Brain edema in acute liver failure (ALF) remains lethal. The role of vasogenic mechanisms of brain edema has not been explored. We previously demonstrated that matrix metalloproteinase-9 (MMP-9) contributes to the pathogenesis of brain edema. Here, we show that MMP-9 mediates disruptions in tight junction (TJ) proteins in vitro and in brains of mice with ALF. We transfected murine brain endothelial cells (ECs) with MMP-9 complementary DNA (cDNA) using pc DNA3.1 (؉)/Myc-His A expression vector. Tissue inhibitor of matrix metalloproteinases (TIMP-1) cDNA transfection or GM6001 was used to inhibit MMP-9. ALF was induced in mice with azoxymethane. Endogenous overexpression of MMP-9 in brain ECs resulted in significant degradation of the TJ proteins occludin and claudin-5. The alterations in TJ proteins correlated with increased permeability to fluorescein isothiocyanate-dextran molecules. The degradation of TJ proteins and the increased permeability were reversed by TIMP-1 and GM6001. Similar results were found when MMP-9 was exogenously added to brain ECs. We also found that TJ protein degradation was reversed with GM6001 in the brains of mice with ALF. In acute liver failure (ALF), brain edema and sepsis are the two leading causes of death. 2 ALF occurs when there is a sudden loss of hepatic function in a person without preexisting liver disease. The mechanisms responsible for the development of brain edema in ALF remain inadequately characterized. Although the cytotoxic mechanism of brain edema is commonly known, 3 the role of a vasogenic mechanism in ALF is not known.Others have reported that vasogenic BBB failure in ALF results in increased selective permeability to small molecules. [4][5][6] However, light and electron microscopy have shown that in subjects with ALF, the BBB and its TJs are grossly intact. [4][5][6][7][8] These findings are consistent with the emerging concept that a vasogenic brain edema results from subtle modifications of TJ proteins without an obvious disruption of the BBB. 9 Consistent with a leaky BBB that lacks obvious structural breakdown, a perturbation in the extracellular loops of occludin can disturb the barrier function. [10][11][12] Similarly, a deletion in claudin-5 results in increased BBB permeability to molecules Ͻ800 Da despite an intact BBB ultrastructure. 13 Matrix metalloproteinases play significant roles in highly complex processes, including regulating cell behavior, cell-cell communication, and tumor progression. 14,15 Matrix metalloproteinases mediate many different proteolytic reactions involving cellular surface elements, in-

MMP-9 is important for the process of PLF. The initial injury is associated with MMP-9 derived from neutrophils, and MMP-9 blockade reduces PLF. MMP-9 may be a potential target to prevent PLF after EH and to overcome an insufficient RL.