title: TIMP-1 attenuates blood-brain barrier permeability in mice with acute liver failure.
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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Evette S
authors.initials: ES
authors.lastname: Radisky
authors.forename: Pritam
authors.initials: P
authors.lastname: Das
authors.forename: Jyotica
authors.initials: J
authors.lastname: Batra
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hata
authors.forename: Tomohide
authors.initials: T
authors.lastname: Hori
authors.forename: Ann-Marie T
authors.initials: AM
authors.lastname: Baine
authors.forename: Lindsay
authors.initials: L
authors.lastname: Gardner
authors.forename: Mei Y
authors.initials: MY
authors.lastname: Yue
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Gregory
authors.initials: G
authors.lastname: del Zoppo
authors.forename: Tushar C
authors.initials: TC
authors.lastname: Patel
authors.forename: Justin H
authors.initials: JH
authors.lastname: Nguyen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000201:enzymology / Q000503:physiopathology*; D015153:Blotting, Western; D002199:Capillary Permeability / Q000502:physiology*; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D017114:Liver Failure, Acute / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9