialoadenectomized (SALX) by removal of the submandibular salivary glands. The mucosal damage in SALX rats was ameliorated by treatment with EGF (5 and 10 micrograms kg-1, i.v.). 4. L-NAME administration resulted in a small reduction of gastric mucosal blood flow as assessed by laser Doppler flowmetry (LDF). The reduction in LDF by 25 and 50 mg kg-1 L-NAME was significantly greater in SALX rats than in rats with intact salivary glands. Pretreatment of SALX rats with indomethacin did not augment this large decrease in LDF suggesting that endogenous prostanoids do not interact with NO and salivary factors in regulating mucosal microcirculation. 5. Mucosal NO biosynthesis as assessed by ['4C]-citrulline formation was reduced in SALX rats when compared to control animals. Pretreatment of SALX animals with parenterally-administered EGF(10 microg kg-1) was associated with an increase in [14C]-citrulline formation in the gastric mucosa to levels observed in control SALX rats.6. These data suggest that factors which originate from the salivary gland such as EGF interact with NO in the maintenance of mucosal integrity. The effects may be mediated at least in part by changes in gastric mucosal blood flow. Salivary glands and EGF may mediate these effects to some extent via changes in mucosal NO biosynthesis.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Blood Pressure; Epidermal Growth Factor; Gastric Mucosa; Gastrointestinal Hemorrhage; Indomethacin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Salivary Glands; Stomach Ulcer; Submandibular Gland

Large amount of EGF-like immunoreactivity was observed in the submandibular gland of rats with immunohistochemical method. The staining is mainly localized in the ductal cells. The level of EGF in gastric juice and serum was measured with a specific and sensitive RIA method. It was observed that EGF level was decreased both in gastric juice and in serum after sialoadenectomy and subsequent healing of chronic gastric ulcer induced by serosal acetic acid was delayed. Oral administration of EGF to sialoadenectomized rats could reverse the lowered rate of ulcer healing to almost normal level. The above results suggested that secretion of EGF may have an important effect on the healing of chronic gastric lesions in rats.

Topics: Animals; Epidermal Growth Factor; Gastric Juice; Male; Rats; Rats, Wistar; Stomach Ulcer; Submandibular Gland

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Cellulose; Drug Therapy, Combination; Epidermal Growth Factor; Humans; Mice; Omeprazole; Rats; Stomach Ulcer; Sucralfate

Previous studies demonstrated that epidermal growth factor (EGF) and polyamines (PA) are capable of protecting gastric mucosa against topical irritants. This study was designed to examine whether EGF, PA, and PG affect the healing of acute gastric lesions induced by water immersion and restraint stress. It was found that the healing process of stress lesions in sham-operated rats was significant after 6 hr after stress, and after 24 hr the number of stress lesions was reduced by about 75%. In sham-operated rats, the healing of ulcerations observed at 6, 12, and 24 hr after the stress was accompanied by gradual restoration of DNA synthesis, and both these processes were significantly reduced by administration of DFMO (an inhibitor of ornithine decarboxylase activity) or indomethacin (an inhibitor of cyclooxygenase). In salivectomized rats, the healing was significantly delayed and the DNA was lowered at all time intervals after the stress. Administration of EGF, spermine, aminoguanidine (an inhibitor of degradation of PA), or 16,16-dmPGE2 after stress promoted significantly the healing and DNA synthesis, but pretreatment with DFMO abolished the effect of EGF but not that of spermine. We conclude that EGF, PA, and PG are implicated in healing of stress lesions and that EGF acts, at least in part, by the stimulation of PA formation in the gastric mucosa.

Topics: Acute Disease; Animals; DNA; Drug Therapy, Combination; Epidermal Growth Factor; Gastric Mucosa; Gastrins; Polyamines; Prostaglandins; Rats; Rats, Wistar; Salivary Glands; Stomach; Stomach Ulcer; Stress, Psychological; Time Factors; Wound Healing

Stomach lesions induced by indomethacin (20 mg.kg-1 i.p.) and ethanol (1 ml 95% intragastrically) were studied after a 24 hour fast in rats which had undergone sialoadenectomy. The size of the lesions was correlated with gastric HCl secretion, with gastric vascular permeability (determined from the Evans blue concentration in the stomach tissue after its i.v. administration) and with the serum gastrin level. These parameters were also studied in sialoadenectomized rats and in animals given epidermal growth factor (EGF) (50 lg.kg-1). It was found that sialoadenectomy significantly (p < 0.01) raised the incidence of stomach lesions after the administration of indomethacin and also after ethanol (p < 0.05). A significant increase in both basal and stimulated HCl secretion was found after sialoadenectomy. Both indomethacin and ethanol also increased gastric vascular permeability in rats not subjected to sialoadenectomy, but sialoadenectomy raised it significantly compared with the non-sialoadenectomized group. The serum gastrin levels fell after sialoadenectomy and the decrease was significant after the subsequent administration of indomethacin or ethanol. The administration of EGF to sialoadenectomized rats lowered the incidence of stomach lesions, inhibited HCl secretion and reduced vascular permeability. The lowered susceptibility of the gastric mucosa to the formation of lesions in sialoadenectomized rats given indomethacin or ethanol can be regarded as the outcome of the uptake of EGF.

