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Toxicologic Pathology
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Progression of Chronic Hepatitis and Preneoplasia in Helicobacter hepaticus-Infected A/JCr Mice

Arlin B. Rogers

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA, abr{at}mit.edu

Samuel R. Boutin

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

Mark T. Whary

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

Nataliya Sundina

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

Zhongming Ge

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

Kathleen Cormier

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

James G. Fox

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

Helicobacter hepaticus infection induces sustained inflammation and carcinoma of the liver in A/JCr mice, and serves as a model of human cancers associated with viral hepatitis and H. pylori chronic gastritis. Here we describe the pathogenesis of premalignant disease in A/JCr mice infected with H. hepaticus. We inoculated dams intragestationally and/or pups postnatally, and evaluated offspring at 3, 6, or 12 months. Mice infected at or before 3 weeks of age, but not at 12 weeks, developed disease. Male mice were most affected, but expressed a bimodal pattern of susceptibility. Males exhibited lobular necrogranulomatous and interface (chronic active) hepatitis, while females usually developed intraportal (chronic persistent) hepatitis. Portal inflammation was slowly progressive, with tertiary lymphoid nodule development by 12 months. Hepatic bacterial load and preneoplastic lesions, including clear and tigroid cell foci of cellular alteration, were correlated with lobular hepatitis severity. No extrahepatic surrogate disease marker reliably predicted individual hepatitis grade. In conclusion, gender and bacterial exposure timing are key determinants of H. hepaticus disease outcomes. Intrahepatic inflammation is driven by local signals characterized by a vigorous but nonsterilizing immune response. Continued study of chronic hepatitis progression may reveal therapeutic targets to reduce the risk of hepatocellular carcinoma.

Key Words: Liver diseases • hepatitis • animal • Helicobacter infections • mice • inbred A • hepatocellular carcinoma.

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Toxicologic Pathology, Vol. 32, No. 6, 668-677 (2004)
DOI: 10.1080/01926230490524247
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