Helicobacter hepaticus is responsible for a new murine disease, """"""""H. hepaticus induced hepatitis"""""""". We have reproduced this type of chronic active hepatitis experimentally in both SPF inbred mice and outbred germfree mice and determined that H. hepaticus is widespread in mouse colonies and causes a persistent hepatitis in susceptible strains of mice. H. hepaticus also persistently colonizes the lower gastrointestinal tract of both A/JCr susceptible and resistant C57Bl/6 mice but does not cause liver lesions in resistant strains of mice. In the A/JCr and B6C3F1 the organism induces hepatic adenomas and hepatocellular carcinomas. We have determined the morphological stages of the H. hepaticus induced liver lesions in the A/JCr which consist of a series of progressive changes beginning with chronic active hepatitis and vasculitis leading to bile duct and oval cell hyperplasia with increased hepatocyte proliferation and hepatomegaly, development of clear cell foci and nodular hyperplasia and finally culminating in adenomas and hepatocellular carcinoma. Several key features of H.hepaticus' role in carcinogenesis have been recently elucidated which strongly suggest H. hepaticus acts as a tumor promoter. Experiments designed to further characterize and elucidate mechanisms responsible for H. hepaticus biological effects will continue to explore in vivo molecular events operable in establishing chronic hepatitis and promotion of tumorigenesis. In this proposal we plan to 1) Utilize isogenic mutants of H. hepaticus lacking putative virulence determinants to determine effects of these bacterial gene products on chronic hepatic inflammation and promotion of tumorigenesis. 2) Utilize congenic recombinant mice to characterize and map the genetic difference(s) responsible for determining the differential susceptibility of strains A/J and C57BL/6 to H. hepaticus induced hepatitis and liver tumors and 3) Determine if H. hepaticus infection promotes onset and progression of hepatitis and tumor formation in mice initiated with hepatic carcinogens and ascertain whether the sequential events operable in tumor induction can be interrupted by eradication of H. hepaticus at different stages of infection.
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