Topics: Animals; Capillary Permeability; Epidermal Growth Factor; Ethanol; Gastrins; Hydrochloric Acid; Indomethacin; Male; Rats; Rats, Wistar; Salivary Glands; Stomach; Stomach Ulcer

This study was designed to determine whether repeated exposures to stress lead to the adaptation of the gastric mucosa to stress ulcerogenesis. Wistar rats with intact or resected salivary glands were exposed to a standard period (3.5 h) of water-immersion and restraint stress every other day up to 8 days. The significant reduction in the severity of gastric lesions was first noticed after the second exposure to stress and was maximal after 6-day exposures to stress. This tolerance to stress ulcerogenesis disappeared after a 6-day rest during which animals were not exposed to stress. Histologically, the hemorrhages and edema seen after a single stress were less frequent during adaptation; instead the mucosa regenerated in spite of continuation of exposure to stress. During adaptation, the mucosal blood flow (MBF) and mucosal biosynthesis of PG were markedly increased. Administration of indomethacin (5 mg/kg i.p.) completely abolished gastric adaptation to stress and this was accompanied by about 85% reduction in mucosal generation of PG and significant decrease in the MBF. Salivectomy, which significantly reduced the luminal contents of epidermal growth factor (EGF) in the stomach, delayed and reduced the adaptation. We conclude that the stomach has the ability to adapt to repeated exposures to stress and that this adaptation is mediated, at least in part, by endogenous PG and EGF.

Topics: Adaptation, Physiological; Animals; Epidermal Growth Factor; Gastric Mucosa; Male; Prostaglandins; Rats; Rats, Wistar; Stomach Ulcer; Stress, Physiological

The effect of a proton pump inhibitor, omeprazole (OPZ), in combination with mouse epidermal growth factor (EGF), on the healing of chronic gastric ulcers induced by acetic acid in submandibular glands removed rats (SMR rat) was investigated. Four separate groups of SMR rats were orally administered 1 ml of distilled water (control), 100 mg/kg of OPZ alone (OPZ), 5 micrograms/kg of mouse EGF alone (EGF), or combination with (EGF + OPZ) twice daily. Two weeks later, ulcer areas of four groups were measured and expressed as the ulcer index (UI). The UI of the OPZ and EGF + OPZ group was significantly reduced as compared with that of the control. Furthermore, the UI of the EGF + OPZ group was significantly smaller than that of the EGF group. The present study indicates that the proton pump inhibitor promotes healing of chronic gastric ulcers in SMR rats and the effect of the proton pump inhibitor is enhanced by administration of mouse EGF.

Topics: Acetates; Acetic Acid; Adenosine Triphosphatases; Animals; Chronic Disease; Drug Therapy, Combination; Epidermal Growth Factor; Gastric Mucosa; Glycoproteins; H(+)-K(+)-Exchanging ATPase; Mice; Omeprazole; Rats; Stomach Ulcer; Submandibular Gland

Ebrotidine is a novel H2-receptor antagonist that exhibits both gastroprotective and ulcer-healing properties. Gastroprotection afforded by ebrotidine against ethanol damage was observed only after intragastric, but not parenteral administration, and it was accompanied by an increase in the mucosal blood flow. Ranitidine given at the same dose (100 mg/kg i.g. or s.c.) did not show any protective activity. When administered twice daily at various doses (1-100 mg/kg) for 10 days, ebrotidine reduced dose dependently the area of chronic gastric ulcers, and it was accompanied by significantly higher contents of epidermal growth factor (EGF) in the ulcer bed than in the intact mucosa. Administration of ranitidine resulted in a similar rate of ulcer healing and in a similar accumulation of EGF in the ulcer area to that observed after ebrotidine, but the increments in plasma gastrin levels in rats treated with ranitidine were observed at lower doses than in tests with ebrotidine. Concurrent administration of indomethacin delayed ulcer healing and reduced the accumulation of EGF in the ulcer area, but did not affect the ulcer healing by ebrotidine or ranitidine. We conclude that ebrotidine but not ranitidine shows gastroprotective activity, but it enhances the healing of chronic ulcerations in a similar manner to ranitidine.

Topics: Acetates; Acetic Acid; Animals; Benzenesulfonates; Epidermal Growth Factor; Ethanol; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Male; Ranitidine; Rats; Rats, Inbred Strains; Regional Blood Flow; Stomach Ulcer; Thiazoles

Transforming growth factor alpha (TGF) and epidermal growth factor (EGF) present in the gastric mucosa are polypeptides with similar biologic activity. This study compares the activity of TGF and EGF in the protection against injury by 100% ethanol and stress and in healing of acute gastric ulcerations. TGF and EGF (12.5-100 micrograms/kg-h) infused subcutaneously 30 min before and during ethanol or stress decreased mucosal lesions dose-dependently. The ID50 for ethanol- and stress-induced lesions after TGF were 40 and 70 micrograms/kg-h and after EGF 60 and 100 micrograms/kg-h. TGF and EGF infused subcutaneously into intact rats inhibited gastric acid secretion but did not affect the gastric blood flow or mucosal generation of prostaglandin E2 (PGE2). Both TGF and EGF also significantly enhanced the healing of stress-induced lesions and the restoration of DNA synthesis. Ethanol and stress reduced blood flow in the oxyntic mucosa by 68% and 51%, respectively, and this effect was partially reversed by EGF and TGF. Pretreatment with indomethacin (5 mg/kg intraperitoneally), which reduced mucosal generation of PGE2 by 85%, decreased in part the protection by TGF and EGF against ethanol-induced damage and virtually abolished the protective action of these peptides against stress-induced injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Animals; Blood Flow Velocity; Epidermal Growth Factor; Gastric Mucosa; Indomethacin; Rats; Rats, Wistar; Stomach Ulcer; Transforming Growth Factor alpha; Wound Healing

