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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 del Zoppo, Gregory Patel, Tushar C Nguyen, Justin H Original Article 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. Nature Publishing Group http://europepmc.org/articles/PMC3705430/ Text en PMC: PMC3705430 2013 doi: 10.1038/jcbfm.2013.45