Occludin is regulated by epidermal growth factor receptor activation in brain endothelial cells and brains of mice with acute liver failure

作者:Feng Chen; Tomohide Hori; Norifumi Ohashi; Ann-Marie Baine; Christopher B. Eckman; Justin H. Nguyen 刊名: 上传者:汪昱


LIVER FAILURE/CIRRHOSIS/PORTAL HYPERTENSION Occludin Is Regulated by Epidermal Growth Factor Receptor Activation in Brain Endothelial Cells and Brains of Mice with Acute Liver Failure Feng Chen,1 Tomohide Hori,1 Norifumi Ohashi,1 Ann-Marie Baine,1 Christopher B. Eckman,1 and Justin H. Nguyen2 Mechanisms of brain edema in acute liver failure (ALF) are not completely understood. We recently demonstrated that matrix metalloproteinase 9 (MMP-9) induces significant altera-tions to occludin in brain endothelial cells in vitro and in brains of mice with experimental ALF (Hepatology 2009;50:1914). In this study we show that MMP-9-induced transactiva-tion of epidermal growth factor receptor (EGFR) and p38 MAPK/NFjB (mitogen-activated protein kinase/nuclear factor-kappa B) signals participate in regulating brain endothelial occludin level. Mouse brain endothelial bEnd3 cells were exposed to MMP-9 or p38 MAPK up-regulation in the presence and absence of EGFR inhibitor, p38 MAPK inhibitor, NFjB inhibitor, and/or appropriate small interfering RNA. Reverse-transcription polymerase chain reaction (RT-PCR) and western blotting were used for messenger RNA and protein expres-sion analyses. Immunohistochemical staining and confocal microscopy were used to demon-strate cellular EGFR activation. Intraperitoneal azoxymethane was use to induce ALF in mice. Brains of comatose ALF mice were processed for histological and biochemical analyses. When bEnd3 cells were exposed to MMP-9, EGFR was significant