| Summary: | 博士 === 高雄醫學大學 === 醫學研究所 === 97 === Since the isolation and culture of Helicobacter pylori in 1983, this germ has been accepted as an important human pathogen for the development of gastritis, peptic ulcer, and gastric cancer. In 1994, WHO designated H. pylori as Class I carcinogen. Therefore, management of H. pylori infection is an important medical issue. Helicobacter pylori eradication rate following triple therapy is decreasing worldwide. It may be due to high antibiotics resistance rate and the adoption of Bismuth-containing regimens become popularly accepted as the second-line therapy. However, the efficacy of conventional second-line therapy is also decreasing gradually. And bismuth use is not available in every area. Therefore, it is still mandatory to search for an optimal rescue regimen for the eradication of H. pylori with consistent and high efficacy.
Despite a recent decline in its incidence, gastric cancer remains one of the most common malignancies in the world and 4th common malignancy in Taiwan. Its pathogenesis is known to be closely associated with several environmental factors, including Helicobacter pylori (Hp). The increasing expression of COX-2 is found in precancerous lesions including intestinal metaplasia, dysplasia and adenoma. In rat model, COX-2 inhibitor (celebrex) was found to inhibit the carcinogenesis induced by N-methyl-N-nitro-N- nitrosoguanidine. Besides these, not every one suffered from disease after H. pylori infection. The possible factors to account for the differences after H. pylori infection may include bacterial factors and host factors. Among these factors, immune response may play a cardinal role.
In order to understand the pathogenesis of H. pylori-inducing gastric carcinogenesis, it is necessary to set up a suitable and reliable animal model that can show pathological changes mimic with human beings. In 1998, Takahashi et al inoculated a human strain of H. pylori into the stomach of Mongolian gerbils. This report concluded that the type of gastritis seen is much more like that of the human than any other model. They concluded that H. pylori infection could induce well-differentiated adenocarcinoma at very high incidences (40%). Therefore, the Mongolian gerbils’ model is to date regarded as the most suitable model for gastric cancer.
This study wants to survey the possible pathogenesis of H. pylori-induced disorder by use of Mongolian gerbil’s model. The aims of this study include 1. To access the reliability of newly developed noninvasive test used for detection of H. pylori infection in children. We also survey current prevalence rate of H. pylori for children in Kaohsiung city. 2.To set up a stable and reliable H. pylori-infected Mongolian gerbil’s model by feeding with carcinogen (MNNG). We wanted to observe the sequential pathological changes and gastric carcinogenesis. 3. To evaluate the accuracy of the non-invasive tests (stool antigen test and serological test) and the optimal time-point for detecting H. pylori infection in a Mongolian gerbil model. We wanted to find the useful method to follow the progressing status of H. pylori infection. 4. To survey the effect of inhibiting H. pylori-associated gastric carcinogenesis in Mongolian gerbils by shorter-term use of a selective COX-2 inhibitor, Celebrex, 5. To survey the role of dendritic cells in acute and chronic H. pylori infection. And we also want to survey the influences of Th1/Th2 balance and different cytokines on H. pylori- associated disease. 6. to compare the efficacies of levofloxacin-based rescue therapy or quadruple therapy for Helicobacter pylori (H. pylori) infection after failure of standard triple therapies. We also studied and evaluated the predictors of this rescue therapy. (compliance, antibiotics resistances and CYP 2C19 polymorphism )
According to results of this study, we find 1. the prevalence of H. pylori infection in Kaohsiung city is lower than previous reports. It may be related to the improvement of hygiene or antibiotics abuse. All three non-invasive tests are suitable for screening test of children. The urine-sampling method is most accurate. 2. We have successfully set up the H. pylori-infected Mongolian gerbil’s model and observed the development of gastric adenocarcinoma. 3. Both stool-sampling and blood-sampling tests are suitable for following the H. pylori status in Mongolian gerbils. 4. Celebrex had a potent anticarcinogenic effect. Celebrex also achieved the chemoprevention of gastric adenocarcinoma even by relatively short-term treatment in the later stages of H. pylori infection. The protective effect of Celebrex might be involved in an early oncogenic phase but not in early inflammation phase. 5. In Lewis Ag-treat gerbils, Th2 response is dominant, resulting in fewer incidences of ulcer and cancer. 6. EAL regimen can archive a similar efficacy as that of standard EBTM therapy. Compliance, CYP2C19 genotype and resistances to antibiotics may influence the outcome of levofloxacin-based rescue therapy.
We would explore this Mongolian gerbil’s model and apply to clinical studies; It would be helpful for us to understand the possible pathogenesis of gastric carcinogenesis in the future. We can develop some new treatments based on this model. Evaluation of the response in the early stage of H. pylori infection should be an important factor in future studies. Chemoprevention (e.g. COX-2 inhibitors) may be necessary for those high-risk groups with refractory H. pylori infection. Finally, levofloxacin-based therapy or quadruple therapy was found to be effective for those eradication-failure patients. It is suggested that the status of CYP2C19 genotypes and sensitivity tests of antibiotics should be examined before starting rescue therapies.
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