TY - JOUR
T1 - TIMP-1/MMP-9 Imbalance in Brain Edema in Rats With Fulminant Hepatic Failure
AU - Yamamoto, Satoshi
AU - Nguyen, Justin H.
PY - 2006/8
Y1 - 2006/8
N2 - 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. Materials and 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/μg, 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.
AB - 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. Materials and 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/μg, 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.
KW - BBB permeability
KW - TIMP-1
KW - acute liver failure
KW - brain edema
KW - gelatinases
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U2 - 10.1016/j.jss.2005.11.588
DO - 10.1016/j.jss.2005.11.588
M3 - Article
C2 - 16488444
AN - SCOPUS:33746189720
SN - 0022-4804
VL - 134
SP - 307
EP - 314
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 2
ER -