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De Witte C, Devriendt B, Flahou B, Bosschem I, Ducatelle R, Smet A, Haesebrouck F. Helicobacter suis induces changes in gastric inflammation and acid secretion markers in pigs of different ages. Vet Res 2017; 48:34. [PMID: 28619040 PMCID: PMC5473008 DOI: 10.1186/s13567-017-0441-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 05/31/2017] [Indexed: 01/02/2023] Open
Abstract
Gastric mRNA expression of markers for acid secretion and inflammation and presence of gastric ulceration was studied in naturally Helicobacter suis-infected and non-infected 2–3 months old, 6–8 months old and adult pigs. In H. suis-infected 2–3 months old pigs, IL-8 and IL-1β transcript levels were upregulated in the pyloric gland zone, indicating an innate immune response. A similar response was demonstrated in the fundic gland zone of adult pigs, potentially due to a shift of H. suis colonization from the pyloric to the fundic gland zone. A Treg response in combination with decreased expressions of IL-8, IL-17A and IFN-γ was indicated to be present in the H. suis-infected 6–8 months old pigs, which may have contributed to persistence of H. suis. In H. suis-infected adult pigs, a Treg response accompanied by a Th17 response was indicated, which may have played a role in the decreased number of H. suis bacteria in the stomach of this age group. The decreased G-cell mass and upregulated expression of somatostatin indicated decreased acid secretion in H. suis-infected 6–8 months old pigs. In H. suis-infected adult pigs, upregulation of most markers for gastric acid secretion and increased G-cell mass was detected. Presence of severe hyperkeratosis and erosions in the non-glandular part of the stomach were mainly seen in the H. suis-positive groups. These results show that H. suis infection affects the expression of markers for acid secretion and inflammation and indicate that these effects differ depending on the infection phase.
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Affiliation(s)
- C De Witte
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
| | - B Devriendt
- Department of Virology, Parasitology, Immunology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - B Flahou
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - I Bosschem
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - R Ducatelle
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - A Smet
- Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Antwerp University, Antwerp, Belgium
| | - F Haesebrouck
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
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Abstract
The role of the peptide hormone gastrin in stimulating gastric acid secretion is well established. Mature amidated gastrin is processed from larger peptide precursor forms. Increasingly these processing intermediates, such as glycine-extended gastrin (G-Gly) and progastrin, have been shown to have biological activities of their own, often separate and complementary to gastrin. Although G-Gly is synthesized and secreted by gastric antral G-cells, the physiological functions of this putative mediator are unclear. Gastrin and cholecystokinin (CCK) stimulate the secretion of somatostatin from gastric D-cells as part of the feedback control of gastric acid. In this study the effect of G-Gly and gastrin on the release of somatostatin from rabbit fundic D-cells was examined. D-cells were obtained by collagenase-EDTA digestion and elutriation and cultured for 48 hours. With a 2 hour exposure to the peptides, gastrin but not G-Gly stimulated somatostatin release. Treatment of D-cells for 24 hours with gastrin or G-Gly individually, significantly enhanced subsequent basal as well as CCK- and GLP-1-stimulated somatostatin release. Twenty four hours exposure to gastrin combined with G-Gly synergistically enhanced basal and agonist-stimulated somatostatin release and cellular somatostatin content. Gastrin and G-Gly may be important in the longer term regulation of D-cell function.
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Affiliation(s)
- Ian Lp Beales
- Department of Gastroenterology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, NR4 7UZ, UK ; Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK ; Royal Postgraduate Medical School, Hammersmith Hospital, London, W12, UK
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Strickertsson JAB, Døssing KBV, Aabakke AJM, Nilsson HO, Hansen TVO, Knigge U, Kjær A, Wadström T, Friis-Hansen L. Interferon-γ inhibits ghrelin expression and secretion via a somatostatin-mediated mechanism. World J Gastroenterol 2011; 17:3117-25. [PMID: 21912454 PMCID: PMC3158411 DOI: 10.3748/wjg.v17.i26.3117] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Revised: 03/05/2011] [Accepted: 03/12/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate if and how the proinflammatory cytokine interferon γ (IFNγ) affects ghrelin expression in mice.
METHODS: The plasma concentration of ghrelin, and gastric ghrelin and somatostatin expression, were examined in wild-type mice and mice infected with Helicobacter pylori (H. pylori). Furthermore, ghrelin expression was examined in two achlorhydric mouse models with varying degrees of gastritis due to bacterial overgrowth. To study the effect of IFNγ alone, mice were given a subcutaneous infusion of IFNγ for 7 d. Finally, the influence of IFNγ and somatostatin on the ghrelin promoter was characterized.
RESULTS: H. pylori infection was associated with a 50% reduction in ghrelin expression and plasma concentration. Suppression of ghrelin expression was inversely correlated with gastric inflammation in achlorhdyric mouse models. Subcutaneous infusion of IFNγ suppressed fundic ghrelin mRNA expression and plasma ghrelin concentrations. Finally, we showed that the ghrelin promoter operates under the control of somatostatin but not under that of IFNγ.
CONCLUSION: Gastric infection and inflammation is associated with increased IFNγ expression and reduced ghrelin expression. IFNγ does not directly control ghrelin expression but inhibits it indirectly via somatostatin.
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Zavros Y, Mesiwala N, Waghray M, Todisco A, Shulkes A, Merchant JL. Histamine 3 receptor activation mediates inhibition of acid secretion during Helicobacter-induced gastritis. World J Gastrointest Pathophysiol 2010; 1:154-65. [PMID: 21607157 PMCID: PMC3097961 DOI: 10.4291/wjgp.v1.i5.154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Revised: 11/24/2010] [Accepted: 12/01/2010] [Indexed: 02/07/2023] Open
Abstract
AIM: To test the hypothesis that histamine 3 receptor (H3R) activation during Helicobacter infection inhibits gastric acid secretion in vivo and in vitro.
METHODS: Helicobacter felis (H. felis) infected and uninfected C57Bl/6 mice were infused with either PBS or the H3 receptor antagonist thioperamide (THIO) for 12 wk. After treatment, mice were analyzed for morphological changes and gastric acid content. Total RNA was prepared from the stomachs of each group and analyzed for changes in somatostatin and gastrin mRNA abundance by real time-polymerase chain reaction (RT-PCR). Location of H3 receptors in the stomach was analyzed by co-localization using antibodies specific for the H3 receptor and parietal cell marker H+, K+-ATPase β subunit.
RESULTS: Inflammation and parietal cell atrophy was observed after 12 wk of H. felis infection. Interestingly, treatment with the H3R antagonist thioperamide (THIO) prior to and during infection prevented H. felis-induced inflammation and atrophy. Compared to the uninfected controls, infected mice also had significantly decreased gastric acid. After eradication of H. felis with THIO treatment, gastric acidity was restored. Compared to the control mice, somatostatin mRNA abundance was decreased while gastrin gene expression was elevated during infection. Despite elevated gastric acid levels, after eradication of H. felis with THIO, somatostatin mRNA was elevated whereas gastrin mRNA was suppressed. Immunofluorescence revealed the presence of H3 receptors on the parietal cells, somatostatin-secreting D-cells as well as the inflammatory cells.
