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

Abstract

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.

Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte‐Mediated Paracrine Mechanism

“…Blood pressures and flows were registered on a multichannel computer‐based recorder (Power Lab; ADInstruments, Sydney, Australia). Body temperature of the animals was maintained at 37 ± 0.5°C, and hemodynamic data were collected after 20 minutes of stabilization . Blood serum and plasma samples were stored for biochemical analysis.…”

Sinusoidal communication in liver fibrosis and regeneration

“…Other NO donors have undesired systemic effects that prevent their use at the bedside [64–67], but simvastatin, an already established medication, appears to be a good anti-fibrotic candidate due to simultaneous effects on different hepatic cells (Figure 2). This potentially occurs through the ability of simvastatin to activate the appropriate molecules, such as KLF2, needed for cell communication [68, 69]. …”

Hepatic Stellate Cells Play a Functional Role in Exacerbating Ischemia-Reperfusion Injury in Rat Liver

“…Among the hepatic nonparenchymal cells, the HSC is thought to be the mechanically functioning cell that regulates sinusoidal diameters [22, 23], although its relationship with some special molecules acting in the inflammatory cytokine network is yet to be investigated. On the other hand, derangement of hepatic microcirculation during I/R injury of the liver is well known [24-27]. A significantly decreased perfusion of the hepatic sinusoids has been confirmed by direct observation under intravital microscope [24, 25].…”