期刊
HEPATOLOGY
卷 50, 期 6, 页码 1914-1923出版社
WILEY
DOI: 10.1002/hep.23203
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资金
- National Institute of Health [R01NS051646-01A2]
- American Heart Association [0655589B]
- Deason Foundation
Brain edema in acute liver failure (ALE) 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 ALE. 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 ALE. Conclusion: TJ proteins are significantly perturbed in brains of mice with ALE. These data corroborate the important role of MMP-9 in the vasogenic mechanism of brain edema in ALE. (HEPATOLOGY 2009;50:1914-1923.)
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