CHRONIC PROLIFERATIVE HEPATITIS IN A JCR MICE ASSOCIATED WITH PERSISTENT HELICOBACTER-HEPATICUS INFECTION - A MODEL OF HELICOBACTER-INDUCEDCARCINOGENESIS/

Helicobacter hepaticus causes hepatitis in selected strains of mice an d in A/JCr mice is linked to liver cancer. To analyze whether H. hepat icus persists in specified ecological niches, to determine whether bio markers of infection exist, and to analyze the influence of H. hepatic us on hepatocyte proliferation, a longitudinal study of H. hepaticus-i nfected A/JCr mice was undertaken. A/JCr mice were serially euthanatiz ed from 3 through 18 months and surveyed by enzyme-linked immunosorben t assay; bacterial culture of liver, colon, and cecum; histology; elec tron microscopy; hepatocyte proliferation indices determined by using 5-bromo-2'-deoxyuridine; and measurement of the liver enzyme alanine a minotransferase. In infected animals throughout the 18-month study, H. hepaticus was consistently isolated from the lower bowel but only spo radically from the liver. By electron microscopy, H. hepaticus was not ed infrequently and only in bile canaliculi. Infected mice, particular ly males, showed chronic inflammation; oval cell, Kupffer cell, and It o cell hyperplasia; hepatocytomegaly; and bile duct proliferation. The inflammatory and necrotizing lesion was progressive and involved the hepatic parenchyma, portal triads, and intralobular venules. Hepatic a denomas were noted only in male mice, whereas 5-bromo-2'-deoxyuridine proliferation indices were markedly increased in both sexes, but espec ially in males, compared with control A/J mice. Infected mice also dev eloped sustained anti-H. hepaticus serum immunoglobulin G antibody res ponses and elevated alanine aminotransferase levels. H. hepaticus, whi ch persists in the lower bowels and livers of A/JCr mice, is associate d with a chronic proliferative hepatitis, and hepatomas in selected ma le mice indicate that this novel bacterium may cause an increased risk of hepatic cancer induction in susceptible strains of mice. This muri ne model should prove useful in dissecting the molecular events operab le in the development of neoplasms induced by bacteria belonging to th is expanding genera of pathogenic Helicobacter species.