Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers
Abstract Background Extrahepatic 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 pro...
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| Format: | Article |
| Language: | English |
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BMC
2017-04-01
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| Series: | BMC Surgery |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12893-017-0235-9 |
| _version_ | 1828446535859306496 |
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| author | Jimme K. Wiggers Rowan F. van Golen Joanne Verheij Annemiek M. Dekker Thomas M. van Gulik Michal Heger |
| author_facet | Jimme K. Wiggers Rowan F. van Golen Joanne Verheij Annemiek M. Dekker Thomas M. van Gulik Michal Heger |
| author_sort | Jimme K. Wiggers |
| collection | DOAJ |
| description | Abstract Background Extrahepatic 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. Methods Male 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. Results I/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. Conclusion Pre-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. |
| first_indexed | 2024-12-10T22:13:47Z |
| format | Article |
| id | doaj.art-54fec2f126354fea92f73fafb561d27d |
| institution | Directory Open Access Journal |
| issn | 1471-2482 |
| language | English |
| last_indexed | 2024-12-10T22:13:47Z |
| publishDate | 2017-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Surgery |
| spelling | doaj.art-54fec2f126354fea92f73fafb561d27d2022-12-22T01:31:31ZengBMCBMC Surgery1471-24822017-04-011711810.1186/s12893-017-0235-9Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat liversJimme K. Wiggers0Rowan F. van Golen1Joanne Verheij2Annemiek M. Dekker3Thomas M. van Gulik4Michal Heger5Department of Surgery, Surgical Laboratory, Academic Medical Center, University of AmsterdamDepartment of Surgery, Surgical Laboratory, Academic Medical Center, University of AmsterdamDepartment of Pathology, Academic Medical Center, University of AmsterdamDepartment of Surgery, Surgical Laboratory, Academic Medical Center, University of AmsterdamDepartment of Surgery, Surgical Laboratory, Academic Medical Center, University of AmsterdamDepartment of Surgery, Surgical Laboratory, Academic Medical Center, University of AmsterdamAbstract Background Extrahepatic 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. Methods Male 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. Results I/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. Conclusion Pre-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.http://link.springer.com/article/10.1186/s12893-017-0235-9AtorvastatinPrimary Biliary CirrhosisCholestasisBile Duct LigationIschemia Induction |
| spellingShingle | Jimme K. Wiggers Rowan F. van Golen Joanne Verheij Annemiek M. Dekker Thomas M. van Gulik Michal Heger Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers BMC Surgery Atorvastatin Primary Biliary Cirrhosis Cholestasis Bile Duct Ligation Ischemia Induction |
| title | Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers |
| title_full | Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers |
| title_fullStr | Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers |
| title_full_unstemmed | Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers |
| title_short | Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers |
| title_sort | atorvastatin does not protect against ischemia reperfusion damage in cholestatic rat livers |
| topic | Atorvastatin Primary Biliary Cirrhosis Cholestasis Bile Duct Ligation Ischemia Induction |
| url | http://link.springer.com/article/10.1186/s12893-017-0235-9 |
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