Estimation of cytoprotective effect of bismuth tripotassium dicitrate on gastric mucosa at H. pylori eradication and long-term drug intake

Aim of investigation. To identify cellular «target» of bismuth tripotassium dicitrate (De-nol) therapy – DNA protection of generative zone cells of stomach mucosa (SM) from damages by oxidative burst products in neutrophilic leukocytes at continued intake of the drug for 4 wks after the ending of eradication therapy.

Material and methods. Overall 53 patients after successful eradication therapy for chronic H. pyloriassociated gastritis were investigated: in 28 of them De-nol treatment was continued, 25 were included to the group of comparison. At control upper GI endoscopy biopsy samples were taken from 5 SM points according to OLGA-system protocol. In biopsy specimens presence of neutrophilic infiltration was estimated in mucosal generative zones exclusively. Borders of a generative zone were determined by the presence of myofibroblasts surrounding glandular epithelium which were identified immunohistochemically, using smooth-muscle actin as a marker. Cells with damaged DNA were revealed by immunehistochemical detection of Р53 protein.

Results. No correlation between neutrophilic infiltration of SM and р53-positive cells quantity in generative zone (–0,14≤r≤0,08) was revealed in both groups. Comparison of cumulative scores of P53 label in generative zones epithelium after treatment demonstrated no significant difference between groups. Only at comparison of P53 expression level in each sampling point statistically significant differences before and after treatment (Wilcoxon W-matched-pairs ranks criterion) have been found only in group of patients who continued treatment.

Conclusions. Detection of the damaged DNA in SM generative zone cells by immunehistochemical assay of P53-positive cells allows to establish significant decrease of their number in biopsies of the patients, who received the drug after cessation of eradication therapy that can be considered as a marker of protective effect for generative zone cells — cytoprotective «target» of bismuth drug.

1. Ивашкин В.Т., Маев И.В., Лапина Т.Л., Шептулин А.А. Рекомендации Российской Гастроэнтерологической Ассоциации по диагностике и лечению инфекции Helicobacter pylori у взрослых. Рос журн гастроэнтерол гепатол колопроктол 2012; 22(1):87-9.

2. Кононов А.В. Цитопротекция слизистой оболочки желудка: молекулярно-клеточные механизмы. Рос журн гастроэнтерол гепатол колопроктол 2006; 16(3):12-6.

3. Кононов А.В., Мозговой С.И., Маркелова М.В., Шиманская А.Г. Морфогенез атрофии слизистой оболочки желудка как основа фенотипа хронического гастрита. Арх патол 2011; 73(3):26-31.

4. Кононов А.В., Мозговой С.И., Шиманская А.Г., Маркелова М.В. и др. Российский пересмотр классификации хронического гастрита: воспроизводимость оценки патоморфологической картины. Арх патол 2011; 73(4):52-6.

5. Лапина Т.Л. Возможности лекарственного воздействия на цитопротективные свойства гастродуоденальной слизистой оболочки. Рос журн гастроэнтерол гепатол колопроктол 2006; 16(5):2-7.

6. Ливзан М.А., Кононов А.В., Мозговой С.И. Эксхеликобактерный гастрит: неологизм или клиническая реальность. Эксперим клин гастроэнтерол 2004; 5:55-60.

7. Bagchi D., McGinn T.R., Ye X., et al. Mechanism of gastroprotection by bismuth subsalicylate against chemically induced oxidative stress in cultured human gastric mucosal cells. Dig Dis Sci 1999; 44(12):2419-28.

8. Geering B., Simon H-U. Peculiarities of cell death mechanisms in neutrophils. Cell Death Differentiation 2011; 18:1457-69.

9. Handa O., Naito Y., Yoshikawa T. Redox biology and gastric carcinogenesis: the role of Helicobacter pylori. Redox Rep 2011; 16(1):1-7.

10. Malfertheiner P., Megraud F., O’Morain C.A., et al. Management of Helicobacter pylori infection-the Maastricht IV/ Florence Consensus Report. Gut 2012; 61(5):646-64.

11. Marchevsky A.M., Wick M.R. Evidence based pathology and laboratory medicine. Springer 2011:361.

12. Nair B.C., Krishnan S.R., Sareddy G.R, et al. Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response. Cell Death Differ 2014; 21(9):1409-18.

13. Rugge M., Correa P., Di Mario F., et al. OLGA staging for gastritis: a tutorial. Dig Liver Dis 2008; 40(8):650-8.

14. Turkez H., Geyikoglu F. The efficiacy of bismuth subnitrate against genotoxicity and oxidative stress induced by aluminum sulphate. Toxicol Ind Health 2011; 27(2):13342.

15. Worthley D.L., Giraud A.S., Wang T.C. Stromal fibroblasts in digestive cancer. Cancer Microenvironment 2010; 3:117-25.