title: Matrix metalloproteinase-9 as a therapeutic target for the progression of fulminant liver failure with hepatic encephalopathy: A pilot study in mice.
abstract: OBJECTIVE
  If progressive liver injury and subsequent hepatic encephalopathy can be prohibited in fulminant liver failure (FLF), it would be ideal for intensive care of FLF and provide an expanded opportunity for liver transplantation (LT). We hypothesized that matrix metalloproteinase (MMP)-9 plays an important role in FLF progression, and investigated MMP-9 behaviors in a murine FLF model, especially at the coma stage.
  
  
  METHODS
  The murine FLF model with azoxymethane recapitulates FLF in humans. The detailed coma status was evaluated, on the assumption that LT is indicated at early, but not late, stage 3. To investigate whether MMP-9 deletion or reduction has beneficial effects, an MMP-9 inhibitor (GM6001) and transfection of tissue inhibitor of metalloproteinases (TIMP)-1 cDNA were used. Mice were divided into five groups: control; FLF; FLF with GM6001 pretreatment; FLF with TIMP-1 plasmid transfection 24 h before disease onset; and FLF with TIMP-1 plasmid transfection 48 h before disease onset. Neurological findings, including survival, were followed. Samples were obtained at early and late stage 3. Biochemical examinations and histopathological assessments were performed. The expression and function of MMP-9 and TIMP-1 were evaluated by western blotting and zymography. A brain permeability study was also performed.
  
  
  RESULTS
  MMP-9 was strongly increased in FLF. The MMP-9 inhibitions worked well, and prolonged the survival, interval to stage 3 and duration of early stage 3. MMP-9 inhibition improved the liver and subsequent brain injuries at early stage 3, with no remarkable improvements at late stage 3.
  
  
  CONCLUSIONS
  MMP-9 has therapeutic potential for FLF progression.
authors.affiliation: Department of Neuroscience, Mayo Clinic in Florida; Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Hori
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Walden
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Ann-Marie T
authors.initials: AM
authors.lastname: Baine
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hata
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kogure
authors.forename: Justin H
authors.initials: JH
authors.lastname: Nguyen
keywords: comatose; hepatic encephalopathy; liver transplantation; matrix metalloproteinase; tissue inhibitor of metalloproteinases