title: Simvastatin protects hepatocytes from apoptosis by suppressing the TNF-α/caspase-3 signaling pathway in mice with burn injury.
abstract: OBJECTIVE
  To investigate the liver cellular apoptosis in response to burn injury and find out if statin treatment can ameliorate this process. The hypothesis is that statin may modulate apoptosis-related gene expression and thereby reduce hepatocytic apoptosis after burn injury.
  
  
  METHODS
  Mice were subjected to 30% full-thickness burn injury and then treated either with or without simvastatin. The livers were harvested for histological assessment and determinations of gene expression. To investigate the mechanism involved, tumor necrosis factor (TNF)-α and caspase-3 knockout (KO) mice were also used to evaluate the effects of burn injury and simvastatin treatment on burn-induced liver injury. The effects of simvastatin on TNF-α and caspase-3 expressions were also evaluated in cultured mouse hepatocytes.
  
  
  RESULTS
  Burn injury induced significant liver damage, which was indicated by striking levels of apoptosis. Simvastatin reduced the apoptotic index in the livers of mice with burn injury and this effect could be abrogated by TNF-α or caspase-3 inhibitors. Simvastatin also decreased burn-induced TNF-α and caspase-3 expression in the liver. TNF-α and caspase-3 KO mice demonstrated lower levels of apoptotic hepatocytes in response to burn, and simvastatin did not further decrease hepatocyte apoptosis in either strain of KO mice. An in vitro study demonstrated that simvastatin suppresses TNF-α and caspase-3 expression in primary cultures of mouse hepatocytes.
  
  
  CONCLUSIONS
  Simvastatin reduces mouse hepatocyte apoptosis by suppressing expression of the TNF-α/caspase-3 pathway.
authors.affiliation: Surgical Service, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston, MA 02114, USA. jingxizh@yahoo.com
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Zhao
authors.forename: Yong-Ming
authors.initials: YM
authors.lastname: Yu
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Fischman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002056:Burns / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects*; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin; D053148:Caspase 3