Proteasome Inhibitor Lactacystin Ablates Liver Injury Induced By Intestinal Ischemia/reperfusion

Purpose: The aim of this study was to investigate the role of proteasome in the pathogenesis of liver injury induced by intestinal ischemia/reperfusion (I/R) , and the effect of proteasome inhibitor Lactacystin on neutrophil infiltration, intracellular adhesion molecule-1 (ICAM-1) and nuclear factor kappa B (NF-κB) expression in liver tissue of rats.Methods: Thirty-two Wistar rats were randomly divided into 4 groups (n = 8 in each): (1) control group: sham operated, (2) I/R group: 1 h of intestinal ischemia and 4 h of reperfusion, (3) 0.2mg/kg Lactacystin pretreatment group: treated with 0.2 mg/kg Lactacystin before intestinal I/R, and (4) 0.6mg/kg Lactacystin pretreatment group: treated with 0.6 mg/kg Lactacystin before intestinal I/R. Liver and intestine histology were observed. Serum levels of aspartate aminotransferase (AST) , alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and 20S proteasome activity in circulating white blood cells were measured. Myeloperoxidase (MPO) activity in the liver tissues, the immunohistochemical expressions of liver NF-κB and intercellular adhesion molecule-1 (ICAM-1) were assayed.Result: Liver and intestine injury was induced by intestinal I/R, characterized as histological damage of edema , hemorrhage and infiltration with inflammatory cells as well as the significant rising of serum AST, ALT and LDH levels (p<0.05,p<0.01,p<0.05).As compared with control group , MPO activity in the liver tissues increased significantly (p<0.05) in I/R group. Strong positive expressions of liver ICAM-1 and NF-κB p65 was observed. Administration of 0.6mg/kgLactacystin markedly reduced 20S proteasome activity in circulating white blood cells (P<0.01) and ameliorated liver injury demonstrated as the decreasing levels of serum AST, ALT and LDH (p<0.05,p<0.05,p<0.05). Compared with intestinal I/R group, MPO activity in the liver tissues decreased significantly (P<0.05), the expressions of liver NF-κB and ICAM-1 markedly ameliorated.Conclusion: The study reveals that proteasome inhibitor Lactacystin ablates liver injury induced by intestinal I/R; One possible mechanism is attributed to the inhibition of enhanced ICAM-1 and neutrophil infiltration through inhibiting the activity of NF-κB. Our results have a feasible implication in clinical use of proteasome inhibitors in intestinal I/R.