Progression of chronic hepatitis and preneoplasia in Helicobacter hepaticus-infected A/JCr mice.
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. pylorichronic 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.
Rogers
Arlin B
AB
Comparative Pathology Laboratory 16-849, Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. abr@mit.edu
Boutin
Samuel R
SR
Whary
Mark T
MT
Sundina
Nataliya
N
Ge
Zhongming
Z
Cormier
Kathleen
K
Fox
James G
JG
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D005260:Female; D016481:Helicobacter Infections / Q000150:complications*; D044923:Helicobacter hepaticus; D006521:Hepatitis, Chronic / Q000209:etiology* / Q000473:pathology; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000209:etiology* / Q000473:pathology
D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase