TIMP-1/MMP-9 Imbalance in Brain Edema in Rats With Fulminant Hepatic Failure

Satoshi Yamamoto, Justin H Nguyen

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)307-314
Number of pages8
JournalJournal of Surgical Research
Volume134
Issue number2
DOIs
StatePublished - Aug 2006

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Tissue Inhibitor of Metalloproteinase-1
Acute Liver Failure
Brain Edema
Matrix Metalloproteinase 9
Coma
Galactosamine
Liver Transplantation
Tissue Inhibitor of Metalloproteinases
Evans Blue
Specific Gravity
Matrix Metalloproteinase Inhibitors
Gelatin
Intraperitoneal Injections
Blood-Brain Barrier
Permeability
Tissue Donors
Injections
Brain

Keywords

  • acute liver failure
  • BBB permeability
  • brain edema
  • gelatinases
  • TIMP-1

ASJC Scopus subject areas

  • Surgery

Cite this

TIMP-1/MMP-9 Imbalance in Brain Edema in Rats With Fulminant Hepatic Failure. / Yamamoto, Satoshi; Nguyen, Justin H.

In: Journal of Surgical Research, Vol. 134, No. 2, 08.2006, p. 307-314.

Research output: Contribution to journalArticle

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title = "TIMP-1/MMP-9 Imbalance in Brain Edema in Rats With Fulminant Hepatic Failure",
abstract = "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.",
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