TIMP-1 Attenuates Blood–Brain Barrier Permeability in Mice with Acute Liver Failure

• Published in: Journal of cerebral blood flow and metabolism 2013-07, Vol.33 (7), p.1041-1049
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Blood-Brain Barrier - enzymology; Blood-Brain Barrier - physiopathology; Blotting, Western; Capillary Permeability - physiology; DNA, Complementary - administration & dosage; DNA, Complementary - genetics; Immunohistochemistry; Injections, Intraventricular; Liver Failure, Acute - enzymology; Liver Failure, Acute - physiopathology; Male; Matrix Metalloproteinase 9 - metabolism; Mice; Mice, Inbred C57BL; Original; Plasmids; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - physiology; Up-Regulation
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2013.45

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.