CONCLUSION: This study shows that during H. felis infection, gastric acidity is suppressed as a consequence of an inhibitory effect on the parietal cell by H3R activation. The stimulation of gastric mucosal H3Rs increases gastrin expression and release by inhibiting release of somatostatin.
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Atherton JC. The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2007; 1:63-96. [PMID: 18039108 DOI: 10.1146/annurev.pathol.1.110304.100125] [Citation(s) in RCA: 409] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori is the main cause of peptic ulceration, distal gastric adenocarcinoma, and gastric lymphoma. Only 15% of those colonized develop disease, and pathogenesis depends upon strain virulence, host genetic susceptibility, and environmental cofactors. Virulence factors include the cag pathogenicity island, which induces proinflammatory, pro-proliferative epithelial cell signaling; the cytotoxin VacA, which causes epithelial damage; and an adhesin, BabA. Host genetic polymorphisms that lead to high-level pro-inflammatory cytokine release in response to infection increase cancer risk. Pathogenesis is dependent upon inflammation, a Th-1 acquired immune response and hormonal changes including hypergastrinaemia. Antral-predominant inflammation leads to increased acid production from the uninflamed corpus and predisposes to duodenal ulceration; corpus-predominant gastritis leads to hypochlorhydria and predisposes to gastric ulceration and adenocarcinoma. Falling prevalence of H. pylori in developed countries has led to a falling incidence of associated diseases. However, whether there are disadvantages of an H. pylori-free stomach, for example increased risk of esosphageal adenocarcinoma, remains unclear.
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Affiliation(s)
- John C Atherton
- Wolfson Digestive Diseases Centre and Institute of Infections, Immunity, and Inflammation, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
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Wilson KT, Crabtree JE. Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies. Gastroenterology 2007; 133:288-308. [PMID: 17631150 DOI: 10.1053/j.gastro.2007.05.008] [Citation(s) in RCA: 190] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2007] [Accepted: 05/02/2007] [Indexed: 02/08/2023]
Abstract
Helicobacter pylori infects the stomach of half of the human population worldwide and causes chronic active gastritis, which can lead to peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The host immune response to the infection is ineffective, because the bacterium persists and the inflammation continues for decades. Bacterial activation of epithelial cells, dendritic cells, monocytes, macrophages, and neutrophils leads to a T helper cell 1 type of adaptive response, but this remains inadequate. The host inflammatory response has a key functional role in disrupting acid homeostasis, which impacts directly on the colonization patterns of H pylori and thus the extent of gastritis. Many potential mechanisms for the failure of the host response have been postulated, and these include apoptosis of epithelial cells and macrophages, inadequate effector functions of macrophages and dendritic cells, VacA inhibition of T-cell function, and suppressive effects of regulatory T cells. Because of the extent of the disease burden, many strategies for prophylactic or therapeutic vaccines have been investigated. The goal of enhancing the host's ability to generate protective immunity has met with some success in animal models, but the efficacy of potential vaccines in humans remains to be demonstrated. Aspects of H pylori immunopathogenesis are reviewed and perspectives on the failure of the host immune response are discussed. Understanding the mechanisms of immune evasion could lead to new opportunities for enhancing eradication and prevention of infection and associated disease.
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Affiliation(s)
- Keith T Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0252, USA
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Abstract
Acute infection with Helicobacter pylori causes hypochlorhydria and gastrointestinal upset. As the infection persists, patients develop chronic antral-predominant or pangastritis. Gastric and duodenal ulcers arise from chronic mucosal inflammation and disordered acid secretion in the stomach. With successful eradication of H. pylori, non-NSAID-related gastric and duodenal ulcers heal even without long-term acid suppression. More importantly, peptic ulcers and their complications rarely recur. Clearing H. pylori infection also reduces the risk of mucosal injury in NSAID and aspirin users; the protective effects are more pronounced in NSAID-naïve and aspirin users. H. pylori is unlikely to be the cause of gastro-oesophageal reflux disease. However, a patient's reflux symptoms may be more difficult to control after clearing the infection. Although there is little evidence to support a causal relationship between H. pylori and non-ulcer dyspepsia, treatment of the infection gives a modest improvement of symptoms.
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Affiliation(s)
- Larry H Lai
- Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, NT, Hong Kong SAR, China
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Algood HMS, Cover TL. Helicobacter pylori persistence: an overview of interactions between H. pylori and host immune defenses. Clin Microbiol Rev 2006; 19:597-613. [PMID: 17041136 PMCID: PMC1592695 DOI: 10.1128/cmr.00006-06] [Citation(s) in RCA: 186] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori is a gram-negative bacterium that persistently colonizes more than half of the global human population. In order to successfully colonize the human stomach, H. pylori must initially overcome multiple innate host defenses. Remarkably, H. pylori can persistently colonize the stomach for decades or an entire lifetime despite development of an acquired immune response. This review focuses on the immune response to H. pylori and the mechanisms by which H. pylori resists immune clearance. Three main sections of the review are devoted to (i) analysis of the immune response to H. pylori in humans, (ii) analysis of interactions of H. pylori with host immune defenses in animal models, and (iii) interactions of H. pylori with immune cells in vitro. The topics addressed in this review are important for understanding how H. pylori resists immune clearance and also are relevant for understanding the pathogenesis of diseases caused by H. pylori (peptic ulcer disease, gastric adenocarcinoma, and gastric lymphoma).
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Affiliation(s)
- Holly M Scott Algood
- Division of Infectious Diseases, A2200 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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Yakabi K, Ro S, Miura S, Tanaka T, Ohno S, Kawashima J, Kurosawa S, Nakamura T. Effect of interleukin-8 on histamine release from totally isolated vascularly perfused rat stomach. J Gastroenterol 2005; 40:1100-6. [PMID: 16378173 DOI: 10.1007/s00535-005-1707-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2005] [Accepted: 07/07/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recent studies have demonstrated relationships between cytokines and gastric acid secretion. The present study was performed in rats to elucidate the effects of interleukin-8 (IL-8) on gastric acid secretion through an increase in histamine release from the stomach. METHODS The experiments were performed in gastric lumen-perfused rats for the study of acid secretion and in totally isolated vascularly perfused rat stomach preparations for the study of histamine release. The histamine in the effluent was determined by radioimmunoassay. RESULTS IL-8 (500 ng) significantly enhanced gastrin-stimulated acid secretion. IL-8, at a concentration of 500 ng/20 ml per 10 min, did not alter basal histamine release, but at 100 ng/20 ml and 500 ng/20 ml it dose-dependently increased gastrin-stimulated histamine release. CONCLUSIONS IL-8 enhances gastrin-stimulated acid secretion and histamine release from the rat stomach, which may explain the enhancing effect of IL-8 on gastric acid secretion.
