Simvastatin protects against cholestasis-induced liver injury.
BACKGROUND
Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. The aim of this study was to evaluate the effect of simvastatin on cholestasis-induced liver inflammation and tissue damage.


METHODS
C57BL/6 mice were treated with simvastatin (0.02 and 0.2 mg.kg(-1)) and vehicle before and after undergoing bile duct ligation (BDL) for 12 h. Leukocyte recruitment and microvascular perfusion in the liver were analysed using intravital fluorescence microscopy. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of myeloperoxidase (MPO) were also determined.


RESULTS
Administration of 0.2 mg.kg(-1) simvastatin decreased ALT and AST by 87% and 83%, respectively, in BDL mice. This dose of simvastatin reduced hepatic formation of CXC chemokines by 37-82% and restored sinusoidal perfusion in cholestatic animals. Moreover, BDL-induced leukocyte adhesion in sinusoids and postsinusoidal venules, as well as MPO levels in the liver, was significantly reduced by simvastatin. Notably, administration of 0.2 mg.kg(-1) simvastatin 2 h after BDL induction also decreased cholestatic liver injury and inflammation.


CONCLUSIONS
These findings show that simvastatin protects against BDL-induced liver injury. The hepatoprotective effect of simvastatin is mediated, at least in part, by reduced formation of CXC chemokines and leukocyte recruitment. Thus, our novel data suggest that the use of statins may be an effective strategy to protect against the hepatic injury associated with obstructive jaundice.
Dold
S
S
Department of Surgery, Malmö University Hospital, Lund University, Sweden.
Laschke
M W
MW
Lavasani
S
S
Menger
M D
MD
Jeppsson
B
B
Thorlacius
H
H
D000818:Animals; D019743:Chemokines, CXC / Q000276:immunology; D002779:Cholestasis / Q000150:complications*; D004730:Endothelium, Vascular / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D036904:Leukocyte Rolling / Q000187:drug effects; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018715:Microscopy, Video; D009195:Peroxidase / Q000378:metabolism; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use*
D019743:Chemokines, CXC; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D009195:Peroxidase