Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice.
OBJECTIVE
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.
Nguyen
Justin H
JH
Department of Transplantation, Division of Transplant Surgery, Mayo Clinic College of Medicine, 4205 Belfort Road, Suite 1100, Jacksonville, FL 32216, USA. nguyen.justin@mayo.edu
Yamamoto
Satoshi
S
Steers
Jeffery
J
Sevlever
Daniel
D
Lin
Wenlang
W
Shimojima
Naoki
N
Castanedes-Casey
Monica
M
Genco
Petrina
P
Golde
Todd
T
Richelson
Elliott
E
Dickson
Dennis
D
McKinney
Michael
M
Eckman
Christopher B
CB
D000818:Animals; D001921:Brain / Q000201:enzymology*; D001929:Brain Edema / Q000201:enzymology*; D002199:Capillary Permeability; D005070:Evans Blue / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D017114:Liver Failure, Acute / Q000201:enzymology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D015854:Up-Regulation
D061965:Matrix Metalloproteinase Inhibitors; D005070:Evans Blue; D020780:Matrix Metalloproteinase 9