Journal Article

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

Hide, Diana, Bosch, Jaime, Garcia-Pagan, Juan-Carlos, Gracia-Sancho, Jordi, Peralta, Carmen, Ortega-Ribera, Martí

2016

Overview

Warm ischemia and reperfusion (WIR) causes hepatic damage and may lead to liver failure, however the mechanisms involved are largely unknown. Here we have characterized the microcirculatory status and endothelial phenotype of livers undergoing WIR and evaluated the use of simvastatin in WIR injury prevention. Male Wistar rats received simvastatin, or vehicle, 30 min before undergoing 60 min of partial warm ischemia (70%) followed by 2 h or 24 h of reperfusion. Hepatic and systemic hemodynamics, liver injury (AST, ALT, LDH), endothelial function (vasodilatation in response to acetylcholine), KLF2 and nitric oxide pathways, oxidative stress, inflammation (neutrophil and macrophage infiltration) and cell death were evaluated. Profound microcirculatory dysfunction occurred rapidly following WIR. This was evidenced by down-regulation of the KLF2 vasoprotective pathway, impaired vasodilatory capability and endothelial activation, altogether leading to increased hepatic vascular resistance and liver inflammation, with significant leukocyte infiltration, oxidative stress and cell death. Simvastatin preserved the hepatic endothelial phenotype and blunted the detrimental effects of WIR on liver hemodynamics and organ integrity. In conclusion, WIR-induced injury to liver sinusoidal endothelial cells is mitigated by pre-treatment with Simvastatin probably through a KLF2-dependent mechanism.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/77 / 692/4020/4021/288 / 692/4020/4021/288/2740 / 82/80 / Acetylcholine / Agents antilipèmics / Animals / Antilipemic agents / Apoptosis / Cell death / Cells, Cultured / Drug Evaluation, Preclinical / Endothelial cells / Fetge / Genotype & phenotype / Hemodynamics / Hepatocytes / Hepatocytes - drug effects / Hepatocytes - metabolism / Humanities and Social Sciences / Infiltration / Ischemia / Isquèmia / Krueppel-like factor / Kruppel-Like Transcription Factors - metabolism / Kupffer Cells - drug effects / Kupffer Cells - metabolism / Liver / Liver - blood supply / Liver - drug effects / Liver - immunology / Liver - pathology / Liver diseases / Macrophages / Male / Microcirculació / Microcirculation / multidisciplinary / Neutrophil Infiltration / Nitric oxide / Nitric Oxide - metabolism / Nitric Oxide Synthase Type III - metabolism / Oxidative stress / Rats, Wistar / Reperfusion / Reperfusion (Physiology) / Reperfusion Injury - prevention & control / Reperfusió (Fisiologia) / Rodents / Science / Simvastatin / Simvastatin - pharmacology / Simvastatin - therapeutic use / Vasodilation / Warm Ischemia - adverse effects