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Affiliation(s)
- Koji Yakabi
- The First Department of Internal Medicine, Saitama Medical Center, Saitama Medical School, 1981 Kamoda Tsujido-machi, Kawagoe 350-8550, Japan
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N/A, 卢 雅, 潘 金. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13:2521-2529. [DOI: 10.11569/wcjd.v13.i21.2521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/26/2023] Open
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Poland GA, Poterucha JJ. Hepatitis B immunization after liver transplantation: what is the answer? Liver Transpl 2005; 11:1181-3. [PMID: 16184563 DOI: 10.1002/lt.20538] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Zavros Y, Merchant JL. Modulating the cytokine response to treat Helicobacter gastritis. Biochem Pharmacol 2005; 69:365-71. [PMID: 15652228 DOI: 10.1016/j.bcp.2004.07.043] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2004] [Accepted: 07/30/2004] [Indexed: 01/20/2023]
Abstract
The conventional view of gastric acid secretion is that a negative feedback mechanism arises in response to high acidity, such that somatostatin keeps G-cells and parietal cells from producing more gastrin and acid, respectively. When the stomach becomes infected, for example with Helicobacter pylori (H. pylori), the feedback mechanism is impaired. In animal models, our laboratory has demonstrated that other types of bacteria besides H. pylori can cause gastritis. For example, under conditions of low acidity, gastritis is secondary to bacterial overgrowth, not production of excessive acid, thus suggesting a new paradigm for the regulation of gastric acid secretion under inflammatory conditions. Cytokines, released during the gastric inflammatory response, including IFN gamma, TNF alpha and IL-1 beta stimulate the G-cell to produce gastrin. Gastrin in turn triggers the release of acid, and hypergastrinemia suppresses somatostatin, the inhibitor of acid. The overall response results in maximal gastric acid output that acts as the stomach's most important anti-microbial agent. The increased acid secretion by the stomach in the presence of H. pylori seems to be part of the innate immune response, in that gastrin and somatostatin are reciprocally regulated by Th1 or Th2 cytokines, respectively. In a mouse model, we showed that octreotide, a somatostatin, analog, is an efficacious treatment for Helicobacter gastritis. In humans, octreotide might accelerate recovery from H. pylori infection, reducing the duration of antibiotic therapy.
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Affiliation(s)
- Yana Zavros
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-0650, USA
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Abstract
Chronic gastritis induced by Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the distal stomach, yet only a minority of people who harbour this organism ever develop cancer. H. pylori isolates possess substantial genotypic diversity, which engenders differential host inflammatory responses that influence clinical outcome. H. pylori strains that possess the cag pathogenicity island and secrete a functional cytotoxin induce more severe gastric injury and further augment the risk for developing distal gastric cancer. However, carcinogenesis is also influenced by host genetic diversity, particularly involving immune response genes such as IL-1ss and TNF-alpha. It is important to gain insight into the pathogenesis of H. pylori-induced gastritis and adenocarcinoma, not only to develop more effective treatments for gastric cancer, but also because it might serve as a paradigm for the role of chronic inflammation in the genesis of other malignancies that arise within the gastrointestinal tract.
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Affiliation(s)
- Richard M Peek
- Division of Gastroenterology, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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Bayraktaroğlu T, Aras AS, Aydemir S, Davutoğlu C, Ustündağ Y, Atmaca H, Borazan A. Serum levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-8 are not increased in dyspeptic patients with Helicobacter pylori-associated gastritis. Mediators Inflamm 2004; 13:25-8. [PMID: 15203561 PMCID: PMC1781536 DOI: 10.1080/09629350410001664789] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION: Helicobacter pylori (H. pylori) is a non-invasive microorganism causing intense gastric mucosal inflammatory and immune reaction. H. pylori-induced gastric mucosal cytokine overproduction has been clearly documented previously. The stomach has a large surface area and continuous spill-over of locally produced cytokines into the blood stream is a possibility. There are few and conflicting data on circulatory proinflammatory cytokine levels in patients with H. pylori infection. MATERIALS AND METHODS: Forty-two dyspeptic patients were enrolled into the study. The presence of H. pylori infection was diagnosed with antral histopathologic examination. After overnight fasting; serum samples were obtained from each patient to determine circulating interleukin (IL)-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) levels. RESULTS: H. pylori was shown in 30 cases using Giemsa stain in antral histopathologic evaluation. Twelve cases were negative for H. pylori staining. Both the age and sex distribution had an insignificant difference in both H pylori-positive and H. pylori-negative groups. The mean circulatory levels of IL-6, IL-8 and TNF-a in both groups were not different. The situation was same in respect to the serum levels of these cytokines and the degree of inflammation, H. pylori density and activation scores according to Sydney classification. CONCLUSION: We could not show elevated circulatory levels of IL-6, IL-8 and TNF-alpha in H. pylori-infected cases. We believe that H. pylori-related cytokine activation become concentrated on gastric mucosa and this pathogen-induced local inflammatory cascade does not cause changes in circulatory levels of these cytokines. Moreover, there is no correlation between the levels of serum cytokines and Sydney parameters.
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Affiliation(s)
- Taner Bayraktaroğlu
- Department of Internal Medicine, Faculty of Medicine, Zonguldak Karaelmas University, Zonguldak, Turkey.
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Zavros Y, Kao JY, Merchant JL. Inflammation and cancer III. Somatostatin and the innate immune system. Am J Physiol Gastrointest Liver Physiol 2004; 286:G698-701. [PMID: 15068961 DOI: 10.1152/ajpgi.00529.2003] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
In the stomach, somatostatin is secreted from D cells and is a potent inhibitor of gastrin-induced acid secretion. During bacterial infection, somatostatin expression and release are suppressed. As a result, gastric infection often induces hypergastrinemia that, in turn, stimulates gastric acid secretion, the stomach's most important antimicrobial agent. There are an abundance of data showing that inflammatory cytokines regulate somatostatin in immune and neural cells. However, it was not until recently that the immunoregulation of gastric somatostatin was studied in vivo. This theme article discusses the role of somatostatin as an immunoregulatory peptide during gastritis.
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Affiliation(s)
- Yana Zavros
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
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Beales ILP, Calam J. Regulation of amylin release from cultured rabbit gastric fundic mucosal cells. BMC PHYSIOLOGY 2003; 3:13. [PMID: 14572315 PMCID: PMC269984 DOI: 10.1186/1472-6793-3-13] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2003] [Accepted: 10/22/2003] [Indexed: 11/21/2022]
Abstract
BACKGROUND Amylin (islet amyloid polypeptide) is a hormone with suggested roles in the regulation of glucose homeostasis, gastric motor and secretory function and gastroprotection. In the gastric mucosa amylin is found co-localised with somatostatin in D-cells. The factors regulating gastric amylin release are unknown. In this study we have investigated the regulation of amylin release from gastric mucosal cells in primary culture. Rabbit fundic mucosal cells enriched for D-cells by counterflow elutriation were cultured for 40 hours. Amylin and somatostatin release over 2 hours in response to agonists were assessed. RESULTS Amylin release was significantly enhanced by activation of protein kinase C with phorbol-12-myristate-13-acetate, adenylate cyclase with forskolin and elevation of intracellular calcium with A23187. Cholecystokinin (CCK), epinephrine and glucagon-like peptide-1 (GLP-1) each stimulated amylin release in a dose-dependent manner. Maximal CCK-stimulated release was greater than either epinephrine or GLP-1, even when the effects of the latter two were enhanced by isobutylmethylxanthine. Stimulated amylin release was significantly inhibited by carbachol (by 51-59%) and octreotide (by 33-42%). Somatostatin release paralleled that of amylin. CONCLUSIONS The cultured D-cell model provides a means of studying amylin release. Amylin secretion is stimulated by receptor-dependent and -independent activation of Ca2+/protein kinase C and adenylate cyclase pathways. Inhibition involves activation of muscarinic receptors and auto-regulation by somatostatin.
