Protective effects and mechanisms of sivelestat against the liver injuries induced by severe acute pancreatitis in rats

Objective To evaluate the protective effects of sivelestat against liver injuries induced by severe acute pancreatitis (SAP) in rats and investigate its potential mechanism.Methods Fifty-four male Sprague-Dawley rats were equally divided into three groups randomly:group C (control group),group P (SAP group) and group S (SAP + sivelestat group).The SAP models were induced by retrograde injection of 4％ sodium taurocholate into bilopancreatic duct of SD rats.Group C rats were injected by isometric physiological saline.Group P rats were subjected to injection of sivelestat [0.2 mg/(kg·h) ] via the caudal vein after models were induced.Serum levels of tumor necrosis factor-α ( TNF-α),alanine aminotransferase (ALT),aspartate aminotransferase (AST) and neutrophil elastase (NE) activity of liver tissue were measured 3,6,and 12 h after operation.Hepatocytes apoptosis was examined by using terminal deoxynuceotidy transferase mediated dUTP nick end labeling (TUNEL) and apoptosis index (AI) was calculated.Hepatocellular apopotosis rate was assayed by using flow cytometry and histopathologic changes of the liver were observed.Results In group P,serum level of TNF-α at 3,6 and 12 h [ (453.58 ±43.49),(359.00±34.17),(256.48 ±29.74) ng/L],those of ALT [( 120.2 ± 10.6),(329.2 ±52.0),(508.7 ± 49.6) U/L],AST [ (331.5 ± 3.5 ),( 579.0 ± 50.6),(708.0 ± 49.8 ) U/L ],and those of NE [ (1.96 ± 0.13 ),(2.67 ± 0.15 ),(3.71 ± 0.38) μg/L] in the liver tissue were significantly increased as compared with those in group C ( all P ＜0.01 ).All the indicators at 3,6 and 12 h in group S,inclusingTNF-α [(337.48 ±33.31),(281.38 ±33.47),(181.00 ±31.05) ng/L],ALT [(89.0 ±29.7),(151.2±27.8),(334.2±25.0) U/L],AST [(237.0±113.7),(305.2±27.4),(529.3±28.9) U/L],NE [ ( 1.07 ±0.08),(2.11 ±0.35),(2.84 ±0.52) μg/L] were significantly decreased after operation as compared with group P (P ＜0.01 ).The hepatocytes apoptosis rate in group P at 3,6 and 12 h (8.1 ±0.7,11.2 ±0.8,15.1 ± 1.0 respectively) was was higher than in group S correspondingly ( 11.4 ± 1.1,15.3 ± 1.1,21.3 ± 1.2,P ＜ 0.01 ).Histopathology showed that the liver injuries in group P were gradually aggravated with disease progression,and alleviated obviously with sivelestat treatment.Conclusion Sivelestat can depress the apoptosis index of hepatocytes and relieve the severity of liver injuries of SAP rats,which may be related to the inhibition of neutrophile elastase and the release of TNF-α. Key words: Pancreatitis; Sivelestat; Liver injury; Apoptosis