Topics: Depression, Chemical; Duodenal Ulcer; Epidermal Growth Factor; Female; Humans; Male; Saliva; Secretory Rate; Smoking; Stomach Ulcer

Orally administered epidermal growth factor (EGF) has been shown to protect the gastric mucosa against injury induced by noxious agents. However, EGF administered by intragastric bolus appears to have less effect on the gastric mucosa because of its rapid excretion from the gastric lumen. In this study, mouse EGF given to rats by gastric intubation was confirmed to remain in the stomach at significantly high concentrations when given in combination with hydroxypropylcellulose (HPC), an agent that retards drug release. The residual mouse EGF levels in the gastric luminal content and tissue 3 h after administration of 50 micrograms/kg of EGF dissolved in 1 ml of 2% HPC were 30 and 60 times higher, respectively, than those obtained after EGF alone. Pretreatment with intragastric bolus administration of EGF and HPC at the same dose for 3 h attenuated significantly the development of gastric lesions induced by absolute ethanol compared to that with HPC alone, EGF alone, or saline (mean values of ulcer index: EGF + HPC, 14.3; HPC, 52.8; EGF, 50.7; and saline, 63.2 mm). There were no significant differences between the ulcer index in the HPC, EGF, and saline groups. The present study indicates that exogenous EGF given as an intragastric bolus protects the gastric mucosa against injury when combined with HPC, which can bind to EGF and prevent its rapid excretion from the gastric lumen.

Topics: Animals; Cellulose; Drug Therapy, Combination; Epidermal Growth Factor; Ethanol; Gastric Mucosa; Male; Rats; Rats, Inbred Strains; Stomach Ulcer

The effect of experimental ulcers on the binding of human epidermal growth factor (hEGF), beta-urogastrone, to plasma membranes isolated from rat gastric mucosa was studied in order to develop hEGF as an anti-ulcer drug. The binding of [125I]hEGF to the gastric plasma membranes was significantly decreased 1 h after treatment with aspirin (300 mg/kg) and after 12 h of water-immersion stress. However, the number of EGF binding sites was increased 12 h after aspirin administration. There was little change in the binding of [125I]insulin to the gastric plasma membranes in response to water-immersion stress. These results indicate that changes in EGF binding to its receptors occur on plasma membranes of the rat gastric mucosa during ulcer.

Topics: Animals; Aspirin; DNA; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Male; Rats; Rats, Inbred Strains; Stomach Ulcer

Solcoseryl, a deproteinized extract of calf blood, protects the gastric mucosa against various topical irritants and enhances the healing of chronic gastric ulcerations but the mechanisms of these effects have been little studied. This study was designed to elucidate the active principle in Solcoseryl and to determine the role of prostaglandins (PG) and polyamines in the antiulcer properties of this agent. Using both, the radioimmunoassay and radioreceptor assay, EGF-like material was detected in Solcoseryl preparation. Solcoseryl given s.c. prevented the formation of stress-induced gastric lesions and this was accompanied by an increase in the generation of PGE2 in the gastric mucosa. Similar effects were obtained with EGF. Pretreatment with indomethacin, to suppress mucosal generation of prostaglandins (PG), greatly augmented stress-induced gastric ulcerations and antagonized the protection exerted by both Solcoseryl and EGF. Solcoseryl, like EGF, enhanced the healing of chronic gastro-duodenal ulcerations. This effect was abolished by the pretreatment with difluoromethylornithine, an inhibitor of ornithine decarboxylase, the key enzyme in the biosynthesis of polyamines. The healing effects of Solcoseryl and EGF was also reduced by prednisolone which decreased the angiogenesis in the granulation tissue in the ulcer area. These results indicate that Solcoseryl 1. contains EGF-like material, 2. displays the protective and ulcer healing effects similar to those of EGF and involving both PG and polyamines and 3. acts via similar mechanism as does EGF.

Topics: Actihaemyl; Analysis of Variance; Animals; Dinoprostone; Eflornithine; Epidermal Growth Factor; Gastric Mucosa; Indomethacin; Male; Polyamines; Prednisolone; Radioimmunoassay; Radioligand Assay; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological

The present study was aimed at assessing whether epidermal growth factor (EGF) and its receptors are present in the gastric mucosa during the healing of gastric ulcers. Immunohistochemical, immunochemical and functional studies were performed in rats after induction of ulcers in the oxyntic mucosa. Controls, which included non-operated and sham-operated animals, displayed only rare cells in the bottom of the oxyntic glands showing EGF-like immunoreactivity. Within one day after ulcer induction, a markedly increased number of chief cells in undamaged mucosa showed intense staining. Concomitantly, there was an increased immunoreactivity for EGF receptors in the mucous neck cells. Maximal immunostaining for both compounds was observed at 3 days after ulcer induction; augmented staining was still demonstrable after 3 weeks. RIA revealed significantly increased EGF concentration in the oxyntic mucosa three days after ulcer induction, and at this stage stimulated gastric acid secretion, measured in a parallel group of chronic fistula rats, indicated significant inhibition. The transient increases in EGF-like and EGF receptor immunoreactivities may stimulate gland cell proliferation. The local release of EGF-like substances may also serve to reduce gastric acidity and thereby promote ulcer healing.

