Since the aetiopathogenesis of primary sclerosing cholangitis (PSC) in humans remains undefined, investigators have studied a variety of animal models to gain insights into immunopathogenetic mechanisms associated with obliterative fibrous cholangitis of intra- and extrahepatic bile ducts. To date, no animal model has been developed that exhibits all of the attributes of PSC. Rodent models instigated by bacteria] cell components or colitis are promising because they may help to explain the strong association between PSC and inflammatory bowel disease (IBD). Other models of direct injury to biliary epithelia, peribiliary vascular endothelia or portal venous endothelia indicate that inflammation, chemokines and cytokines can produce diffuse sclerosis of bile ducts. Models of toxic, infectious or intra-luminal injury of the biliary tract also exhibit focal biliary sclerosis mediated by inflammation and cytokines. The histopathology of several models suggests a sequence of events beginning with secretion of proinflammatory cytokines by activated hepatic macrophages followed by peribiliary infiltration with CD4 and CD8 T cells with a T helper I phenotype. These results strongly suggest co-ordinated, pathogenetic roles for both the innate and adaptive immune responses. However, the stimuli that initiate and perpetuate peribiliary fibrosis remain unknown. Interestingly, several models are also associated with the development of anti-neutrophil cytoplasmic antibodies that react in a perinuclear and cytoplasmic pattern similar to that observed in patients with ulcerative colitis and/or PSC. Finally, models of extra-hepatic biliary obstruction continue to provide important information about the pathogenesis of portal fibrosis and secondary biliary cirrhosis that occurs in PSC and other diseases with obstruction of bile flow. Future studies in either existing or new animal models should advance our understanding of the pathogenesis of PSC, the major prerequisite for the development of effective therapies.
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