Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice

Justin H Nguyen, Satoshi Yamamoto, Jeffery Steers, Daniel Sevlever, Wenlang Lin, Naoki Shimojima, Monica Castanedes-Casey, Petrina Genco, Todd Golde, Elliott Richelson, Dennis W Dickson, Michael McKinney, Christopher B. Eckman

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Background/Aims: Fulminant hepatic failure (FHF) can be dreadful. When coma sets in, brain edema develops taking FHF into a lethal course. Mechanisms of brain extravasation leading to brain edema remain incompletely understood. Matrix metalloproteinase (MMP)-9 is implicated in various brain injuries. We hypothesized that MMP-9 contributes to brain edema in FHF. Methods: MMP-9 and its proform were assayed using SDS-PAGE and in situ gelatin zymographies. Brain extravasation was assessed with Evans blue. Brain water was determined by specific gravity and astrocytic endfoot swelling by electron microscopy. FHF in mice was induced by azoxymethane. MMP inhibitor GM6001 and MMP-9 monoclonal antibody were used. Results: Active MMP-9 was significantly increased at the onset of coma and brain extravasation in FHF mice. Blocking MMP-9 with either GM6001 or MMP-9 monoclonal antibody significantly attenuated brain extravasation, astrocytic endfoot swelling, and brain edema. Brains of FHF mice did not show MMP-9 activity. In contrast, livers of these animals showed marked up-regulation of MMP-9 activity. Conclusions: Our findings suggest that MMP-9 contributes to the pathogenesis of brain extravasation and edema in FHF. The necrotic liver is the source of MMP-9 in FHF. Inhibition of MMP-9 may protect against the development of brain edema in FHF.

Original languageEnglish (US)
Pages (from-to)1105-1114
Number of pages10
JournalJournal of Hepatology
Volume44
Issue number6
DOIs
StatePublished - Jun 2006

Fingerprint

Acute Liver Failure
Brain Edema
Matrix Metalloproteinase 9
Brain
Coma
Monoclonal Antibodies
Azoxymethane
Evans Blue
Specific Gravity
Matrix Metalloproteinase Inhibitors
Liver
Gelatin
Brain Injuries
Polyacrylamide Gel Electrophoresis
Electron Microscopy
Up-Regulation

Keywords

  • Acute liver failure
  • Brain edema
  • Brain extravasation
  • Gelatinase
  • Matrix metalloproteinase-9

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice. / Nguyen, Justin H; Yamamoto, Satoshi; Steers, Jeffery; Sevlever, Daniel; Lin, Wenlang; Shimojima, Naoki; Castanedes-Casey, Monica; Genco, Petrina; Golde, Todd; Richelson, Elliott; Dickson, Dennis W; McKinney, Michael; Eckman, Christopher B.

In: Journal of Hepatology, Vol. 44, No. 6, 06.2006, p. 1105-1114.

Research output: Contribution to journalArticle

Nguyen, JH, Yamamoto, S, Steers, J, Sevlever, D, Lin, W, Shimojima, N, Castanedes-Casey, M, Genco, P, Golde, T, Richelson, E, Dickson, DW, McKinney, M & Eckman, CB 2006, 'Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice', Journal of Hepatology, vol. 44, no. 6, pp. 1105-1114. https://doi.org/10.1016/j.jhep.2005.09.019
Nguyen, Justin H ; Yamamoto, Satoshi ; Steers, Jeffery ; Sevlever, Daniel ; Lin, Wenlang ; Shimojima, Naoki ; Castanedes-Casey, Monica ; Genco, Petrina ; Golde, Todd ; Richelson, Elliott ; Dickson, Dennis W ; McKinney, Michael ; Eckman, Christopher B. / Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice. In: Journal of Hepatology. 2006 ; Vol. 44, No. 6. pp. 1105-1114.
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AU - Nguyen, Justin H

AU - Yamamoto, Satoshi

AU - Steers, Jeffery

AU - Sevlever, Daniel

AU - Lin, Wenlang

AU - Shimojima, Naoki

AU - Castanedes-Casey, Monica

AU - Genco, Petrina

AU - Golde, Todd

AU - Richelson, Elliott

AU - Dickson, Dennis W

AU - McKinney, Michael

AU - Eckman, Christopher B.

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N2 - Background/Aims: Fulminant hepatic failure (FHF) can be dreadful. When coma sets in, brain edema develops taking FHF into a lethal course. Mechanisms of brain extravasation leading to brain edema remain incompletely understood. Matrix metalloproteinase (MMP)-9 is implicated in various brain injuries. We hypothesized that MMP-9 contributes to brain edema in FHF. Methods: MMP-9 and its proform were assayed using SDS-PAGE and in situ gelatin zymographies. Brain extravasation was assessed with Evans blue. Brain water was determined by specific gravity and astrocytic endfoot swelling by electron microscopy. FHF in mice was induced by azoxymethane. MMP inhibitor GM6001 and MMP-9 monoclonal antibody were used. Results: Active MMP-9 was significantly increased at the onset of coma and brain extravasation in FHF mice. Blocking MMP-9 with either GM6001 or MMP-9 monoclonal antibody significantly attenuated brain extravasation, astrocytic endfoot swelling, and brain edema. Brains of FHF mice did not show MMP-9 activity. In contrast, livers of these animals showed marked up-regulation of MMP-9 activity. Conclusions: Our findings suggest that MMP-9 contributes to the pathogenesis of brain extravasation and edema in FHF. The necrotic liver is the source of MMP-9 in FHF. Inhibition of MMP-9 may protect against the development of brain edema in FHF.

AB - Background/Aims: Fulminant hepatic failure (FHF) can be dreadful. When coma sets in, brain edema develops taking FHF into a lethal course. Mechanisms of brain extravasation leading to brain edema remain incompletely understood. Matrix metalloproteinase (MMP)-9 is implicated in various brain injuries. We hypothesized that MMP-9 contributes to brain edema in FHF. Methods: MMP-9 and its proform were assayed using SDS-PAGE and in situ gelatin zymographies. Brain extravasation was assessed with Evans blue. Brain water was determined by specific gravity and astrocytic endfoot swelling by electron microscopy. FHF in mice was induced by azoxymethane. MMP inhibitor GM6001 and MMP-9 monoclonal antibody were used. Results: Active MMP-9 was significantly increased at the onset of coma and brain extravasation in FHF mice. Blocking MMP-9 with either GM6001 or MMP-9 monoclonal antibody significantly attenuated brain extravasation, astrocytic endfoot swelling, and brain edema. Brains of FHF mice did not show MMP-9 activity. In contrast, livers of these animals showed marked up-regulation of MMP-9 activity. Conclusions: Our findings suggest that MMP-9 contributes to the pathogenesis of brain extravasation and edema in FHF. The necrotic liver is the source of MMP-9 in FHF. Inhibition of MMP-9 may protect against the development of brain edema in FHF.

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