Topics: Animals; Body Weight; Epidermal Growth Factor; ErbB Receptors; Female; Gastric Acid; Gastric Mucosa; Immunohistochemistry; Male; Rats; Rats, Inbred Strains; Stomach Ulcer; Wound Healing

EGF, produced mainly by salivary glands, inhibits gastric acid secretion, stimulates the proliferation of gastric mucosal cells and protects the mucosa against various ulcerogens, but its role in the pathogenesis of stress ulcerations is unknown. In this study, rats with intact or resected salivary glands were exposed to water immersion and restraint stress (WRS) without and with pretreatment with exogenous EGF or dimethyl PGE2 (dmPGE2) at doses which were shown previously to protect the mucosa against topical irritants. During 1.5-12 h of WRS, the formation of gastric ulcerations increased progressively with the duration of stress reaching peak after 6 h of stress and being significantly higher in rats with removed salivary glands than in intact animals. Gastric acid secretion and DNA synthesis in oxyntic mucosa declined with the duration of WRS, but after sialoadenectomy a significant increase in gastric acid secretion and a further decline in DNA synthesis were observed after WRS. EGF contents in the gastric lumen and the gastric mucosa were several times higher in rats subjected to stress than in control unstressed animals, indicating that stress causes an extensive release of EGF. Both exogenous EGF (17 nmol/kg/h) and dmPGE2 (143 nmol/kg) prevented, in part, the formation of gastric lesions, while inhibiting gastric acid secretion both in rats with intact or resected salivary glands. We conclude that water immersion and restraint stress is accompanied by an excessive release of EGF, which appears to attenuate gastric secretion, enhances the DNA synthesis and may limit the formation of stress-induced gastric ulcerations.

Topics: Animals; DNA; Epidermal Growth Factor; Gastric Acid; Gastric Mucosa; Male; Rats; Rats, Inbred Strains; Salivary Glands; Stomach Ulcer; Stress, Physiological; Water

We have observed that removal of the salivary glands is associated with an increase in the susceptibility to gastric mucosal damage in the rat. In the present study, we have examined the effect of sialoadenectomy on ethanol-induced mucosal hemorrhagic damage and myeloperoxidase (MPO) activity. Hemorrhagic damage and MPO activity in response to intragastric 50% w/v ethanol were greater in sialoadenectomized rats when compared with sham-operated animals. Pretreatment with 16,16-dimethylprostaglandin E2 (0.3 micrograms/kg s.c.) reduced damage and MPO activity in both sialoadenectomized and sham control rats receiving 50% ethanol. The reduction in these parameters was greater in control than in sialoadenectomized rats. Pretreatment with epidermal growth factor (5 micrograms/kg s.c.) significantly reduced MPO activity but did not significantly affect the extent of damage. These data suggest that sialoadenectomy is associated with an increase in mucosal inflammation in animals given ethanol. However, in some situations tissue inflammation (as indicated by MPO activity) was reduced, while the proportion of gastric mucosa exhibiting hemorrhagic damage was not changed.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Dinoprostone; Epidermal Growth Factor; Ethanol; Gastrointestinal Hemorrhage; Male; Neutrophils; Peroxidase; Rats; Rats, Inbred Strains; Salivary Glands; Stomach Ulcer

The effect of removal of the submandibular-sublingual salivary gland (sialoadenectomy) has been examined in terms of the effects on the susceptibility of the gastric mucosa to the inflammatory and damaging actions of ethanol. In addition, the effects of sialoadenectomy on cell turnover in the gastric mucosa has been examined. Animals were examined at one to five weeks after removal of the submandibular-sublingual salivary gland complex. In response to 100% w/v ethanol, sialoadenectomized rat displayed greater hemorrhagic damage to the gastric mucosa than sham-operated control rats. The difference between sialoadenectomized and sham control rats was significant at two to five weeks after surgery. The rate of [3H]thymidine incorporation into gastric mucosa was significantly reduced in sialoadenectomized rats at one and two weeks. Mucosal DNA concentration was significantly reduced in sialoadenectomized rats at four and five weeks after surgery. Mucosal myeloperoxidase activity was greater in sialoadenectomized rats treated with ethanol compared to control animals, but this difference was only significant at two weeks after surgery. Sialoadenectomy was also associated with a reduction in duodenal and gastric mucosal levels of immunoreactive epidermal growth factor (EGF). Differences between sialoadenectomized and control rats were not significant until three to four weeks after surgery. These data indicate that sialoadenectomy was associated with an increase in the susceptibility of rat gastric mucosa to ethanol-mediated damage. Sialoadenectomy also resulted in a reduction in gastric mucosal growth and gastroduodenal mucosal levels of EGF. However, the influence of sialoadenectomy on the susceptibility of the rat gastric mucosa to ethanol-mediated damage occurred prior to any significant effect on mucosal DNA concentration or EGF levels.

