| Abstract:bjective:Cholestasis, defined as an impairment in bile formation, is a common occurrence in human liver diseases and results in progressive liver injury culminating in cirrhosis and liver failure. Unfortunately, the therapeutic options for treating this syndrome remain limited, in part, because the essential mechanisms mediating cholestatic liver injury remain incompletely understood. The cellular complexity of liver injury in cholestatic syndromes is highlighted by the role of the transcription factor NF-κB. BElevated concentrations of bile acids within the hepatocyte during cholestasis activate NF-κB. The innate immune system also contributes to cholestatic liver injury with Kupffer cell activation and neutrophil infiltration. Kupffer cell activation occurs by a NF-κB-dependent process; in this context, NF-κB activation, by promoting expression of death ligands by Kupffer cells (i.e., Fas ligand and TNF-α), is cytotoxic to the liver. NF-κB activation is a pivotal feature of stellate cell activation, and inhibition of NF-κB activation in stellate cells induces their apoptosis,diminishing hepatic fibrosis. The overall objective of this study was to examine the effect of proteasome inhibition on liver injury in the BDL rats. Methods:Healthy adult male Spague-Dawlay (SD) 30 rats were randomly divided into 3 groups randomly table, sham operation group (A) 10, common bile duct ligation group (B) 10, common bile duct ligation+Bortezomib group (C) 10.One day before surgery, A, B group with saline 11m, C group bortezomib plus saline diluted by 0.2mg/kg intraperitoneal injection 1ml. Fasting 12 h, free access to water, to ketamine,100 mg/kg by intraperitoneal injection anesthesia, under sterile condition upper abdominal transverse incision, A group only line of separation of common bile duct, not sterilization, B, C group from the hepatic portal 5mm Office free after bile duct ligation with 5-0 surgical silk double common bile duct, close the abdominal cavity. Four days after repeat injection. Seven days after the same in each group were sacrificed under anesthesia all rats, abdominal aortic blood, measured serum aminotransferase, total bilirubin and total bile acid value, and the hepatic tissue, part of the 4% paraformaldehyde fixed, paraffin sections, hematoxylin-line-eosin (HE) staining of liver tissue pathological changes under light microscope; immunohistochemical detection of NF-κB expression in liver tissue; part of the-70℃preservation, RT-PCR used to detect the expression of TNF-αmRNA.Measuring data was demonstrated with mean±standard deviation (x±S).With t test, the groups were compared with variance analysis. If there was homogeneity of variance, one-way ANOVA analysis was used,and if there was heterogeneity of variance H test was used. The difference between the model group and the control group in the serum, pathology and extent of apoptosis was compared. Count data was used chi-square test; the difference of P<0.05 has statistical significance. Results:All 30 rats were survived, (1) HE staining, A group of abnormal liver tissue no significant changes; B group showed intrahepatic biliary dilatation, Liver cell swelling, hydropic degeneration, Vacuolar degeneration, a small amount of point-like or spotty necrosis; Portal area with significant bile duct, capillaries and connective tissue proliferation; C group changes in the liver was significantly reduced compared with B group, Shows a small amount of fibrous tissue, new bile duct hyperplasia, But still shows a small amount of liver cell swelling and focal necrosis. (2) serology showed ALT, TB, TBA levels of A group were 40.67±7.34, 13.82±4.83,5.25±3.08; B group were 145.65±17.49,150.20±10.67; C group were 99.40±15.43,117.53±17.16,115.45±17.47 (P <0.01). C group were 99.40±15.43,117.53±17.16,115.45±17.47 (P <0.01). (3) RT-PCR A group of TNF-αmRNA expression relative average gray ratio 0.78±0.09, B group was 1.25±0.37, C group was 1.12±0.21, B group the expression of TNF-αmRNA than A group (P <0.01), C group than in group B decreased (P<0.05). (4) Immunohistochemistry of experimental data using integral optical density (IOD) for semi-quantitative analysis, C group of NF-κB p65 protein expression was significantly lower than the B group (P<0.01). Conclusion:1) Obstructive jaundice, bile deposition can lead to liver cell damage;2) NF-κB/p65 expression, leading to TNF-αand other inflammatory factors lead to damage liver.3) Bortezomib can be inhibited NF-κB activation and thus reduce the liver damage caused by Cs.
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