Progressive development of a Th1-type hepatic cytokine profile in rats with experimental cholangitis

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) ar e presumed autoimmune chronic cholestatic liver diseases characterized by c holangitis and progressive loss of bile ducts. Cytokines have been postulat ed to be involved in the progression of these diseases, but their role is p oorly defined. Our objectives were to characterize a rat model of cholangit is and to determine Type 1/Type 2 (Th1/Th2) cytokine profile shifts in this model. Cholangitis was induced in Sprague-Dawley rats (200 to 225 g) by lo w-dose oral administration of the biliary toxin alpha-naphthy-lisothiocyana te (ANIT) (1 g/kg powdered rat chow ad libitum) for 4, 7, and 14 days. Chol estasis was observed in ANIT-treated animals. liver histology of ANIT-treat ed rats showed hepatic inflammation centered on damaged bile ducts, signifi cant bile duct proliferation, and progressive fibrosis, Immunohistochemistr y showed enhanced staining of hepatic major histocompatibility complex (MHC ) II, CD4, and CD8 in portal areas of ANIT-treated animals. In addition, th e hepatic cytokine profile became increasingly Th1 in nature with progressi ve ANIT treatment. In summary, experimental cholangitis biochemically and h istologically mimics human chronic cholangitis and furthermore, is associat ed with a progressive shift to a more Th1-dominant hepatic cytokine profile . Therefore, this model may be useful for examining the role of cytokines i n the progression of chronic cholangitic diseases.