title: Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice.
abstract: 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.
authors.affiliation: 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
authors.forename: Justin H
authors.initials: JH
authors.lastname: Nguyen
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Jeffery
authors.initials: J
authors.lastname: Steers
authors.forename: Daniel
authors.initials: D
authors.lastname: Sevlever
authors.forename: Wenlang
authors.initials: W
authors.lastname: Lin
authors.forename: Naoki
authors.initials: N
authors.lastname: Shimojima
authors.forename: Monica
authors.initials: M
authors.lastname: Castanedes-Casey
authors.forename: Petrina
authors.initials: P
authors.lastname: Genco
authors.forename: Todd
authors.initials: T
authors.lastname: Golde
authors.forename: Elliott
authors.initials: E
authors.lastname: Richelson
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.forename: Michael
authors.initials: M
authors.lastname: McKinney
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Eckman
mesh_terms: 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
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D005070:Evans Blue; D020780:Matrix Metalloproteinase 9