Simvastatin attenuates hepatic sensitization to lipopolysaccharide after partial hepatectomy.
BACKGROUND
Hepatic resection may be curative in patients with hepatobiliary malignancies but excessive loss of liver volume may cause hepatic dysfunction and increase susceptibility to subsequent postoperative infections and sepsis. Herein, we hypothesized that pretreatment with simvastatin may protect against lipopolysaccharide (LPS)-induced liver damage after partial hepatectomy.


METHODS
Male C57Bl/6 mice underwent 68% hepatectomy and exposed to LPS after 24h. Animals were pretreated with simvastatin (0.02 and 0.2mg/kg). Serum alanine aminotransferase (ALT) and tumor necrosis factor-alpha (TNF-alpha) as well as leukocyte infiltration and hepatocyte apoptosis were examined 6h after LPS challenge. An in vitro endothelial cell adhesion assay was used to study the mechanisms of simvastatin on leukocyte adhesion and the role of P-selectin and lymphocyte function antigen-1 (LFA-1).


RESULTS
Partial hepatectomy increased the sensitivity of the remnant liver tissue to LPS-provoked tissue injury. Simvastatin pretreatment reduced the LPS-induced increase in serum levels of ALT by 65% in hepatectomized animals. Moreover, simvastatin decreased leukocyte infiltration and hepatocyte apoptosis in the liver remnant of endotoxemic mice. LPS-provoked serum levels of TNF-alpha were decreased by 83% in hepatectomized animals treated with simvastatin. TNF-alpha-induced leukocyte adhesion as well as P-selectin expression in endothelial cells and LFA-1 function were inhibited by simvastatin in vitro.


CONCLUSIONS
These novels findings demonstrate that simvastatin protects the remnant liver against endotoxemic injury following major hepatectomy. Thus, simvastatin reduced LPS-induced leukocyte recruitment and hepatocyte apoptosis in the liver remnant. One key mechanism appears to be related to the inhibition of TNF-alpha formation and function (P-selectin expression) as well as to direct actions on LFA-1 function. Thus, simvastatin may represent a novel therapeutic approach to prevent septic liver damage after partial liver resection.
Slotta
Jan E
JE
Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
Laschke
Matthias W
MW
Schilling
Martin K
MK
Menger
Michael D
MD
Jeppsson
Bengt
B
Thorlacius
Henrik
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D006498:Hepatectomy / Q000009:adverse effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D019007:P-Selectin / Q000235:genetics; D011183:Postoperative Complications / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000517:prevention & control; D019821:Simvastatin / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017931:DNA Primers; D018076:DNA, Complementary; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D019007:P-Selectin; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin; D000410:Alanine Transaminase