Topics: Animals; DNA; Epidermal Growth Factor; Ethanol; Gastric Mucosa; Male; Peroxidase; Rats; Rats, Inbred Strains; Stomach Ulcer; Sublingual Gland; Submandibular Gland; Time Factors

Epidermal growth factor (EGF) has been shown to enhance healing of experimental gastric ulcers when given subcutaneously or orally in the drinking water. This effect of EGF occurs without reducing gastric acid secretion. On the other hand, EGF reportedly is excreted rapidly from gastric lumen when administered by intragastric bolus. This suggests that further stimulation of ulcer healing may be expected if EGF is given with an acid-suppressive agent or with an agent allowing EGF to remain in rat gastric lumen at high concentrations. In the present study, EGF administered by gastric intubation at a dose of 10 micrograms/kg, which is three times smaller than reported in previous studies, was evaluated for its effect on acetic acid-induced rat gastric ulcers in combination with sucralfate or omeprazole. Sucralfate is well known selectively to bind proteins covering the ulcer base, and omeprazole is a potent acid-suppressive agent. Prior to the study of combined EGF and sucralfate, oral sucralfate was confirmed to allow endogenous gastric EGF and mouse EGF given exogenously to remain at high concentrations in gastric contents and tissues. EGF and sucralfate (2 g/kg/day) given alone failed to stimulate ulcer healing in submandibularectomized rats (SMR rat) whose endogenous gastric EGF was depleted. However, the combination of both drugs administered at the same doses significantly accelerated ulcer healing in the SMR rat. Omeprazole (200 mg/kg/day) significantly enhanced ulcer healing regardless of removal of the submandibular glands. The combination of EGF and omeprazole further stimulated ulcer healing in the SMR rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetates; Acetic Acid; Animals; Drug Therapy, Combination; Epidermal Growth Factor; Male; Omeprazole; Rats; Rats, Inbred Strains; Stomach Ulcer; Sucralfate; Wound Healing

Epidermal growth factor promotes the growth of and protects gastric mucosa against various ulcerogens, including stress, but little is known about its role in the pathogenesis of stress ulcerations. In this study, Wistar rats with intact and resected salivary glands were exposed to water-immersion and restraint stress. During 2-14 hours of water-immersion restraint stress, the formation of gastric ulcerations increased progressively and the duration of stress was accompanied by a decrease in DNA synthesis in the gastric mucosa. Following sialoadenectomy, a significant increase in the number of stress ulcerations and further reduction in DNA synthesis were observed. Exogenous epidermal growth factor and dimethyl prostaglandin E2 significantly reduced the ulcerations in the stressed rats with intact salivary glands, but this reduction was significantly less pronounced after sialoadenectomy. Water-immersion restraint stress also resulted in about 50% reduction in mucosal prostaglandin E2 generation, and the pretreatment with indomethacin, which suppressed prostaglandin E2 by about 90%, almost doubled the number of stress ulcerations and abolished the gastro-protective effect of exogenous epidermal growth factor (but not dimethyl prostaglandin E2) against the stress lesions. An inhibition of ornithine decarboxylase activity by difluoromethyl ornithine also augmented stress-induced ulcerogenesis and abolished the protective action of epidermal growth factor while the administration of spermine almost completely prevented stress ulcerations in rats both without and with pretreatment with difluoromethylornithine. Water-immersion restraint stress also significantly reduced mucosal content of glutathione. Cysteamine increased tissue glutathione and reduced stress ulcerations but N-ethylmaleimide, an sulfhydryl blocker, decreased mucosal content of glutathione without affecting the stress ulcerations. This study indicates that the stress ulcers are accompanied by the reduction in mucosal synthesis of DNA, prostaglandin, and glutathione and that the presence of salivary glands attenuates the stress ulcerogenesis probably by releasing epidermal growth factor which acts, in part, by enhancing ornithine decarboxylase activity, mucosal growth, and prostaglandin and glutathione formation.

Topics: 16,16-Dimethylprostaglandin E2; Animals; DNA; Eflornithine; Epidermal Growth Factor; Ethylmaleimide; Gastric Mucosa; Glutathione; Male; Ornithine Decarboxylase; Prostaglandins; Rats; Rats, Inbred Strains; Salivary Glands; Stomach Ulcer; Stress, Physiological; Sulfhydryl Compounds; Thymidine

Topics: Arthritis, Rheumatoid; Epidermal Growth Factor; Humans; Radioimmunoassay; Saliva; Sjogren's Syndrome; Stomach Ulcer

We examined the effects of orally administered human epidermal growth factor (hEGF) on healing of acetic acid-induced gastric ulcers in rats. hEGF, given twice daily at 30 and 100 micrograms/kg for 2 weeks or at 100 micrograms/kg for 4 weeks to rats with ulcers, had no effect on natural healing or the gastric secretion, delayed one caused by indomethacin. Oral hEGF had no effect on basal histamine-stimulated gastric secretion, and stomach weight. These results indicate that oral hEGF has no biological activity on the pathophysiology of the stomach.

Topics: Acetates; Animals; Anti-Ulcer Agents; Epidermal Growth Factor; Gastric Acid; Gastric Fistula; Histamine; Indomethacin; Male; Pylorus; Rats; Stomach Ulcer

Topics: Animals; Epidermal Growth Factor; ErbB Receptors; Female; Gastric Acid; Gastric Mucosa; Hydrogen-Ion Concentration; Male; Rats; Rats, Inbred Strains; Stomach Ulcer

Immunoreactive epidermal growth factor (IR-EGF) was measured by a highly sensitive and specific radioimmunoassay in gastric juice samples obtained during endoscopy from 26 control subjects, 44 patients with duodenal ulcers, and 18 with benign gastric ulcers. In the active stage, the concentrations of the peptide were consistently reduced, compared with those found in control subjects (592.7 +/- 55.8 pg/ml), in both duodenal (262.6 +/- 21.4 pg/ml) and gastric ulcer patients (320.2 +/- 34.1 pg/ml) (p less than 0.001 and 0.01, respectively). Mean IR-EGF values distinctly lower than in the controls were still present in the gastric juice of patients with inactive duodenal ulcers (349.7 +/- 35.9 pg/ml; p less than 0.001), whereas no difference was observed in patients with healed gastric ulcers (502.2 +/- 132.3 pg/ml). Although these findings suggest a possible role for EGF deficiency in the pathogenesis of peptic ulcer disease, the pathophysiological significance of our results (if any) remains to be elucidated.

