TIMP-1/MMP-9 imbalance in brain edema in rats with fulminant hepatic failure.
BACKGROUND
Fulminant hepatic failure (FHF) is a devastating disease. When coma sets in, brain edema develops, changing FHF into a lethal condition. Liver transplantation is the definitive treatment. However, a third of these patients die as the result of brain edema before a donor becomes available. Tissue inhibitor of matrix metalloproteinase (MMP), or TIMP, and MMP-9 are implicated in ischemic brain edema. We thus hypothesized that an imbalance in TIMP-1/MMP-9 relationship plays a role in the development of increased brain extravasation and edema in FHF.


METHODS
FHF was induced with a single intraperitoneal injection of D-galactosamine (250 mg/kg). Control rats received saline. GM6001, a synthetic MMP inhibitor, was administered (30 mg/kg) every 12 h for 3 doses starting at 12 h after D-galactosamine injection. MMP-9 was assayed with standard gelatin zymography. Brain extravasation, a measurement of the blood-brain barrier permeability, was determined with Evans blue. Brain edema was determined using specific gravity method.


RESULTS
The active MMP-9 in the systemic circulation was significantly increased in the comatose FHF as compared to the precoma FHF and control animals (6.5 +/- 0.7 versus 4.6 +/- 0.4 versus 2.6 +/- 0.5 pg/microg, respectively; P < 0.05). Conversely, TIMP-1 was steadily decreased in precoma and coma FHF rats by 35% and 45%, respectively. Blocking MMP-9 activity with GM6001 significantly attenuated brain extravasation and edema in rats with FHF.


CONCLUSIONS
Our study strongly supports that the perturbation of decreased TIMP-1 and increased MMP-9 contributes to the pathogenesis of brain edema in FHF. Our findings present a potential therapeutic approach to effectively increase the window of opportunity for life-saving liver transplantation.
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Satoshi
S
Yamamoto
Justin H
JH
Nguyen
D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001929:Brain Edema / Q000097:blood* / Q000209:etiology* / Q000517:prevention & control; D017364:Collagenases / Q000097:blood; D004151:Dipeptides / Q000008:administration & dosage; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004792:Enzyme Precursors / Q000097:blood; D005688:Galactosamine / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000150:complications*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
D004151:Dipeptides; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D019715:Tissue Inhibitor of Metalloproteinase-1; D005688:Galactosamine; D017364:Collagenases; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9