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Long-term morpho-functional development of Helicobacter pylori-induced gastritis in Mongolian gerbils
Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
Pathology Research Department, Ryhov Hospital, Jönköping.
Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland.
Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
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2005 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 40, no 10, 1157-1167 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:

Epidemiological studies have shown that Helicobacter pylori infection with associated chronic gastritis is the main risk factor for development of gastric cancer. The aim of this study was to investigate the long-term development of H. pylori-induced gastritis in Mongolian gerbils in terms of morphology, gastrin secretion, epithelial proliferation and gene expression of pro-inflammatory cytokines.

MATERIAL AND METHODS:

A total of 133 gerbils were inoculated with H. pylori and 62 served as controls. The gerbils were killed at different time-points between 6 and 94 weeks after inoculation. Serum concentrations of anti-H. pylori IgG and gastrin were determined by enzyme-linked immunoabsorbent assay (ELISA) and radioimmunoassay (RIA), respectively. Epithelial proliferation was evaluated immunohistochemically after labeling with 5-bromo-2'-deoxy-uridine. Gene expression of beta-actin, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were measured by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Histological parameters of gastritis were assessed semiquantitatively and expressed as a "gastritis score".

RESULTS:

Serum concentrations of anti-H. pylori IgG and gastrin increased over time. Epithelial proliferation in the antrum was increased 6 weeks after inoculation, followed by increased proliferation in the corpus 32 weeks after inoculation. Gene expression of IL-1beta and TNF-alpha were increased in H. pylori-infected gerbils. Beta-actin was not a reliable endogenous control for RT-PCR. With time, gastritis expanded from the antrum to the corpus and the gastritis score increased to reach a peak 32 weeks after inoculation. Pseudopyloric metaplasia (loss of specialized cells) was a characteristic feature in the corpus mucosa. Gastric ulcers, but neither dysplasia nor carcinoma, were observed during 94 weeks of infection.

CONCLUSIONS:

Long-term H. pylori infection in Mongolian gerbils led to progressive gastritis, glandular atrophy, hypergastrinemia, increased epithelial proliferation and elevated gene expression of pro-inflammatory cytokines.

Place, publisher, year, edition, pages
2005. Vol. 40, no 10, 1157-1167 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-30811DOI: 10.1080/00365520510023378Local ID: 16441OAI: oai:DiVA.org:liu-30811DiVA: diva2:251634
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-26Bibliographically approved
In thesis
1. Experimental Helicobacter pylori infection in an animal model
Open this publication in new window or tab >>Experimental Helicobacter pylori infection in an animal model
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Helicobacter pylori is a microaerophilic Gram-negative bacterium colonizing the human stomach. The prevalence of this infection is between 20-90% depending on geographic location. Comprehensive studies have shown significant relationships between H. pylori infection and chronic gastritis, peptic ulcer and gastric carcinoma. The mechanisms behind these associations are still unclear in many aspects. The objective of this thesis was to elucidate some pathogenetic aspects of H. pylori infection based on an animal model using Mongolian gerbils.

Aims: To determine bacterial profiles in the stomach of gerbils with and without H. pylori infection. To study the long-term morpho-functional development of H. pylori-induced gastritis. To investigate the gastric mucosal barrier function and to explore the effects of dietary antioxidant vitamin supplements on H. pylori-associated chronic gastritis.

Methods and results: Mongolian gerbils were inoculated with H. pylori ATCC 43504 or culture broth (controls). The animals were killed at scheduled time points. The gastric microflora was profiled and identified by temporal temperature gradient gel electrophoresis (TTGE), cloning and pyrosequencing of 16S rDNA variable V3 region. TTGE and pyrosequencing revealed the presence of a mixed bacterial flora in the stomach of both H. pylori infected and control animals. In both cases, lactobacilli appeared to prevail. In H. pylori-infected gerbils, serum concentrations of anti-H. pylori IgG and gastrin increased over time. Mucosal epithelial proliferation quantified after immunohistochemical labeling with 5-bromo-2'-deoxy-uridine was increased in the antrum in short-term gastritis, followed by an increase in the corpus in the long-term. Gene expression of pro-inflammatory cytokines was quantitated by real-time RT-PCR. Interleukin-1beta and tumor necrosis factor-alpha expression was increased in H. pylori-infected gerbils. Beta-actin was not a reliable endogenous control for relative quantitative RT-PCR. Histological parameters of gastritis were semiquantitatively assessed and expressed as a "gastritis score". Gastritis scores increased over time and reached a peak 32 weeks after inoculation. With time there was an expansion of gastritis from the antrum to the corpus. Severe inflammation, ulcer development and pseudopyloric metaplasia (glandular atrophy) were characteristic features. Gastric mucosal samples were mounted in Ussing chambers and 51Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP, protein antigen) were used as indicators of gastric mucosal barrier function. Short-term gastritis showed increased mucosal permeability to 51Cr-EDTA in the antrum. Long-standing gastritis was associated with increased 51Cr-EDTA permeation in both the antrum and corpus and an increased HRP flux in the antrum. In the vitamin supplement study, concentrations of 3-nitrotyrosine (nitrosative protein damage) and thiobarbituric acid reactive substances (TBARS) (oxidative lipid damage) in the gastric mucosa were determined with an immunodot blot and a fluorometric method, respectively. Mucosal concentrations of carbonyl carbons on proteins (oxidative protein damage) and 8-hydroxydeoxyguanosine (oxidative DNA damage) were determined by ELISA. Vitamin supplements had no effect on the colonization with H. pylori. Vitamin C as well as vitamin E supplements reduced mucosal 3-nitrotyrosine concentrations to normal levels in the infected animals. Vitamin E supplement induced decreased mucosal protein carbonyls and TBARS in short-term gastritis. In addition, vitamin C supplement caused attenuated mucosal oxidative DNA damage and milder mucosal inflammation in short-term gastritis.

Conclusions: Lactobacilli, the prevailing indigenous bacterium in the stomach of gerbils, may have a probiotic impact on the colonization of H. pylori. The long-term morpho-functional development in the stomach of H. pylori-infected Mongolian gerbils resembles that of H. pylori-infected humans. H. pylori-induced gastritis in gerbils is associated with a long-standing gastric mucosal barrier dysfunction, which follows the extension of chronic gastritis from the antrum into the corpus over time. This impaired barrier function may contribute to perpetuation of chronic inflammation and may be involved in H. pylori-associated carcinogenesis. Vitamin C as well as vitamin E supplements lead to some short-term protective effects on H. pylori-induced stritis but these effects seem to subside over time when the infection persists.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2004. 62 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 876
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24034 (URN)3590 (Local ID)91-7373-850-6 (ISBN)3590 (Archive number)3590 (OAI)
Public defence
2004-12-10, Berzeliussalen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-26Bibliographically approved

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Sun, Yi-QianMonstein, Hans-JürgSöderholm, Johan DBorch, Kurt

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