Imbalance of pro- and antifibrogenic genes and bile duct injury in murine Schistosoma mansoni infection-induced liver fibrosis.
OBJECTIVE
The murine model of Schistosoma mansoni infection is characterized by strong fibrosis and little hepatocellular injury. The objective of this study was to evaluate the potential link between hepatic schistosomiasis and bile duct injury in relation to the expression of profibrotic cytokines and fibrosis-related genes.


METHODS
Hepatic schistosomiasis was induced via percutaneous infection of mice with 50 S. mansoni cercariae. Markers of fibrosis including matrixmetalloproteinases (MMPs) and tissue-inhibitors of metalloproteinases (TIMPs), as well as markers of bile duct injury (keratin-19, VCAM-1) were studied during 24 weeks after infection by RT-PCR and immunohistochemistry.


RESULTS
Liver biochemistry revealed no differences in serum transaminase and alkaline phosphatase levels in infected and uninfected mice. Total liver hydroxyproline content was increased 5-fold (P < 0.05) after infection. Gene expression analysis revealed MMP-2 (12-fold, P < 0.05) and TIMP-1 (48-fold, P < 0.05) up-regulation after infection. The balance of MMP and TIMP was shifted towards TIMP. Bile ducts were engulfed by adjacent granulomas resulting in ductular proliferation (keratin-19). VCAM-1 expression and inflammatory infiltrates were reduced.


CONCLUSIONS
This study demonstrates that schistosomiasis is associated with (i) an imbalance of MMP-2 and TIMP-1 as key players of fibrogenesis and (ii) with secondary bile duct alterations leading to ductular proliferation possibly contributing to fibrosis.
Loebermann
Micha
M
University of Rostock, Germany. micha.loebermann@med.uni-rostock.de
Sombetzki
Martina
M
Langner
Cord
C
Fuchsbichler
Andrea
A
Gumhold
Judith
J
Silbert
Dagmar
D
Riebold
Diana
D
Holtfreter
Martha
M
Fickert
Peter
P
Nizze
Horst
H
Trauner
Michael
M
Reisinger
Emil C
EC
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001649:Bile Duct Diseases / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D053539:Keratin-19 / Q000378:metabolism; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics*; D045726:Metalloproteases / Q000032:analysis / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012550:Schistosoma mansoni / Q000235:genetics; D012555:Schistosomiasis mansoni / Q000235:genetics*; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis / Q000235:genetics; D000637:Transaminases / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D015415:Biomarkers; D016207:Cytokines; D053539:Keratin-19; D019714:Tissue Inhibitor of Metalloproteinases; D019010:Vascular Cell Adhesion Molecule-1; D000637:Transaminases; D000469:Alkaline Phosphatase; D045726:Metalloproteases