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J Hepatol. 2015 Apr;62(4):871-8. doi: 10.1016/j.jhep.2014.11.020. Epub 2014 Nov 21.

24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis.

Author information

1
Division of Tropical Medicine and Infectious Diseases, Department of Internal Medicine, University of Rostock, Germany.
2
Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
3
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Institute of Pathology, Medical University Graz, Austria.
4
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Austria.
5
Institute of Immunology, University of Rostock, Germany.
6
Institute of Pathology, Medical University Graz, Austria.
7
Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Austria.
8
Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
9
Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria. Electronic address: michael.trauner@meduniwien.ac.at.

Abstract

BACKGROUND & AIMS:

Intrahepatic granuloma formation and fibrosis characterize the pathological features of Schistosoma mansoni infection. Based on previously observed substantial anti-fibrotic effects of 24-nor-ursodeoxycholic acid (norUDCA) in Abcb4/Mdr2(-/-) mice with cholestatic liver injury and biliary fibrosis, we hypothesized that norUDCA improves inflammation-driven liver fibrosis in S. mansoni infection.

METHODS:

Adult NMRI mice were infected with 50 S. mansoni cercariae and after 12 weeks received either norUDCA- or ursodeoxycholic acid (UDCA)-enriched diet (0.5% wt/wt) for 4 weeks. Bile acid effects on liver histology, serum biochemistry, key regulatory cytokines, hepatic hydroxyproline content as well as granuloma formation were compared to naive mice and infected controls. In addition, effects of norUDCA on primary T-cell activation/proliferation and maturation of the antigen-presenting-cells (dendritic cells, macrophages) were determined in vitro.

RESULTS:

UDCA as well as norUDCA attenuated the inflammatory response in livers of S. mansoni infected mice, but exclusively norUDCA changed cellular composition and reduced size of hepatic granulomas as well as TH2-mediated hepatic fibrosis in vivo. Moreover, norUDCA affected surface expression level of major histocompatibility complex (MHC) class II of macrophages and dendritic cells as well as activation/proliferation of T-lymphocytes in vitro, whereas UDCA had no effect.

CONCLUSIONS:

This study demonstrates pronounced anti-inflammatory and anti-fibrotic effects of norUDCA compared to UDCA in S. mansoni induced liver injury, and indicates that norUDCA directly represses antigen presentation of antigen presenting cells and subsequent T-cell activation in vitro. Therefore, norUDCA represents a promising drug for the treatment of this important cause of liver fibrosis.

KEYWORDS:

Anti-inflammatory/anti-fibrotic therapy; Bile acids; Hepatic granulomas; Liver fibrosis; Schistosoma mansoni infection

PMID:
25463533
PMCID:
PMC4368108
DOI:
10.1016/j.jhep.2014.11.020
[Indexed for MEDLINE]
Free PMC Article

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