Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers

BMC Surgery

Research Article

Joanne Verheij¹  Michal Heger²  Jimme K. Wiggers²  Rowan F. van Golen²  Thomas M. van Gulik²  Annemiek M. Dekker² 

[1] Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Department of Surgery, Surgical Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;

关键词: Atorvastatin;    Primary Biliary Cirrhosis;    Cholestasis;    Bile Duct Ligation;    Ischemia Induction;   

DOI  :  10.1186/s12893-017-0235-9

 received in 2016-12-27, accepted in 2017-04-05,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundExtrahepatic cholestasis sensitizes the liver to ischemia/reperfusion (I/R) injury during surgery for perihilar cholangiocarcinoma. It is associated with pre-existent sterile inflammation, microvascular perfusion defects, and impaired energy status. Statins have been shown to protect against I/R injury in normal and steatotic mouse livers. Therefore, the hepatoprotective properties of atorvastatin were evaluated in a rat model of cholestatic I/R injury.MethodsMale Wistar rats were subjected to 70% hepatic ischemia (during 30 min) at 7 days after bile duct ligation. Rats were randomized to atorvastatin treatment or vehicle-control in three test arms: (1) oral treatment with 5 mg/kg during 7 days after bile duct ligation; (2) intravenous treatment with 2.5, 5, or 7.5 mg/kg at 24 h before ischemia; and (3) intravenous treatment with 5 mg/kg at 30 min before ischemia. Hepatocellular damage was assessed by plasma alanine aminotransferase (ALT) and histological necrosis.ResultsI/R induced severe hepatocellular injury in the cholestatic rat livers (~10-fold increase in ALT at 6 h after I/R and ~30% necrotic areas at 24 h after I/R). Both oral and intravenous atorvastatin treatment decreased ALT levels before ischemia. Intravenous atorvastatin treatment at 5 mg/kg at 24 h before ischemia was the only regimen that reduced ALT levels at 6 h after reperfusion, but not at 24 h after reperfusion. None of the tested regimens were able to reduce histological necrosis at 24 h after reperfusion.ConclusionPre-treatment with atorvastatin did not protect cholestatic livers from hepatocellular damage after I/R. Clinical studies investigating the role of statins in the protection against hepatic I/R injury should not include cholestatic patients with perihilar cholangiocarcinoma. These patients require (pharmacological) interventions that specifically target the cholestasis-associated hepatopathology.

【 授权许可】

CC BY   
© The Author(s). 2017