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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-\u03b1 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.<\/jats:p>","DOI":"10.1038\/jcbfm.2013.45","type":"journal-article","created":{"date-parts":[[2013,3,27]],"date-time":"2013-03-27T05:00:18Z","timestamp":1364360418000},"page":"1041-1049","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":41,"title":["TIMP-1 Attenuates Blood\u2013Brain Barrier Permeability in Mice with Acute Liver Failure"],"prefix":"10.1177","volume":"33","author":[{"given":"Feng","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evette S","family":"Radisky","sequence":"additional","affiliation":[{"name":"Department of Cancer Basic Science, Mayo Clinic, Jacksonville, Florida, 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