Topics: Adult; Duodenal Ulcer; Epidermal Growth Factor; Female; Gastric Juice; Humans; Male; Radioimmunoassay; Stomach Ulcer

In an attempt to elucidate the role of granulation vessels in the healing of gastric ulcer, healing and angiogenesis in granulation tissue of acetic acid ulcers were studied in rats. In addition, the effects of prednisolone and synthetic human epidermal growth factor (EGF) on angiogenesis and ulcer healing were investigated. The newly formed granulation vessels in the ulcer base were measured by means of a carmine dye infusion method. Prednisolone, administered subcutaneously at 40 mg/kg/day, significantly decreased angiogenesis in the ulcer base on the 10th day after ulcer production, and on the 30th day ulcer healing was found to be significantly delayed. In contrast, angiogenesis was significantly increased, and ulcer healing was enhanced by intragastric administration of 100 micrograms/kg/day of EGF. With combined administration of prednisolone and EGF, angiogenesis was significantly increased compared to that observed with prednisolone treatment alone. The authors conclude that suppression of angiogenesis by prednisolone is a delaying factor in gastric ulcer healing and that exogenous EGF promotes ulcer healing, partly through restoration of angiogenesis.

Topics: Acetates; Acetic Acid; Animals; Drug Combinations; Epidermal Growth Factor; Granulation Tissue; Male; Neovascularization, Pathologic; Prednisolone; Rats; Stomach Ulcer; Wound Healing

Epidermal growth factor (EGF, 10 micrograms/kg po, ip, or sc, BID, and 20 micrograms/kg iv) had no protective activity in the indomethacin-induced intestinal lesion model (6 h model). In the ethanol-induced gastric lesion model, EGF (10 micrograms/kg sc) reduced lesions by 52% and reduced gastric acid secretion by 68% (5 micrograms/kg iv). In the 24 h indomethacin-induced intestinal lesion model, pretreatment with EGF (10 micrograms/kg sc, BID; 1 day before and during indomethacin treatment) had no beneficial effects. Therefore, EGF had no protective effects against non-steroidal antiinflammatory drug (NSAID)-induced intestinal lesions at doses that protect against the necrotizing action of ethanol and that inhibit gastric acid secretion in the rat.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dimaprit; Epidermal Growth Factor; Ethanol; Gastric Acid; Histamine H2 Antagonists; Humans; Indomethacin; Intestinal Mucosa; Male; Rats; Rats, Inbred Strains; Recombinant Proteins; Stomach Ulcer; Thiourea

This study examines the effect of excision of the submandibular salivary glands, the main source of epidermal growth factor (EGF), and the role of gender on the healing of acetic acid-induced gastric ulcers in rats. In male rats excision of the submandibular glands delayed ulcer healing. At 15 and 25 days the unhealed ulcer areas were significantly larger in the sialoadenectomy group than in control animals, and fewer completely healed ulcers were seen in this group at 25 days. Ulcer healing in female rats was slower. At day 25 ulcers were healed in 12% of female rats with intact salivary glands, compared with 68% in males. Female rats also showed larger unhealed ulcer areas after sialoadenectomy than controls. We conclude that removal of the main source of EGF in the gastrointestinal tract is associated with a delay in healing of gastric ulcers. The significant difference in healing observed between female and male rats may be influenced by the known androgenic regulation of EGF production in the salivary glands.

Topics: Animals; Epidermal Growth Factor; Female; Male; Rats; Rats, Inbred Strains; Sex Factors; Stomach Ulcer; Submandibular Gland; Wound Healing

We examined the effect of human epidermal growth factor (hEGF) on the healing rate of gastric ulcers induced in rats. These ulcers were produced by a submucosal injection of 0.03 ml of 20% acetic acid into the stomach. Healing of the ulcers was delayed when a daily s.c. injection of indomethacin (1 mg/kg) was given for 4 wks. hEGF (100 and 300 micrograms/kg), given s.c. for 2 and 4 wks, significantly accelerated both natural and delayed healing of the ulcers. hEGF significantly inhibited both basal (pylorus ligation) and histamine-stimulated acid secretion (acute fistula). Thus, hEGF accelerates the healing of acetic acid-induced gastric ulcers, presumably because of its potent antisecretory activity.

Topics: Acetates; Acetic Acid; Animals; Dose-Response Relationship, Drug; Epidermal Growth Factor; Gastric Acid; Humans; Indomethacin; Male; Organ Size; Rats; Rats, Inbred Strains; Stomach; Stomach Ulcer; Wound Healing

Numerous studies have indicated a role of epidermal growth factor in the maintenance of the gastrointestinal mucosa. In the present study epidermal growth factor concentrations in saliva and gastric juice of patients with gastric or duodenal ulcer or gastritis are compared with those of healthy controls. For this purpose a novel ELISA system has been developed and shown to be sensitive and specific. It is demonstrated that gastric juice and saliva of patients with gastric ulcer contain less epidermal growth factor than the samples of healthy controls (p less than 0.01). Epidermal growth factor concentrations and outputs (product of epidermal growth factor concentration and the volume secreted in 15 min) in the gastric juice of patients with duodenal ulcer do not differ from those of healthy controls.

