The Effect of Cholestasis on Hepatitis B Virus Replications.
- Author:
Hong Kyu BAIK
1
;
Dongho CHOI
;
Kwang Soo LEE
Author Information
1. Department of Surgery, College of Medicine, Hanyang University, Seoul, Korea. hkbaik@hanyang.ac.kr
- Publication Type:Original Article
- Keywords:
Cholestasis;
Hepatitis B virus
- MeSH:
Animals;
Bilirubin;
Blotting, Northern;
Cholestasis*;
Common Bile Duct;
Cytokines;
DNA;
Female;
Fibrosis;
Hepatitis B e Antigens;
Hepatitis B virus*;
Hepatitis B*;
Hepatitis*;
Humans;
Immunity, Cellular;
Inflammation;
Interferon-gamma;
Interferons;
Interleukins;
Ligation;
Mice;
Mice, Transgenic;
Necrosis;
Ribonucleases;
RNA;
RNA, Messenger;
T-Lymphocytes;
Tumor Necrosis Factor-alpha
- From:Journal of the Korean Surgical Society
2002;63(6):486-492
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
PURPOSE: HBV infection acquired later in life elicits an inflammatory response. The quality and intensity of the response determines whether virus clears or persists. Clearance is mediated through antigen-specific cytotoxic T-cells. The immune response often precipitates cholestasis while releasing a number of inflammatory cytokines, such as tumor necrosis factor-alpha and interferon-gamma, which are known to inhibit HBV replication in vivo. Transgenic mice which replicate HBV provide a useful model for studying viral pathogenesis. We try to determine whether cholestasis, apart from inflammation, modulates HBV replication. Method: HBV-expressing female 9-wk old BALD/B6 mice matched for HBeAg titer were utilized. Cholestasis was achieved by mid-length ligation and transection of the common bile duct in anesthesized animals. Sham and ligated animals were sacrificed over at 4 h, 12 h, 24 h, 48 h, and 72 h after operation (4 animals/interval). Sera were assayed for ALT, GGT, and direct bilirubin. Histopathology was obtained. Cytokine profiles for interferons, interleukins and tumor necrosis factor were monitored by RNase protection assay. HBV replication was quantitated by measurement of HBV DNA and RNA using Southern and Northern blotting. RESULTS: Sham-operated animals remained without biochemical, pathological or serological changes. Operated animals demonstrated markedly elevated total bilirubin, ALT and GGT levels. Histologic examination showed marked periductular fibrosis and ductular proliferation and area of focal hepato cellular necrosis. Ribonuclease protection assays demon strated minimal infiltration of CD3 cells, and minimal to no migration of CD4 and CD8 cells. Interferon-gamma mRNA was not detected. TNF-alpha peaked between 1 and 3 days post surgery, but to a much lesser extent than that found in naive virus-challenged animals. Both major HBV RNA species remained unchanged during the experiment. HBV DNA production demonstrated no changes in the quantity of the relaxed circular or single-stranded intermediates for the first 2 days. However, by days 5 and 7, reduction in the quantity of viral intermediates were seen. This diminution did not appear to be due to the presence of inflammatory cytokines or CTLs (cytotoxic T lymphocytes) previously implicated in viral clearance. CONCLUSION: Whereas inflammatory cytokines and cellular immunity are essential for viral attenuation and clearance, Acute cholestasis does not appear to contribute independently to biological modulation of HBV replication.