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Affiliation(s)
- Ian LP Beales
- Gastrointestinal Research Unit, Department of Physiology and Cell Biology, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, United Kingdom
- Department of Gastroenterology, Norfolk and Norwich University Hospital NHS Trust, Norwich NR4 7UZ, United Kingdom
| | - John Calam
- Department of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom
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Zavros Y, Rathinavelu S, Kao JY, Todisco A, Del Valle J, Weinstock JV, Low MJ, Merchant JL. Treatment of Helicobacter gastritis with IL-4 requires somatostatin. Proc Natl Acad Sci U S A 2003; 100:12944-9. [PMID: 14555768 PMCID: PMC240724 DOI: 10.1073/pnas.2135193100] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Fifty percent of the world's population is infected with Helicobacter pylori; however, treatment has been insufficient to eradicate the organisms due to rising antibiotic resistance. Helicobacter infection is characterized by induction of a T helper 1 lymphocyte (Th1) immune response, hypergastrinemia, and suppressed tissue somatostatin (SOM) levels. However, the mechanism by which the immune response regulates acid secretion is not known. We show here that treatment with IFN-gamma, a Th1 cytokine, was sufficient to induce gastritis, increase gastrin, and decrease SOM levels within 7 days. In contrast, the T helper 2 lymphocyte cytokine IL-4 increased SOM levels and effectively suppressed gastrin expression and secretion. This result demonstrated reciprocal regulation of acid regulatory peptides by immune modulators. IL-4 pretreatment prevented gastritis in infected wild-type but not in SOM null mice. Thus, the ability of IL-4 to oppose a Th1-mediated infection required SOM. Immunofluorescence was used to document the presence of IL-4 receptors on the gastric SOM-secreting cell (D cell). Moreover, IL-4 stimulated SOM release from primary D cell cultures. Treatment of mice chronically infected with Helicobacter felis for 2 mo with the SOM analogue octreotide resolved the inflammation. Thus, a mechanism by which IL-4 resolves inflammation in the stomach is by stimulating the release of SOM from gastric D cells.
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Affiliation(s)
- Yana Zavros
- Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; and Vollum Institute, Oregon Health and Science University, Portland, OR 97239-3098
| | - Sivaprakash Rathinavelu
- Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; and Vollum Institute, Oregon Health and Science University, Portland, OR 97239-3098
| | - John Y. Kao
- Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; and Vollum Institute, Oregon Health and Science University, Portland, OR 97239-3098
| | - Andrea Todisco
- Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; and Vollum Institute, Oregon Health and Science University, Portland, OR 97239-3098
| | - John Del Valle
- Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; and Vollum Institute, Oregon Health and Science University, Portland, OR 97239-3098
| | - Joel V. Weinstock
- Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; and Vollum Institute, Oregon Health and Science University, Portland, OR 97239-3098
| | - Malcolm J. Low
- Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; and Vollum Institute, Oregon Health and Science University, Portland, OR 97239-3098
| | - Juanita L. Merchant
- Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; and Vollum Institute, Oregon Health and Science University, Portland, OR 97239-3098
- To whom correspondence should be addressed. E-mail:
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20
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Hopman WPM, Jong DJD, Naber AHJ, J B M J Jansen. Tumour Necrosis Factor Alpha Antibody Affects Gastrin Release in Crohn Disease. Scand J Gastroenterol 2003; 38:522-525. [PMID: 28443771 DOI: 10.1080/00365520310002896] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gastrin plays an important role in the regulation of gastric acid secretion in humans. Tumour necrosis factor alpha (TNF-α) stimulates gastrin release from antral G cells in vitro. The aim was to determine whether gastrin release decreases in patients with Crohn disease treated with monoclonal antibody to TNF-α. METHODS Twenty-five consecutive patients with Crohn disease (10 M, 15 F; 18 with fistulas) were treated with a single intravenous infusion of the monoclonal antibody to TNF-α, infliximab, at a dose of 5 mg/kg. Basal and bombesin stimulated gastrin was measured after an overnight fast immediately before and 2 weeks after infliximab. Helicobacter pylori status was determined by serology. RESULTS Twenty-two patients were H. pylori-negative. Basal plasma gastrin was 21 (16-26) pmol/L before and 19 (15-25) pmol/L after infliximab (NS). Bombesin stimulated gastrin decreased from 49 (40-62) pmol/L before to 36 (33-59) pmol/L (P < 0.005) 2 weeks after infliximab. CONCLUSION Gastrin release in response to bombesin decreases in patients with Crohn disease treated with infliximab.
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Affiliation(s)
- W P M Hopman
- a Dept. of Gastroenterology and Hepatology University Medical Center Nijmegen Nijmegen The Netherlands
| | - D J de Jong
- a Dept. of Gastroenterology and Hepatology University Medical Center Nijmegen Nijmegen The Netherlands
| | - A H J Naber
- a Dept. of Gastroenterology and Hepatology University Medical Center Nijmegen Nijmegen The Netherlands
| | - J B M J Jansen
- a Dept. of Gastroenterology and Hepatology University Medical Center Nijmegen Nijmegen The Netherlands
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21
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Deprez P, Sempoux C, Van Beers BE, Jouret A, Robert A, Rahier J, Geubel A, Pauwels S, Mainguet P. Persistent decreased plasma cholecystokinin levels in celiac patients under gluten-free diet: respective roles of histological changes and nutrient hydrolysis. REGULATORY PEPTIDES 2002; 110:55-63. [PMID: 12468110 DOI: 10.1016/s0167-0115(02)00162-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Celiac disease is associated with impaired cholecystokinin (CCK) release. The mechanism by which CCK release is impaired is poorly understood and seems to be related to the mucosal atrophy or to decreased stimulation due to reduced intraduodenal nutrient hydrolysis. The aims of our study were to evaluate basal and postprandial CCK in celiac patients presenting with distinctive types of mucosal lesions (normal, infiltrative and atrophic), and to study the role of protein hydrolysis on CCK release. Plasma CCK was measured in 20 celiac patients (normal mucosa: n=6; infiltrative type: n=6; atrophic type=8) and 9 controls, before and after ingestion of a polymeric or a semi-elemental meal. Significant decreases in basal CCK plasma (B 0.6 [95% CI, 0.3-1.3] pmol/l; p<0.003) and postprandial CCK area under curve (AUC 34 [19-61] pmol/l x 120 min, p<0.0001) were observed in patients with an atrophic mucosa compared with treated patients (B 1.6 [1.0-2.4] pmol/l, AUC 267 [172-414] pmol/l x 120 min) or healthy volunteers (B 1.0 [0.7-1.4] pmol/l, AUC 186 [131-264] pmol/l x 120 min). A significant defective CCK release was also observed in patients with an infiltrative type: B 0.4 [0.2-0.7] pmol/l and AUC 56 [31-101] pmol/l x 120 min; p<0.0001. Administration of a semi-elemental diet did not correct the defective CCK release. In conclusion, the decreased CCK levels observed in celiac patients are not strictly related to the mucosal atrophy but rather to the lymphocytic infiltrate. Administration of a predigested meal did not correct the impaired CCK release. Some inhibitory mechanism could be involved in the CCK cell dysfunction observed in celiac patients presenting with lesser degrees of disease activity.
