TIMP-1 attenuates blood-brain barrier permeability in mice with acute liver failure

Feng Chen, Evette S Radisky, Pritam Das, Jyotica Batra, Toshiyuki Hata, Tomohide Hori, Ann Marie T Baine, Lindsay Gardner, Mei Y. Yue, Guojun D Bu, Gregory Del Zoppo, Tushar C Patel, Justin H Nguyen

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Blood-brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and D-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.

Original languageEnglish (US)
Pages (from-to)1041-1049
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume33
Issue number7
DOIs
StatePublished - Jul 2013

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Tissue Inhibitor of Metalloproteinase-1
Acute Liver Failure
Blood-Brain Barrier
Permeability
Matrix Metalloproteinase 9
Plasmids
Central Nervous System
Complementary DNA
Occludin
Tight Junction Proteins
Tissue Inhibitor of Metalloproteinases
Galactosamine
p38 Mitogen-Activated Protein Kinases
Fluorescein
Epidermal Growth Factor Receptor
Liver Transplantation
Tumor Necrosis Factor-alpha
Injections
Liver

Keywords

  • acute liver failure
  • BBB permeability
  • tight junction
  • TIMP-1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

Cite this

TIMP-1 attenuates blood-brain barrier permeability in mice with acute liver failure. / Chen, Feng; Radisky, Evette S; Das, Pritam; Batra, Jyotica; Hata, Toshiyuki; Hori, Tomohide; Baine, Ann Marie T; Gardner, Lindsay; Yue, Mei Y.; Bu, Guojun D; Del Zoppo, Gregory; Patel, Tushar C; Nguyen, Justin H.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 33, No. 7, 07.2013, p. 1041-1049.

Research output: Contribution to journalArticle

Chen, Feng ; Radisky, Evette S ; Das, Pritam ; Batra, Jyotica ; Hata, Toshiyuki ; Hori, Tomohide ; Baine, Ann Marie T ; Gardner, Lindsay ; Yue, Mei Y. ; Bu, Guojun D ; Del Zoppo, Gregory ; Patel, Tushar C ; Nguyen, Justin H. / TIMP-1 attenuates blood-brain barrier permeability in mice with acute liver failure. In: Journal of Cerebral Blood Flow and Metabolism. 2013 ; Vol. 33, No. 7. pp. 1041-1049.
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