Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy

Ischemia/reperfusion injury is the phenomenon of interruption of blood supply followed by restoration of blood flow and the accompanying oxygen, nutrient supply and shear stress. Clinically, warm ischemia/reperfusion (WIR) injury is almost unavoidable in liver resection surgery, liver transplantation, and in blood transfusion for hemorrhagic shock, and may lead to delayed graft function and liver failure. Two different phases can be distinguished during reperfusion: an early phase (within 2 h after restoring reperfusion), which is characterized by the release of reactive oxygen species (ROS) and production of inflammatory mediators (TNFα, chemokines)1,2, and a late phase (6–48 h after reperfusion), in which inflammatory responses caused by neutrophil and macrophage infiltration exacerbate the liver damage3. As demonstrated recently by our group, the effects of ischemia reperfusion are already significant under cold ischemia when further deterioration of hepatic microcirculation and endothelial dysfunction is seen4. Kruppel-like factor 2 (KLF2) is a transcription factor predominantly expressed by the endothelial cell5 that induces expression of vasodilator, anti-thrombotic and anti-inflammatory genes (e.g. endothelial nitric oxide synthase (eNOS) and thrombomodulin)6,7 and inhibits the expression of adhesion molecules (vascular cell adhesion molecule 1 (VCAM-1) and E-selectin)6,8 maintaining a vasoprotective endothelial phenotype. Experimental studies using endothelial cells have demonstrated that KLF2 expression is induced by physiological blood flow-derived shear stress9,10. Statins are HMG-CoA inhibitors originally designed to lower cholesterol levels, however they have shown other therapeutic effects independent on lipid lowering11. Administration of simvastatin in experimental models of chronic and acute liver injury has demonstrated its effectiveness in protecting the liver sinusoidal endothelium12,13,4, nevertheless its potential applicability in situations of hepatic WIR is unknown. These beneficial effects of statins are due in part to the activation of KLF2 pathway that contributes in maintaining/restoring a healthy endothelial phenotype14,15. In the present study we have characterized for the first time the hepatic microcirculatory status and sinusoidal endothelial phenotype of livers undergoing warm ischemia and reperfusion injuries, and evaluated the applicability of simvastatin to improve or prevent warm ischemia/reperfusion injury.