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Affiliation(s)
- Pierre Deprez
- Department of Gastroenterology, Cliniques Universitaires St-Luc, Catholic University of Louvain, Av. Hippocrate 10, B-1200, Brussels, Belgium.
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22
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Abstract
The discovery of Helicobacter pylori has greatly changed our approach to peptic ulcer disease. Bacterial, host, and environmental factors all have a role in peptic-ulcer disease. Although the prevalence of uncomplicated peptic ulcers is falling, hospital admissions for ulcer complications associated with non-steroidal anti-inflammatory drugs (NSAIDs) are rising. Evidence suggests that prescription of NSAIDs along with potent antiulcer agents and the use of highly selective cyclo-oxygenase-2 inhibitors reduce gastroduodenal ulceration. Whether these therapeutic advances will translate into clinical benefits remains to be seen. The interaction between H pylori and NSAIDs is one of the most controversial issues in peptic ulcer disease. With the fall in rates of H pylori infection, the proportion of ulcers not related to this organism and NSAIDs has risen, which will affect the management of peptic ulcer.
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Affiliation(s)
- Francis K L Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China.
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23
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Beales ILP. Effect of interlukin-1beta on proliferation of gastric epithelial cells in culture. BMC Gastroenterol 2002; 2:7. [PMID: 11936957 PMCID: PMC103665 DOI: 10.1186/1471-230x-2-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2001] [Accepted: 04/05/2002] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Helicobacter pylori is the main risk factor for the development of non-cardia gastric cancer. Increased proliferation of the gastric mucosa is a feature of H. pylori infection. Mucosal interkeukin-1beta production is increased in H. pylori infection and IL-1beta genotypes associated with increased pro-inflammatory activity are risk factors for the development of gastric cancer. The effect of IL-1beta on gastric epithelial cell proliferation has been examined in this study. METHODS AGS cells were cultured with IL-1beta. DNA synthesis was assed by [3H]thymidine incorporation and total viable cell numbers by MTT assay. RESULTS IL-1beta dose dependently increased DNA synthesis and cell numbers. The enhanced proliferation was blocked by interleukin-1 receptor antagonist. Addition of neutralising antibody to GM-CSF reduced IL-1beta-stimulated proliferation by 31 +/- 4 %. GM-CSF alone significantly stimulated proliferation. Addition or neutralisation of IL-8 had no effect on basal or IL-1beta-stimulated proliferation. The tyrosine kinase inhibitor genistein completely blocked IL-1beta-stimulated proliferation and inhibition of the extracellular signal related kinase pathway with PD 98059 inhibited IL-1beta stimulated proliferation by 58 +/- 5 %. CONCLUSIONS IL-1beta stimulates proliferation in gastric epithelial cells. Autocrine stimulation by GM-CSF contributes to this proliferative response. Signalling via tyrosine kinase activity is essential to the mitogenic response to IL-1beta. The extracellular signal related kinase pathway is involved in, but not essential to downstream signalling. IL-1beta may contribute to the hyperproliferation seen in H. pylori- infected gastric mucosa, and be involved in the carcinogenic process.
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Affiliation(s)
- Ian L P Beales
- Department of Cell Biology School of Medicine, Health Policy and Practice, University of East Anglia Norwich, NR4 7TJ, United Kingdom.
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24
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Sobhani I, Canedo S, Alchepo B, Vissuzaine C, Chevalier C, Buyse M, Moizo L, Laigneau JP, Mignon M, Lewin JM, Bado A. Putative effect of Helicobacter pylori and gastritis on gastric acid secretion in cat. Am J Physiol Gastrointest Liver Physiol 2002; 282:G727-34. [PMID: 11897633 DOI: 10.1152/ajpgi.00282.2001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Helicobacter pylori may increase or inhibit gastric acid. We studied acid variations and plasma gastrin in cats harboring Helicobacter felis, harboring H. pylori, or free of gastric pathogens with reference to thioperamide (H(3) receptor antagonist) and SR-27417A (PAF receptor antagonist). In cats harboring H. felis, gastric mucosa were histologically normal. After H. felis eradication, pentagastrin-stimulated acid secretion was increased (40%) compared with the situation before eradication. Thioperamide abolished this inhibitory effect of H. felis, whereas SR-27417A did not. Basal and meal-stimulated plasma gastrin levels were not affected by eradication therapy. Acid secretion was inhibited (-80%) in week 3, increased from weeks 5 to 9, and remained constant for up to 42 weeks after H. pylori infection. SR-27417A had no effect on acid secretion before week 8 but inhibited it thereafter, and thioperamide increased it (20%) only before week 7 in those cats. Helicobacter inhibits gastric acid via an H(3) receptor pathway. Inflammatory mediators are thus involved in adaptation to the inhibitory effects of H. pylori on acid secretion.
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Affiliation(s)
- Iradj Sobhani
- INSERM Unité 410, Hôpital Bichat Claude Bernard, 75877 Cedex Paris 18, France.
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25
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Zavros Y, Rieder G, Ferguson A, Samuelson LC, Merchant JL. Hypergastrinemia in response to gastric inflammation suppresses somatostatin. Am J Physiol Gastrointest Liver Physiol 2002; 282:G175-83. [PMID: 11751171 DOI: 10.1152/ajpgi.00287.2001] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hypergastrinemia and a reduction in tissue somatostatin occur in Helicobacter pylori-infected patients. We investigated whether the D cell may be a direct target of gastric inflammation and hypergastrinemia. D cells were quantified by morphometry and flow cytometry in 16-wk-old wild-type (G+/+) and gastrin-deficient (G-/-) mice. Hypochlorhydric G-/- mice were treated with either antibiotics for 20 days or infused with gastrin (G-17) for 14 days. G+/+ mice were made hypochlorhydric by treating them with omeprazole for 2 mo. G-/- mice showed significant inflammation compared with the G+/+ mice, which resolved after 20 days of antibiotic treatment. D cell numbers were not significantly different between G-/- and G+/+ mice. After G-17 was infused, fundic and antral D cell numbers decreased in the G-/- mice. G+/+ animals made hypergastrinemic with omeprazole exhibited decreased D cell numbers. When omeprazole-treated mice were treated with antibiotics alone, elevated plasma gastrin levels returned to baseline and D cell numbers returned to resting levels despite persistent hypochlorhydria. Hypergastrinemia, induced by inflammation, results in decreased D cell numbers. Thus the stomach responds to the presence of inflammation by reducing somatostatin levels, thereby releasing the inhibition on the G and parietal cells to maximize gastric acid output.
