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.
OBJECTIVE
The cholangiopathies represent hepatobiliary diseases in which bile-duct epithelial cells are targets for destructive processes, including immune-mediated damage. We describe a novel rat model of chronic fibrosing cholangitis induced by administration of the hapten reagent 2,4,6-trinitrobenzenesulfonic 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 laparotomy.


RESULTS
TNBS-treatment reproducibly resulted in chronic fibrosing cholangitis. In retrograde cholangiography the bile ducts showed irregularities, beading and strictures. Alkaline phosphatase levels remained abnormal throughout the study period. Immunohistochemical staining showed an increased number of macrophages, CD3+ T-lympbocytes and MHC class II antigen upregulation. The spontaneous interferon-gamma, tumor necrosis factor-alpha and interleukin-10 production of liver-derived mononuclear cells was increased. Anti-neutrophil 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 cholangitis with histologic, cholangiographic, serologic and immunologic similarities to human primary sclerosing cholangitis. This model may be used to study pathomechanisms of chronic cholangitis without concomitant inflammatory bowel disease.
Orth
T
T
I. Medizinische Klinik und Pohklinik, Johannes Gutenberg Universität, Mainz, Germany. orth@mail.uni-mainz.de
Neurath
M
M
Schirmacher
P
P
Galle
P R
PR
Mayet
W J
WJ
D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000032:analysis / Q000276:immunology; D001323:Autoantibodies / Q000032:analysis*; D001652:Bile Ducts / Q000473:pathology; D002758:Cholangiography; D015209:Cholangitis, Sclerosing / Q000139:chemically induced* / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002908:Chronic Disease; D000939:Epitopes; D005260:Female; D007267:Injections; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011915:Rats, Inbred BUF; D011917:Rats, Inbred Lew; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D000939:Epitopes; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid