A novel rat model of chronic fibrosing cholangitis induced by local administration of a hapten reagent into the dilated bile duct is associated with increased TNF-alpha production and autoantibodies

Background/Aim: The cholangiopathies represent hepatobiliary diseases in wh ich bile-duct epithelial cells are targets for destructive processes, inclu ding immune-mediated damage. We describe a novel rat model of chronic fibro sing cholangitis induced by administration of the hapten reagent 2,4,6-trin itrobenzenesulfonic acid (TNBS) into the dilated bile duct. Methods: The common bile duct was dilated due to a mild stenosis in 8-week- old female Lewis rats. TNBS (50 mg/kg) was injected during a second laparot omy. Results: TNBS-treatment reproducibly resulted in chronic fibrosing cholangi tis, In retrograde cholangiography the bile ducts showed irregularities, be ading and strictures. Alkaline phosphatase levels remained abnormal through out the study period. Immunohistochemical staining showed an increased numb er of macrophages, CD3+ T-lymphocytes and MHC class II antigen upregulation , The spontaneous interferon-gamma, tumor necrosis factor-alpha and interle ukin-10 production of liver-derived mononuclear cells was increased. Anti-n eutrophil cytoplasmic antibodies with specificity against myeloperoxidase, catalase and actin were found between 1 and 12 weeks after TNBS injection. Conclusions: We established a novel rat model of chronic fibrosing cholangi tis with histologic, cholangiographic, serologic and immunologic similariti es to human primary sclerosing cholangitis, This model may be used to study pathomechanisms of chronic cholangitis without concomitant inflammatory bo wel disease.