Matrix metalloproteinase-9 as a therapeutic target for the progression of fulminant liver failure with hepatic encephalopathy: A pilot study in mice

Tomohide Hori, Shinji Uemoto, Lindsay B. Walden, Feng Chen, Ann Marie T Baine, Toshiyuki Hata, Takayuki Kogure, Justin H Nguyen

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Aim: 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)-1cDNA were used. Mice were divided into five groups: control; FLF; FLF with GM6001 pretreatment; FLF with TIMP-1 plasmid transfection 24h before disease onset; and FLF with TIMP-1 plasmid transfection 48h 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. Conclusion: MMP-9 has therapeutic potential for FLF progression.

Original languageEnglish (US)
Pages (from-to)651-662
Number of pages12
JournalHepatology Research
Volume44
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Hepatic Encephalopathy
Acute Liver Failure
Matrix Metalloproteinase 9
Tissue Inhibitor of Metalloproteinase-1
Therapeutics
Transfection
Matrix Metalloproteinase Inhibitors
Coma
Liver Transplantation
Plasmids
Azoxymethane
Tissue Inhibitor of Metalloproteinases
Survival
Liver
Critical Care
Brain Injuries
Permeability
Western Blotting

Keywords

  • Comatose
  • Hepatic encephalopathy
  • Liver transplantation
  • Matrix metalloproteinase
  • Tissue inhibitor of metalloproteinases

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases

Cite this

Matrix metalloproteinase-9 as a therapeutic target for the progression of fulminant liver failure with hepatic encephalopathy : A pilot study in mice. / Hori, Tomohide; Uemoto, Shinji; Walden, Lindsay B.; Chen, Feng; Baine, Ann Marie T; Hata, Toshiyuki; Kogure, Takayuki; Nguyen, Justin H.

In: Hepatology Research, Vol. 44, No. 6, 2014, p. 651-662.

Research output: Contribution to journalArticle

Hori, Tomohide ; Uemoto, Shinji ; Walden, Lindsay B. ; Chen, Feng ; Baine, Ann Marie T ; Hata, Toshiyuki ; Kogure, Takayuki ; Nguyen, Justin H. / Matrix metalloproteinase-9 as a therapeutic target for the progression of fulminant liver failure with hepatic encephalopathy : A pilot study in mice. In: Hepatology Research. 2014 ; Vol. 44, No. 6. pp. 651-662.
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T1 - Matrix metalloproteinase-9 as a therapeutic target for the progression of fulminant liver failure with hepatic encephalopathy

T2 - A pilot study in mice

AU - Hori, Tomohide

AU - Uemoto, Shinji

AU - Walden, Lindsay B.

AU - Chen, Feng

AU - Baine, Ann Marie T

AU - Hata, Toshiyuki

AU - Kogure, Takayuki

AU - Nguyen, Justin H

PY - 2014

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N2 - Aim: 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)-1cDNA were used. Mice were divided into five groups: control; FLF; FLF with GM6001 pretreatment; FLF with TIMP-1 plasmid transfection 24h before disease onset; and FLF with TIMP-1 plasmid transfection 48h 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. Conclusion: MMP-9 has therapeutic potential for FLF progression.

AB - Aim: 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)-1cDNA were used. Mice were divided into five groups: control; FLF; FLF with GM6001 pretreatment; FLF with TIMP-1 plasmid transfection 24h before disease onset; and FLF with TIMP-1 plasmid transfection 48h 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. Conclusion: MMP-9 has therapeutic potential for FLF progression.

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KW - Hepatic encephalopathy

KW - Liver transplantation

KW - Matrix metalloproteinase

KW - Tissue inhibitor of metalloproteinases

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