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Simvastatin Attenuates Hepatic Sensitization to Lipopolysaccharide After Partial Hepatectomy.

Slotta, Jan E; Laschke, Matthias LU ; Schilling, Martin K; Menger, Michael D; Jeppsson, Bengt LU and Thorlacius, Henrik LU (2010) In The Journal of surgical research 162. p.184-192
Abstract
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. MATERIALS AND 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... (More)
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. MATERIALS AND 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Journal of surgical research
volume
162
pages
184 - 192
publisher
Elsevier
external identifiers
  • wos:000280499500009
  • pmid:19631345
  • scopus:77955982170
ISSN
1095-8673
DOI
10.1016/j.jss.2009.03.057
language
English
LU publication?
yes
id
9ec4c95d-d749-4163-97a2-48b72cb37469 (old id 1452806)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19631345?dopt=Abstract
date added to LUP
2009-08-05 10:47:58
date last changed
2017-07-23 04:56:57
@article{9ec4c95d-d749-4163-97a2-48b72cb37469,
  abstract     = {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. MATERIALS AND 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.},
  author       = {Slotta, Jan E and Laschke, Matthias and Schilling, Martin K and Menger, Michael D and Jeppsson, Bengt and Thorlacius, Henrik},
  issn         = {1095-8673},
  language     = {eng},
  pages        = {184--192},
  publisher    = {Elsevier},
  series       = {The Journal of surgical research},
  title        = {Simvastatin Attenuates Hepatic Sensitization to Lipopolysaccharide After Partial Hepatectomy.},
  url          = {http://dx.doi.org/10.1016/j.jss.2009.03.057},
  volume       = {162},
  year         = {2010},
}