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Affiliation(s)
- Yana Zavros
- Howard Hughes Medical Institute, Ann Arbor, Michigan 48109-0650, USA
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26
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Suzuki T, Grand E, Bowman C, Merchant JL, Todisco A, Wang L, Del Valle J. TNF-alpha and interleukin 1 activate gastrin gene expression via MAPK- and PKC-dependent mechanisms. Am J Physiol Gastrointest Liver Physiol 2001; 281:G1405-12. [PMID: 11705745 DOI: 10.1152/ajpgi.2001.281.6.g1405] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Helicobacter pylori and proinflammatory cytokines have a direct stimulatory effect on gastrin release from isolated G cells, but little is known about the mechanism by which these factors regulate gastrin gene expression. We explored whether tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 directly regulate gastrin gene expression and, if so, by what mechanism. TNF-alpha and IL-1 significantly increased gastrin mRNA in canine G cells to 181 +/- 18% and 187 +/- 28% of control, respectively, after 24 h of treatment. TNF-alpha and IL-1 stimulated gastrin promoter activity to a maximal level of 285 +/- 12% and 415 +/- 26% of control. PD-98059 (a mitogen-activated protein kinase kinase inhibitor), SB-202190 (a p38 kinase inhibitor), and GF-109203 (a protein kinase C inhibitor) inhibited the stimulatory action of both cytokines on the gastrin promoter. In conclusion, both cytokines can directly regulate gastrin gene expression via a mitogen-activated protein kinase- and protein kinase C-dependent mechanism. These data suggest that TNF-alpha and IL-1 may play a direct role in Helicobacter pylori-induced hypergastrinemia.
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Affiliation(s)
- T Suzuki
- Department of Internal Medicine, The University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
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27
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Beales IL. Monoclonal antibody to tumor necrosis factor-alpha reduces hypergastrinemia in Helicobacter pylori infection. Am J Med 2001; 111:77-78. [PMID: 11460851 DOI: 10.1016/s0002-9343(01)00786-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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28
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Yamamoto S, Kaneko H, Konagaya T, Mori S, Kotera H, Hayakawa T, Yamaguchi C, Uruma M, Kusugami K, Mitsuma T. Interactions among gastric somatostatin, interleukin-8 and mucosal inflammation in Helicobacter pylori-positive peptic ulcer patients. Helicobacter 2001; 6:136-45. [PMID: 11422469 DOI: 10.1046/j.1523-5378.2001.00020.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND To investigate whether Helicobacter pylori infection, but not drugs, affects gastric somatostatin, interleukin-8 (IL-8), histological inflammation through eradication therapy, and interactions among these parameters. METHODS Twenty-eight H. pylori-positive patients (21 males; mean age 47.0 years) with either gastric ulcer (GU: n = 11) or duodenal ulcer (n = 17) diagnosed endoscopically were treated with dual therapy. Eradication was defined as negative microbiologic tests and 13C-urea breath test. Levels of antral and gastric juice somatostatin and mucosal IL-8 were measured by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. Histology was assessed by the Sydney system. RESULTS H. pylori was eradicated in 15 patients (10 males, 6 GU) out of 28 (54%). The patients' backgrounds did not affect the eradication of H. pylori. Successes in eradication significantly increased antral and juice somatostatin contents, and dramatically decreased IL-8 levels and histological gastritis. In contrast, persistent H. pylori infection did not affect somatostatin and histological gastritis. An inverse correlation was present between changes in somatostatin levels and histological activity. No relationship was observed in changed values between antral somatostatin and IL-8. CONCLUSIONS These results indicate that eradication of H. pylori, but not the drugs used, induced an increase in somatostatin levels in the antrum and gastric juice, suggesting a close relationship between H. pylori and gastric somatostatin regulation. A close correlation between an increase in gastric somatostatin levels and the normalization of histological activity was present, suggesting that certain peptide-immune interactions in the gastric mucosa exist in H. pylori infection.
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Affiliation(s)
- S Yamamoto
- First Department of Internal Medicine, Nagoya University School of Medicine, Japan
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29
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30
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Konturek PC, Konturek SJ, Starzyska T, Marlicz K, Bielanski W, Pierzchalski P, Karczewska E, Hartwich A, Rembiasz K, Lawniczak M, Ziemniak W, Hahn EC. Helicobacter pylori-gastrin link in MALT lymphoma. Aliment Pharmacol Ther 2000; 14:1311-8. [PMID: 11012476 DOI: 10.1046/j.1365-2036.2000.00832.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND There is accumulating evidence for the role of Helicobacter pylori in the development of gastric cancer as well as of lymphomas that arise in mucosa-associated lymphoid tissue (MALT). We reported recently that gastric cancer patients show high prevalence of cagA-positive H. pylori and express gastrin and gastrin receptors enabling them to stimulate tumour growth in autocrine fashion. AIMS Since the H. pylori infection is considered to be more strongly associated with MALT lymphoma than with gastric cancer, we decided to determine the gastrin and its receptors' mRNA expression and gastrin content in this tumour as well as the release of this hormone both into plasma and gastric lumen. Twenty MALT lymphoma patients were compared with 100 age- and gender-matched controls with similar dyspeptic symptoms. RESULTS The overall H. pylori seropositivity in MALT lymphoma was about 90% and CagA positivity was 70%, compared to 56% and 33%, respectively, in controls. The serum gastrin in MALT lymphoma was about sixfold higher than in controls while gastric luminal gastrin in these patients was over 70 times higher than in controls. Gastrin content in tumour was about 10-fold higher than in antral mucosa. Gastrin and gastrin-receptor (CCKB-receptor) mRNA were detected by reverse transcriptase-polymerase chain reaction in cancer tissue whilst in the fundic and antral mucosa, only enhanced expression of CCKB-receptor mRNA and gastrin mRNA was detected, respectively. Histamine stimulation in MALT lymphoma induced acid secretion that was only about 30% of control value due to atrophic gastritis. This study confirms an important role of CagA-positive H. pylori in the pathogenesis of MALT lymphoma and shows that this lymphoma is capable of synthesizing and releasing potent growth promoting gastrin, possibly due to the action on G-cells of H. pylori-originated Nalpha-methyl histamine and cytokines (tumour necrosis factor alpha and interleukin-8). CONCLUSIONS Gastric MALT lymphoma is closely linked to CagA-positive H. pylori infection. Gastrin and its receptors may be implicated in the pathogenesis of gastric lymphoma.
