title: 24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Tropical Medicine and Infectious Diseases, Department of Internal Medicine, University of Rostock, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Sombetzki
authors.affiliation: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Fuchs
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Institute of Pathology, Medical University Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Austria.
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Österreicher
authors.affiliation: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
authors.forename: Thierry
authors.initials: T
authors.lastname: Claudel
authors.affiliation: Division of Tropical Medicine and Infectious Diseases, Department of Internal Medicine, University of Rostock, Germany.
authors.forename: Micha
authors.initials: M
authors.lastname: Loebermann
authors.affiliation: Institute of Immunology, University of Rostock, Germany.
authors.forename: Robby
authors.initials: R
authors.lastname: Engelmann
authors.affiliation: Institute of Pathology, Medical University Graz, Austria.
authors.forename: Cord
authors.initials: C
authors.lastname: Langner
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Austria.
authors.forename: Emine
authors.initials: E
authors.lastname: Sahin
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Schwinge
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nina D
authors.initials: ND
authors.lastname: Guenther
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.affiliation: Institute of Immunology, University of Rostock, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Mueller-Hilke
authors.affiliation: Division of Tropical Medicine and Infectious Diseases, Department of Internal Medicine, University of Rostock, Germany.
authors.forename: Emil C
authors.initials: EC
authors.lastname: Reisinger
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
mesh_terms: D000818:Animals; D002756:Cholagogues and Choleretics / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D016903:Drug Monitoring; D006099:Granuloma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D012555:Schistosomiasis mansoni / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid; C081331:24-norursodeoxycholic acid
keywords: Anti-inflammatory/anti-fibrotic therapy; Bile acids; Hepatic granulomas; Liver fibrosis; Schistosoma mansoni infection