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      <dc:title>TIMP-1 attenuates blood–brain barrier permeability in mice with acute liver failure</dc:title>
      <dc:creator>Chen, Feng</dc:creator>
      <dc:creator>Radisky, Evette S</dc:creator>
      <dc:creator>Das, Pritam</dc:creator>
      <dc:creator>Batra, Jyotica</dc:creator>
      <dc:creator>Hata, Toshiyuki</dc:creator>
      <dc:creator>Hori, Tomohide</dc:creator>
      <dc:creator>Baine, Ann-Marie T</dc:creator>
      <dc:creator>Gardner, Lindsay</dc:creator>
      <dc:creator>Yue, Mei Y</dc:creator>
      <dc:creator>Bu, Guojun</dc:creator>
      <dc:creator>del Zoppo, Gregory</dc:creator>
      <dc:creator>Patel, Tushar C</dc:creator>
      <dc:creator>Nguyen, Justin H</dc:creator>
      <dc:subject>Original Article</dc:subject>
      <dc:description>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 &#x1d49f;-(+)-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.</dc:description>
      <dc:publisher>Nature Publishing Group</dc:publisher>
      <dc:identifier>http://europepmc.org/articles/PMC3705430/</dc:identifier>
      <dc:type>Text</dc:type>
      <dc:language>en</dc:language>
      <dc:rights/>
      <dc:identifier>PMC: PMC3705430</dc:identifier>
      <dc:date>2013</dc:date>
      <dc:identifier>doi: 10.1038/jcbfm.2013.45</dc:identifier>
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