Topics: Duodenal Ulcer; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Gastric Juice; Gastritis; Humans; Saliva; Stomach Ulcer; Thirst

The authors examined the influence of pregnancy on the healing of chronic gastric and duodenal ulcers in connection with pregnancy-induced changes of growth parameters of gastric-duodenal mucosa and changes in the level of endogenic EGF. Besides, the level of EGF was lowered by the resection of submandibular glands (sialadenectomy). Pregnancy caused an increase in the speed of the healing of gastric and duodenal ulcers, this effect being the result of the appearance of hyperplastic changes in the gastric-duodenal mucosa. This hyperplasia was the result of the increase in the level of endogenic EGF. Sialadenectomy decreased the level of EGF in the blood serum preventing total pregnancy hyperplasia of the mucosa in the stomach and partly in the duodenum, which resulted in the total abolition of favourable influence of pregnancy on the healing of gastric ulcers and reduction of the influence of pregnancy on the healing of duodenal ulcers. The results obtained show that the gastric and duodenal mucosa during pregnancy has an increased ability to regenerate, this ability resulting from the hyperplasia of the mucosa taking place in pregnancy, which is the effect of an increase in the level of endogenic EGF.

Topics: Chronic Disease; Duodenal Ulcer; Epidermal Growth Factor; Female; Humans; Pregnancy; Pregnancy Complications; Stomach Ulcer; Wound Healing

The healing of acetic acid-induced gastric and duodenal ulcers was examined together with biochemical indices of growth in gastric and duodenal mucosa in rats with intact or removed salivary glands after treatment with epidermal growth factor (EGF) or somatostatin, or both. After the extirpation of salivary glands, the healing rate of gastric and duodenal ulcerations was delayed and gastric content of immunoreactive EGF was reduced. This was accompanied by a significant decrease in the contents of deoxyribonucleic acid and ribonucleic acid in the gastric and duodenal mucosa. Repeated administration of EGF either subcutaneously or orally accelerated the healing of gastroduodenal ulcers in rats with intact salivary glands and completely reversed the delay in ulcer healing in sialoadenectomized animals. These effects were also accompanied by a significant increase in the growth parameters of gastric and duodenal mucosa. Administration of somatostatin, which prevented the growth-promoting action of subcutaneous EGF, resulted in a significant decrease in the EGF-stimulated healing of gastric and duodenal ulcerations in both intact and sialoadenectomized rats. Our findings suggest that cell proliferation is an important factor in healing of gastric and duodenal ulcerations and that EGF plays an important role in ulcer healing due to its mitogenic action.

Topics: Administration, Oral; Animals; Duodenal Ulcer; Epidermal Growth Factor; Gastric Acid; Gastrins; Infusions, Parenteral; Intestinal Mucosa; Male; Nucleic Acids; Rats; Rats, Inbred Strains; Somatostatin; Stomach Ulcer; Wound Healing

In experimental studies, 0.6 N HCl-induced gastric mucosal injury was significantly severe in submandibularectomized rats (SMR rats) than that in either SMR rats receiving exogenous mouse EGF (SMR + EGF rats) or controls. This was also true in gastric injury induced by 0.4 N HCl under pretreatment with indomethacin to reduce gastric mucosal prostaglandins (PGs). Somatostatin (SLI), PGE2, and PAS-stained mucus in the corpus were significantly reduced in SMR rats in comparison to SMR + EGF and control rats. In clinical studies, salivary EGF secretion was much higher in peptic ulcer patients than healthy controls. beta-Urogastrone was effective in the treatment of gastric ulcers. On the basis of experimental studies, we conclude that the protective effect of EGF on the gastric mucosa is, in part, mediated indirectly by increases in SLI, PGE2, and mucus production. However, endogenous, as well as exogenous, EGF has an important direct, cytoprotective effect on the gastric mucosa. From the clinical studies, we also conclude that salivary EGF secretion in ulcer patients increases in a homeostatic response to the presence of an ulcer, facilitating ulcer healing. Furthermore, we believe that beta-urogastrone, human EGF, might prove to be an effective drug in the clinical treatment of gastric ulcers.

Topics: Animals; Epidermal Growth Factor; Gastric Mucosa; Humans; Male; Rats; Rats, Inbred Strains; Saliva; Salivation; Stomach Ulcer

Epidermal growth factor (EGF) is a mitogenic peptide synthesized in the submandibular glands and released in saliva. EGF is able to prevent the development of gastrointestinal ulcers in the rat and to accelerate their healing. The present work was undertaken to examine whether Sucralfate acts via the effector system of EGF. We conclude that Sucralfate does not change the binding of EGF to its receptor, but it is able to bind EGF in a pH dependent manner and at pH below 4.5 virtually all EGF is bound to Sucralfate. In vivo studies in rats with acid-induced gastric ulcers show that sucralfate carries EGF to the ulcer, and that EGF is available for a longer period of time (3 hours) when EGF and Sucralfate are is given together than when EGF is given alone.