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Affiliation(s)
- P C Konturek
- Department of Medicine, University Erlangen-Nuremberg, Erlangen, Germany
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Oka S, Gabazza EC, Taguchi Y, Yamaguchi M, Nakashima S, Suzuki K, Adachi Y, Imoto I. Role of activated protein C in Helicobacter pylori-associated gastritis. Infect Immun 2000; 68:2863-9. [PMID: 10768983 PMCID: PMC97498 DOI: 10.1128/iai.68.5.2863-2869.2000] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The protein C (PC) pathway has recently been suggested to play a role in the regulation of the inflammatory response. To further extend the anti-inflammatory effect of activated PC (APC) in vivo, particularly its biological relevance to human disease, the activity of APC in the mucosa of patients with Helicobacter pylori-associated gastritis and the effect of vacuolating cytotoxin (VacA), cytotoxin-associated antigen (CagA), and H. pylori lipopolysaccharide (LPS) on PC activation were evaluated. This study comprised 35 patients with chronic gastritis. There were 20 patients with and 15 without H. pylori infection. The levels of PC and APC-PC inhibitor (PCI) complex were measured by immunoassays. The level of PC was significantly decreased and the level of APC-PCI complex was significantly increased in biopsy specimens from gastric corpus and antrum in patients with H. pylori-associated gastritis as compared to H. pylori-negative subjects. The concentrations of VacA, CagA, and LPS were significantly correlated with those of the APC-PCI complex in biopsy mucosal specimens from the gastric corpus and antrum. H. pylori LPS, VacA, and CagA induced a dose-dependent activation of PC on the surface of monocytic cells. APC inhibited the secretion of tumor necrosis factor alpha (TNF-alpha) induced by H. pylori LPS. Overall, these results suggest that H. pylori infection is associated with increased APC generation in the gastric mucosa. The inhibitory activity of APC on TNF-alpha secretion may serve to protect H. pylori-induced gastric mucosal damage.
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Affiliation(s)
- S Oka
- The Third Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie, Japan
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32
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Lamberts R. Morphological changes of the human gastric mucosa under long-term proton pump inhibitor therapy and their clinical relevance. Microsc Res Tech 2000; 48:357-66. [PMID: 10738317 DOI: 10.1002/(sici)1097-0029(20000315)48:6<357::aid-jemt6>3.0.co;2-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Proton pump inhibitors are potent drugs for the treatment of acid-related diseases. The moderate hypergastrinaemia observed during therapy is a physiological response to low intragastric pH and the increase is limited to the first months of therapy with no further changes thereafter. Reports on endocrine cell changes in the antral mucosa under chronic PPI therapy are controversial and lack clinical relevance. In contrast, in the oxyntic mucosa hyperplastic argyrophil cell changes have been reported, dependent on the degree and duration of hypergastrinaemia, the severity of oxyntic mucosal gastritis, especially atrophy, and the presence of H. pylori infection. Current data do not support a progression from hyperplastic to dysplastic argyrophil cell lesions in humans in the absence of additional genetic factors. Data on the progression of oxyntic gastritis under chronic PPI treatment in comparison to untreated controls could not be confirmed in more recent studies including a well-matched control population. The main factor for gastritis progression is the presence of Helicobacter pylori infection. The bacterium not only causes a chronic inflammation of the gastric mucosa, resulting in atrophy and intestinal metaplasia, but also influences endocrine cell populations involved in the regulation of gastric acid secretion. The clinical benefit of H. pylori eradication in reflux esophagitis patients is still a matter of debate. The complex relations in humans between hypergastrinaemia, (oxyntic) gastritis and atrophy, H. pylori infection, argyrophil cell hyperplasia, and the effects of long-term PPI treatment of acid-related diseases do not allow a quantification of the contribution of each single factor for the observed changes.
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Affiliation(s)
- R Lamberts
- Department of Gastroenterology, Hepatology and Infectious Diseases, University of Tübingen, 72076 Tübingen, Germany
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33
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Bliss PW, Healey ZV, Arebi N, Calam J. Nalpha-methyl histamine and histamine stimulate gastrin release from rabbit G-cells via histamine H2-receptors. Aliment Pharmacol Ther 1999; 13:1669-74. [PMID: 10594403 DOI: 10.1046/j.1365-2036.1999.00649.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND Gastrin release by Helicobacter pylori may be an important step in the pathway leading to duodenal ulceration. A histamine H3-receptor agonist was found to release gastrin from antral mucosal fragments; this was interpreted as being due to suppression of somatostatin release. H. pylori is reported to produce Nalpha-methyl histamine (NalphaMH), which is an agonist of H3 as well as other histamine receptors. H. pylori infection also recruits mast cells, which release histamine. AIM To determine the direct effects of histamine receptor agonists on isolated gastrin cells. METHODS Rabbit G-cells were prepared by countercurrent elutriation and cultured on 24-well plates. RESULTS NalphaMH (10-6-10-4 M) caused a dose-dependent increase in gastrin release from a basal level of 2.3 +/- 0.2% total cell content (TCC; mean +/- S.E.M.) to a maximum of 5.1 +/- 0.7%, an increase of 117% (P < 0. 005) above basal. This was abolished by the H2-antagonist ranitidine (10-5 M), but not by immunoblockade with anti-somatostatin antibody, the H1-antagonist chlorpheniramine (10-5 M) or the H3-antagonist thioperamide (10-4 M). The histamine H2-receptor agonist dimaprit (10-6-10-4 M) increased gastrin release from 2.4 +/- 0.2% to 3.6 +/- 0.2% TCC (P < 0.001). Gastrin release was also stimulated by histamine (10-7-10-4 M) from a basal value of 3.0 +/- 0.3% to 5.4 +/- 0.5% TCC (P < 0.001). This also was inhibited by ranitidine (10-5 M) (P < 0.01). CONCLUSION NalphaMH and histamine release gastrin from G-cells via H2-receptors; this might contribute to H. pylori-associated hypergastrinaemia.
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Affiliation(s)
- P W Bliss
- Department of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK
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Bauer J. Advances in cell separation: recent developments in counterflow centrifugal elutriation and continuous flow cell separation. JOURNAL OF CHROMATOGRAPHY. B, BIOMEDICAL SCIENCES AND APPLICATIONS 1999; 722:55-69. [PMID: 10068133 DOI: 10.1016/s0378-4347(98)00308-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Cell separation by counterflow centrifugal elutriation (CCE) or free flow electrophoresis (FFE) is performed at lower frequency than cell cloning and antibody-dependent, magnetic or fluorescence-activated cell sorting. Nevertheless, numerous recent publications confirmed that these physical cell separation methods that do not include cell labeling or cell transformation steps, may be most useful for some applications. CCE and FFE have proved to be valuable tools, if homogeneous populations of normal healthy untransformed cells are required for answering scientific questions or for clinical transplantation and cells cannot be labeled by antibodies, because suitable antibodies are not available or because antibody binding to a cell surface would induce the cell reaction which should be investigated on purified cells or because antibodies bound to the surface hamper the use of the isolated cells. In addition, the methods are helpful for studying the biological reasons for, or effects of, changes in cell size and cellular negative surface charge density. Although the value of the methods was confirmed in recent years by a considerable number of important scientific results, activities to further develop and improve the instruments have, unfortunately, declined.
