Primary biliary cirrhosis (PBC) and
primary sclerosing cholangitis (PSC) are presumed autoimmune chronic cholestatic
liver diseases characterized by
cholangitis and progressive loss of bile ducts.
Cytokines have been postulated to be involved in the progression of these diseases, but their role is poorly defined. Our objectives were to characterize a rat model of
cholangitis 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 low-dose
oral administration of the biliary toxin
alpha-naphthylisothiocyanate (ANIT) (1 g/kg powdered rat chow ad libitum) for 4, 7, and 14 days.
Cholestasis was observed in ANIT-treated animals. Liver histology of ANIT-treated rats showed hepatic
inflammation centered on damaged bile ducts, significant bile duct proliferation, and progressive
fibrosis. Immunohistochemistry showed enhanced staining of hepatic major histocompatibility complex (MHC) II, CD4, and CD8 in portal areas of ANIT-treated animals. In addition, the hepatic
cytokine profile became increasingly Th1 in nature with progressive ANIT treatment. In summary, experimental
cholangitis biochemically and histologically mimics human chronic
cholangitis and furthermore, is associated with a progressive shift to a more Th1-dominant hepatic
cytokine profile. Therefore, this model may be useful for examining the role of
cytokines in the progression of chronic cholangitic diseases.