Suppressed apoptosis in the inflamed gastric mucosa of Helicobacter pylori-colonized iNOS-knockout mice

Masaharu Miyazawa, Hidekazu Suzuki, Tatsuhiro Masaoka, Akemi Kai, Makoto Suematsu, Hiroshi Nagata, Soichiro Miura, Hiromasa Ishii

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24 Citations (Scopus)

Abstract

Deregulated cell turnover in Helicobacter pylori (H. pylori)-colonized gastric mucosa has been suggested to be linked to the gastric carcinogenesis pathway. We previously reported attenuation of apoptosis and enhancement of cellular proliferation in the H. pylori-colonized gastric mucosa of Mongolian gerbils as compared to that in mice, which might reflect a specific link between H. pylori colonization and carcinogenesis in the Mongolian gerbils; the difference between the two strains could be attributable to differences in the host genetic background. Inducible-type nitric oxide synthase (iNOS) is thought to participate in not only the inflammatory response, but also in the regulation of gastric mucosal cell turnover in H. pylori-colonized gastric mucosa. Thus, the present study was designed to examine gastric leukocyte activation and epithelial cell apoptosis in the gastric mucosa following H. pylori inoculation in iNOS-knockout mice. Methods: iNOS-knockout mice (iNOS-/-) and their iNOS+/+ littermates were orally inoculated with the Sydney strain of H. pylori (SS1, 108 colony-forming units [CFU]). H. pylori infection was confirmed by microaerobic bacterial culture. The stomach of each mouse was evaluated 14 weeks and 30 weeks after the inoculation. Gastric mucosal accumulation of polymorphonuclear leukocytes (PMN) was assessed by determining the myeloperoxidase (MPO) activity and histological score based on the updated Sydney system. The level of apoptosis was determined by estimation of the cytoplasmic levels of mono- and oligonucleosomes and by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method. Results: The SS1-inoculated mice showed persistent H. pylori colonization for 12 weeks. While gastric mucosal PMN infiltration increased following SS1 inoculation in both iNOS+/+ and iNOS-/-strains, enhanced DNA fragmentation was observed in only SS1-colonized iNOS+/+ mice, and not in the iNOS-/- mice. In conclusion, although the recruitment of PMN in response to H. pylori was evoked even in the gastric mucosa of iNOS-/- mice, epithelial cell apoptosis induced by H. pylori was attenuated in this strain. These data suggest that iNOS may play an important role in promoting apoptosis in the H. pylori-infected inflamed gastric mucosa, and that persistent inflammation without apoptosis in iNOS-/- mice with H. pylori infection may be linked to preneoplastic transformation.

Original languageEnglish
Pages (from-to)1621-1630
Number of pages10
JournalFree Radical Biology and Medicine
Volume34
Issue number12
DOIs
Publication statusPublished - 2003 Jun 15

Keywords

  • Leukocyte
  • Myeloperoxidase
  • Nitric oxide
  • Oligonucleosome

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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