title: bak deletion stimulates gastric epithelial proliferation and enhances Helicobacter felis-induced gastric atrophy and dysplasia in mice.
abstract: Helicobacter infection causes a chronic superficial gastritis that in some cases progresses via atrophic gastritis to adenocarcinoma. Proapoptotic bak has been shown to regulate radiation-induced apoptosis in the stomach and colon and also susceptibility to colorectal carcinogenesis in vivo. Therefore we investigated the gastric mucosal pathology following H. felis infection in bak-null mice at 6 or 48 wk postinfection. Primary gastric gland culture from bak-null mice was also used to assess the effects of bak deletion on IFN-γ-, TNF-α-, or IL-1β-induced apoptosis. bak-null gastric corpus glands were longer, had increased epithelial Ki-67 expression, and contained fewer parietal and enteroendocrine cells compared with the wild type (wt). In wt mice, bak was expressed at the luminal surface of gastric corpus glands, and this increased 2 wk post-H. felis infection. Apoptotic cell numbers were decreased in bak-null corpus 6 and 48 wk following infection and in primary gland cultures following cytokine administration. Increased gastric epithelial Ki-67 labeling index was observed in C57BL/6 mice after H. felis infection, whereas no such increase was detected in bak-null mice. More severe gastric atrophy was observed in bak-null compared with C57BL/6 mice 6 and 48 wk postinfection, and 76% of bak-null compared with 25% of C57BL/6 mice showed evidence of gastric dysplasia following long-term infection. Collectively, bak therefore regulates gastric epithelial cell apoptosis, proliferation, differentiation, mucosal thickness, and susceptibility to gastric atrophy and dysplasia following H. felis infection.
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom;
authors.forename: C A
authors.initials: CA
authors.lastname: Duckworth
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom;
authors.forename: A A
authors.initials: AA
authors.lastname: Abuderman
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom;
authors.forename: M D
authors.initials: MD
authors.lastname: Burkitt
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom;
authors.forename: J M
authors.initials: JM
authors.lastname: Williams
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; and Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; mark.pritchard@liverpool.ac.uk.
authors.forename: D M
authors.initials: DM
authors.lastname: Pritchard
mesh_terms: D000818:Animals; D001284:Atrophy; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D016207:Cytokines / Q000494:pharmacology; D004848:Epithelium / Q000254:growth & development*; D005260:Female; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism; D016481:Helicobacter Infections / Q000473:pathology*; D044922:Helicobacter felis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061251:Primary Cell Culture; D013270:Stomach / Q000166:cytology* / Q000473:pathology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics*
chemical_list: D016207:Cytokines; D050998:bcl-2 Homologous Antagonist-Killer Protein
keywords: Helicobacter felis; bcl-2 family; gastric cancer