GASTROENTEROLOGY 1996;110:155 – 166 Hypertrophic Gastropathy in Helicobacter felis – Infected Wild- Type C57BL/6 Mice and p53 Hemizygous Transgenic Mice JAMES G. FOX,* XIANTANG LI,* RACHEL J. CAHILL,* KARL ANDRUTIS,* ANIL K. RUSTGI, ‡ ROBERT ODZE, § and TIMOTHY C. WANG ‡ *Division of Comparative Medicine, Massachusetts Institute of Technology, Boston; ‡ Gastrointestinal Unit and Department of Medicine, Massachusetts General Hospital, Boston; and § Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts Background & Aims: Helicobacter pylori infection plasia. 4 Other possible premalignant conditions, such as causes gastritis and peptic ulcers and is linked epide- hypertrophic gastropathy or Me ´ne ´trier’s disease, are rare, miologically to gastric cancer. To analyze host genetic and their relationship to H. pylori is unclear. 5,6 factors and the influence of Helicobacter on cell prolif- Although several studies have shown an epidemiologi- eration, we used an inbred and p53 hemizygous mouse cal association between H. pylori and gastric cancer, a model of Helicobacter felis – induced gastritis. Meth- definite causative link has not been firmly established ods: H. felis was inoculated by gastric intubation into and the underlying mechanisms have not been eluci- SPF C57BL/6 wild-type and p53 hemizygous mice that dated. One hypothesis proposes that H. pylori induces a were followed up for 1 year and compared with unin- chronic inflammatory response that leads to an increased fected controls of the same genotype using histology, rate of mucosal proliferation 7,8 and subsequently to an proliferating cell nuclear antigen (PCNA) staining, and increased risk of malignant transformation. In fact, recent 5-bromo-2-deoxyuridine (BrdU) analysis. Results: In- studies have shown increased proliferating cell nuclear fected animals developed sustained anti – H. felis se- rum immunoglobulin G antibody responses. Six months antigen (PCNA) staining, 5-bromo-2-deoxyuridine after infection, both wild-type and p53 hemizygous (BrdU) incorporation, and proliferative indices in pa- mice showed active chronic inflammation and marked tients with H. pylori infection. 9–11 An increased prolifera- mucosal hyperplasia compared with uninfected con- tive rate may increase the risk of malignant transforma- trols. One year after infection with H. felis, the wild- tion by allowing more opportunity for mutagenic events type and p53 hemizygous mice showed severe adeno- to occur. matous and cystic hyperplasia of the surface foveolar To investigate this possibility, a well-characterized an- epithelium. BrdU uptake and PCNA staining were mark- imal model of Helicobacter infection would be useful. edly increased in both sets of infected mice compared While a number of animal models have been introduced, with controls. Infected p53 hemizygous mice had a Helicobacter felis – associated gastritis in mice simulates higher proliferative index than the infected wild-type many of the pathological features noted in human H. mice. Conclusions: H. felis can induce a hypertrophic pylori infection. 12 H. felis is a spiral organism originally gastropathy in the C57BL/6 genotype; loss of one p53 allele, although insufficient to initiate carcinogenesis isolated from the feline gastric tissue. After experimental at 1 year, enhances the proliferative index, which may oral inoculation, H. felis efficiently colonizes the gastric lead to an increased risk of cancer induction. mucosa in mice, rats, and dogs. 13 Recent studies in our laboratory indicated that H. felis chronically infected VAF Swiss – Webster mice, leading to an active chronic A gastritis characterized by marked polymorphonuclear and clear relationship has been established between Helicobacter pylori infection and a variety of patho- mononuclear cell infiltration. 14 However, after 1 year, logical disorders of the stomach, such as chronic gastritis, H. felis – infected outbred Swiss – Webster mice did not peptic ulcer disease, gastric mucosa – associated lymphoid develop any preneoplastic or neoplastic changes. tissue lymphoma, and gastric cancer. 1,2 Although peptic The response to H. pylori infection varies greatly ulcer disease remains an important health problem in among individuals, and it is clear that the majority of developed countries, gastric cancer, which is the second infected patients do not develop gastric cancer. Although leading cause of cancer death worldwide, is actually a more important global health problem, particularly in Abbreviations used in this paper: BrdU, 5-bromo-2-deoxyuridine; developing countries. 3 H. pylori infection has been associ- PCNA, proliferating cell nuclear antigen. ated with pathological conditions that predispose to gas-  1996 by the American Gastroenterological Association 0016-5085/96/$3.00 tric cancer, such as atrophic gastritis and intestinal meta-