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Updated: Aug 11, 2026
A Murine Model of Subarachnoid Hemorrhage
Published on: November 21, 2013
Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice
Justin H Nguyen1, Satoshi Yamamoto, Jeffery Steers
1Department of Transplantation, Division of Transplant Surgery, Mayo Clinic College of Medicine, 4205 Belfort Road, Suite 1100, Jacksonville, FL 32216, USA. nguyen.justin@mayo.edu
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.
Insights
Matrix metalloproteinase-9 (MMP-9) contributes to brain edema in fulminant hepatic failure (FHF). Inhibiting MMP-9 may prevent brain swelling and protect against FHF complications.
Area of Science:
- Neuroscience
- Hepatology
- Biochemistry
Background:
- Fulminant hepatic failure (FHF) can lead to coma and fatal brain edema.
- The mechanisms of brain extravasation causing edema in FHF are not fully understood.
- Matrix metalloproteinase-9 (MMP-9) is implicated in various brain injuries.
Purpose of the Study:
- To investigate the role of MMP-9 in brain edema development during FHF.
- To determine if MMP-9 contributes to brain extravasation in FHF.
Main Methods:
- Assayed MMP-9 levels using SDS-PAGE and zymography.
- Measured brain extravasation with Evans blue and brain water content.
- Utilized azoxymethane-induced FHF model in mice, employing MMP inhibitor GM6001 and an MMP-9 antibody.
Main Results:
- Active MMP-9 significantly increased with coma onset and brain extravasation in FHF mice.
- Blocking MMP-9 attenuated brain extravasation, astrocytic swelling, and brain edema.
- MMP-9 activity originated from the necrotic liver, not the brain.
Conclusions:
- MMP-9 plays a role in the pathogenesis of brain extravasation and edema in FHF.
- The liver is identified as the source of MMP-9 in FHF.
- Inhibiting MMP-9 shows potential for protecting against brain edema in FHF.
