Original ArticleBiomedicalHepatic Ischemia/Reperfusion Injury Is Diminished by Atorvastatin in Wistar Rats
Introduction
Hepatic ischemia/reperfusion (I/R) occurs in clinical settings such as shock, trauma and when Pringle's maneuver (occlusion of the hepatoduodenal ligament) is performed in order to reduce blood loss during liver surgery (1). Liver transplantation procedures also involve a variable period of ischemia, which causes organ damage during preservation and reperfusion and may diminish graft quality, a factor that can reduce transplant effectiveness (2). I/R injury is mediated by the activation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), induction of hepatocyte apoptosis, release of free radicals and the influx of inflammatory cells, among other factors 3, 4, 5. Activation of the coagulation cascade, alterations in endothelium-derived molecular vasoactive products such as endothelins (ET) and nitric oxide, as well as upregulation of endothelial adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1) have also been recently described as important mediators of hepatic I/R injury 6, 7, 8. These microvascular and endothelial alterations are possible targets for therapeutic intervention (9).
Atorvastatin (ATOR) is a member of the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor family, a group of drugs considered to be the most effective therapeutic option to clinically reduce cholesterol levels and treat dyslipidemias (10). Recently, statins have been found to possess various antiinflammatory and immunoregulatory effects, independent of their lipid-lowering actions (11). Due to the pleiotropic effects of statins, they have been proposed as ideal candidates for use as protective agents during conditions of I/R (12). Statins have also shown beneficial effects over altered endothelial function in clinical settings of coronary disease (13). Statins have been used to protect other organs against I/R injury in experimental settings. A recent study showed that ATOR could protect the kidney against I/R injury in the rat (14). Similar studies have reported the protective effects of statins in models of I/R injury in brain, skeletal muscle, lungs and intestine 15, 16, 17, 18.
In this study we evaluated the protective effects of ATOR over hepatic I/R injury, using a rodent experimental model. We measured circulating serum levels of TNF-α, ET-1, antithrombin-III (ATIII) and ICAM-1 in order to establish some of the mechanisms involved.
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Procedures and Models
Animal procedures were performed in accordance with the proper use and care of laboratory animals. Experiments were performed using 6-month-old male Wistar rats weighing 200–250 g. Animals were maintained under standard conditions such as stable room temperature, 12-h light:12-h dark cycle, and access to commercial rat pellets and water ad libitum.
The Pringle maneuver was performed as follows. After anesthesia with sodium pentobarbital (40 mg/kg, Anestesal, Pfizer Inc., México) and skin
Animal Survival Rates
All five animals survived in group A. In group B, 5/8 (62.5 %) animals survived the procedure, and in group C, 5/11 (45.45%) survived the entire reperfusion period. In group D, 5/7 (71.42%) animals survived the procedure, and in group E, 5/8 (62.5%) survived the entire reperfusion period. The majority of deaths had respiratory distress as a common feature.
Serum ALT and AST
Sham group (A) had AST and ALT levels of 271 ± 96.6 U/L and 118 ± 49.3 U/L respectively. After I/R, levels of both AST and ALT (Figure 1)
Discussion
In this study we showed that ATOR at a dose of 10 mg/kg reduced hepatic I/R injury as evidenced by reductions in AST and ALT levels as well as by attenuated histopathological alterations. Mortality rates were also reduced in ATOR-treated animals. This dose was chosen based on previous studies that showed that ATOR could protect the kidneys and intestine against I/R injury in the rat 14, 18. ATOR could also prevent the depletion of ATIII and the elevations of both TNF-α and ICAM-1 that follow
Acknowledgments
We would like to thank MVZ Jose Luis Vazquez Juarez, Department of Physiology, UANL, for providing animals and ensuring their care. We declare no conflict of interest.
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