Topics: Animals; Epidermal Growth Factor; ErbB Receptors; Humans; Male; Mice; Rats; Rats, Inbred Strains; Stomach Ulcer; Sucralfate

Topics: Animals; Epidermal Growth Factor; Gastric Acid; Gastric Acidity Determination; Gastric Mucosa; Hydrochloric Acid; Male; Mucus; Rats; Rats, Inbred Strains; Stomach Ulcer; Submandibular Gland

The effect of extirpation of the submandibular glands, an exocrine organ for epidermal growth factor/urogastrone (EGF/URO), and the effect of oral administration of synthetic human (EGF/URO) on healing of chronic gastric ulcers in rats has been investigated. Removal of the submandibular glands delayed healing of chronic gastric ulcers when examined after 50, 100, and 200 days. Oral administration of synthetic human EGF/URO stimulated gastric ulcer healing when examined after 25 and 50 days of treatment. The effect of synthetic human EGF/URO was comparable with that of cimetidine. The combined administration of synthetic human EGF/URO and cimetidine further increased healing of gastric ulcers compared with administration of each substance. Neither synthetic human EGF/URO, nor removal of the submandibular glands had any influence on gastric acid secretion. This study showed that the submandibular glands influence healing of chronic gastric ulcers and suggest that EGF/URO participate in healing of chronic gastric ulcers in rats.

Topics: Animals; Chronic Disease; Cimetidine; Combined Modality Therapy; Epidermal Growth Factor; Female; Gastric Acid; Rats; Rats, Inbred Strains; Stomach Ulcer; Submandibular Gland

The pathophysiological structure shows aggressors like increased acid and pepsin, an impaired defence system of the mucosa (mucus, mucosal circulation and possibly PG's and epidermal growth hormone). Disturbances in the interdigestive and digestive motility brings about most clearly the pathophysiological differences between GU and DU. Therapeutic corrections of the high secretion lead to pathological reactions in other parts of the system (gastrin). SPV is the only therapeutic procedure which reduces irreversibly the enlarged secretory capacity of the gastric mucosa (parietal cell reduction). This surgical treatment should therefore have priority in the treatment also of uncomplicated duodenal ulcers and with some exceptions of GU.

Topics: Duodenal Ulcer; Epidermal Growth Factor; Epithelium; Gastric Acid; Gastric Emptying; Gastric Mucosa; Gastrointestinal Motility; Histamine Release; Humans; Membrane Potentials; Postoperative Complications; Prostaglandins; Stomach Ulcer; Vagotomy, Proximal Gastric

The role of submandibular epidermal growth factor in protection of the gastric mucosa was investigated in rats. Removal of the submandibular glands and thereby submandibular epidermal growth factor (EGF) caused rats to develop gastric lesions (ulcerations and ulcers) after administration of the duodenal ulcerogen cysteamine. The median output of EGF in gastric juice was reduced from 45.6 pmol/12 h (total range 17.5-65.0) in unoperated controls to less than 0.06 pmol/12 h (total range less than 0.06-1.82) in rats given cysteamine after extirpation of the submandibular glands. The contents of EGF in the submandibular glands was unchanged during cysteamine treatment. Furthermore, the effects of intragastric instillation of exogenous EGF, infusion of saliva without EGF, and infusion of saliva with a high concentration of EGF on the development of cysteamine-induced gastric lesions were investigated in rats without submandibular glands. Exogenous EGF and saliva with a high but still physiological concentration of EGF significantly reduced the median area in the stomach displaying ulcers and ulcerations, whereas saliva without EGF had no effect. Although EGF is a known inhibitor of gastric acid secretion, the dose used in the present study had no effect on gastric acid secretion in chronic gastric fistula rats; removal of the submandibular glands also did not have any such effect. We conclude that exocrine secretion of submandibular EGF has a cytoprotective function in the stomach, an effect that may be physiological.

Topics: Animals; Cysteamine; Epidermal Growth Factor; Female; Gastric Acid; Gastric Mucosa; Radioimmunoassay; Rats; Rats, Inbred Strains; Saliva; Stomach Ulcer; Submandibular Gland

Topics: Animals; Epidermal Growth Factor; Glucocorticoids; Humans; Rats; Stomach Ulcer; Sulfhydryl Compounds

Topics: Animals; Cats; Disease Models, Animal; DNA; Epidermal Growth Factor; Epoprostenol; Female; Gastric Mucosa; Male; Peptides; Prostaglandins; Prostaglandins E; Rats; Stomach Ulcer

This study compares the effect of epidermal growth factor and prostaglandins (PGE2 or PGI2), applied topically to gastric mucosa, on gastric secretion and formation of ASA-induced gastric ulcerations in rats. Epidermal growth factor given topically in non-antisecretory doses prevented dose-dependently the formation of ASA-induced ulcers without affecting prostaglandin generation but with a significant rise in DNA synthesis in the oxyntic mucosa. The anti-ulcer effect of topical prostaglandins was also accompanied by an increase in DNA synthesis. This study indicates that topical epidermal growth factor, like PGE2 or PGI2, is cytoprotective and that this cytoprotection is not mediated by the inhibition of gastric secretion or prostaglandin formation but related to the increase in DNA synthesis in oxyntic mucosa.

Topics: Animals; Dinoprostone; DNA; Epidermal Growth Factor; Epoprostenol; Gastric Acid; Gastric Mucosa; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Stomach Ulcer

Topics: Animals; Blood Glucose; Electroshock; Epidermal Growth Factor; Gastric Acidity Determination; Gastric Juice; Gastrointestinal Hormones; Gastrointestinal Motility; Hypothalamus; Injections, Intravenous; Insulin; Rats; Secretory Rate; Stomach Ulcer

Topics: Carboxylic Acids; Epidermal Growth Factor; Gastrointestinal Hormones; Humans; Peptic Ulcer; Peptides; Quinolines; Stomach Ulcer