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Affiliation(s)
- J Bauer
- Max-Planck-Institut für Biochemie, Martinsried, Germany
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35
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Abstract
Helicobacter pylori is a gram-negative spiral bacterium confined to the habitat of gastric-type epithelium. H. pylori causes duodenal ulceration by a cumulative effect of antral predominant gastritis with increased acid secretion, consequent gastric metaplasia in the duodenum (a site of further colonization by H. pylori), duodenitis, reduced duodenal bicarbonate secretion, and mucosal damage. Bacterial factors influence outcome. Major determinants are the production of a vacuolating toxin and the presence of CagA, an immunodominant product of a nonconserved gene cagA, a marker for the cag pathogenicity island that encodes virulence genes involved in induction of epithelial chemokine responses. In ulcer patients the mucosal immune response is polarized to a T-helper-1 (Th1) cell-mediated response, which may contribute to mucosal damage. Eradication of H. pylori restores acid output to normal. Loss of both acid and bacteria halts gastroduodenitis and allows ulcer healing. Gastric metaplasia does not regress in the short term.
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Affiliation(s)
- M M Walker
- Department of Histopathology, Imperial College School of Medicine at St Mary's, London, United Kingdom
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36
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Beales IL. Effect of cytokines on acid secretion and gastrin secretion in Helicobacter pylori infection and aspirin-induced gastritis. Scand J Gastroenterol 1998; 33:1230-1232. [PMID: 9867106 DOI: 10.1080/00365529850172638] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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37
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Kleveland PM, Waldum HL. Intragastric pH and Helicobacter pylori treatment with proton pump inhibitors combined with amoxycillin. Scand J Gastroenterol 1998; 33:1230. [PMID: 9867105 DOI: 10.1080/00365529850172629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Abstract
Helicobacter pylori is the cause of chronic type B gastritis and occurs in almost all patients with duodenal ulcers. Infection with H. pylori is characterized by an increased production of several inflammatory cytokines. Increasing evidence suggests a central role of these cytokines in the pathogenesis of H. pylori-associated gastritis and peptic ulcer disease. Cytokines may be crucial in the recruitment and activation of inflammatory cells and in stimulation of gastrin release. In addition to their proinflammatory properties, cytokines may also inhibit the ulcer occurrence by stimulation of prostaglandins and somatostatin release and by direct impairment of acid secretion. The balance of these factors may determine the clinical outcome of H. pylori infection.
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Briard N, Guillaume V, Frachebois C, Rico-Gomez M, Sauze N, Oliver C, Dutour A. Endotoxin injection increases growth hormone and somatostatin secretion in sheep. Endocrinology 1998; 139:2662-9. [PMID: 9607770 DOI: 10.1210/endo.139.6.6072] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Endotoxin has been shown to stimulate GH secretion in human and sheep. However, changes in hypothalamic neurohormones involved in the GH regulation by endotoxin have never been studied in vivo. In sheep it is possible to collect hypophysial portal blood (HPB) and quantify GH-releasing hormone (GHRH) and somatostatin (SRIH) secretion under physiological conditions. The purpose of this study was to determine the effect of an acute i.v. endotoxin administration on the secretion of these peptides in sheep. Endotoxin induced a sustained increase of GH (x6.2 +/- 1.3) in intact rams. This stimulation was delayed and less marked when compared with the hypothalamic-pituitary-adrenal axis. Surprisingly, the GH increase was associated with an important rise of jugular (x10.6 +/- 2.4) and portal (x7.9 +/- 3) SRIH levels, without a significant GHRH increase. To determine if the portal SRIH increase was a consequence of an increased short feedback of GH, we studied GH response to endotoxin after a previous GHRH injection to deplete the pituitary pools of GH. In that case, despite the absence of increase of GH after endotoxin treatment, SRIH levels was markedly increased. For the first time we have observed an experimental situation in sheep with a simultaneous and closed amplitude increase in jugular and portal SRIH. The source of jugular SRIH is likely the gastrointestinal tract and the increased jugular SRIH release in systemic circulation might be in part responsible for the increase of hypophysial portal SRIH. Ultimately our results show that endotoxin induced a complex reaction at multiple levels with a specific increase in both portal and peripheral SRIH levels. The surprising association of a lack of change in GHRH release and an increased secretion of SRIH with the increase of GH suggests that the effect of endotoxin on GH axis is mainly a pituitary one. The selective blockade of somatostatin should be useful for a better knowledge of the role of SRIH stimulation in the physiopathology of septic shock.
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Affiliation(s)
- N Briard
- Laboratoire de Neuroendocrinologie Experimentale, INSERM U297, Institut Fédératif Jean Roche, Marseille, France
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40
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Testino G, Testino R. Helicobacter pylori and maximal acid output in chronic gastritis. Scand J Gastroenterol 1997; 32:1275-6. [PMID: 9438329 DOI: 10.3109/00365529709028160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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41
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Calam J, Gibbons A, Healey ZV, Bliss P, Arebi N. How does Helicobacter pylori cause mucosal damage? Its effect on acid and gastrin physiology. Gastroenterology 1997; 113:S43-9; discussion S50. [PMID: 9394759 DOI: 10.1016/s0016-5085(97)80010-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Helicobacter pylori infection increases gastric acid secretion in patients with duodenal ulcers but diminishes acid output in patients with gastric cancer and their relatives. Investigation of the basic mechanisms may show how H. pylori causes different diseases in different persons. Infection of the gastric antrum increases gastrin release. Certain cytokines released in H. pylori gastritis, such as tumor necrosis factor alpha and specific products of H. pylori, such as ammonia, release gastrin from G cells and might be responsible. The infection also diminishes mucosal expression of somatostatin. Exposure of canine D cells to tumor necrosis factor alpha in vitro reproduces this effect. These changes in gastrin and somatostatin increase acid secretion and lead to duodenal ulceration. But the acid response depends on the state of the gastric corpus mucosa. The net effect of corpus gastritis is to decrease acid secretion. Specific products of H. pylori inhibit parietal cells. Also, interleukin 1 beta, which is overexpressed in H. pylori gastritis, inhibits both parietal cells and histamine release from enterochromaffin-like cells. H. pylori also promotes gastric atrophy, leading to loss of parietal cells. Factors such as a high-salt diet and a lack of dietary antioxidants, which also increase corpus gastritis and atrophy, may protect against duodenal ulcers by decreasing acid output. However, the resulting increase of intragastric pH may predispose to gastric cancer by allowing other bacteria to persist and produce carcinogens in the stomach.
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Affiliation(s)
- J Calam
- Department of Gastroenterology, Imperial College School of Medicine, Hammersmith Hospital, London, England.
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