Simvastatin Prevents Liver Microthrombosis and Sepsis Induced Coagulopathy in a Rat Model of Endotoxemia

Abstract

Background: Endotoxemia causes endothelial dysfunction and microthrombosis, which are pathogenic mechanisms of coagulopathy and organ failure during sepsis. Simvastatin has potential anti-thrombotic effects on liver endothelial cells. We investigated the hemostatic changes induced by lipopolysaccharide (LPS) and explored the protective effects of simvastatin against liver vascular microthrombosis. Methods and results: We compared male Wistar rats exposed to LPS (5 mg/kg one i.p. dose) or saline in two experimental protocols—placebo (vehicle) and simvastatin (25 mg/kg die, orally, for 3 days before LPS). Morphological studies were performed by light- and electron-microscopy analyses to show intravascular fibrin deposition, vascular endothelial structure and liver damage. Peripheral- and organ-hemostatic profiles were analyzed using whole blood viscoelastometry by ROTEM, liver biopsy and western-blot/immunohistochemistry of thrombomodulin (TM), as well as immunohistochemistry of the von Willebrand factor (VWF). LPS-induced fibrin deposition and liver vascular microthrombosis were combined with a loss of sinusoidal endothelial TM expression and VWF-release. These changes were associated with parenchymal eosinophilia and necrosis. ROTEM analyses displayed hypo-coagulability in the peripheral blood that correlated with the degree of intrahepatic fibrin deposition (p < 0.05). Simvastatin prevented LPS-induced fibrin deposition by preserving TM expression in sinusoidal cells and completely reverted the peripheral hypo-coagulability caused by endotoxemia. These changes were associated with a significant reduction of liver cell necrosis without any effect on eosinophilia. Conclusions: Simvastatin preserves the antithrombotic properties of sinusoidal endothelial cells disrupted by LPS, deserving pharmacological properties to contrast sepsis-associated coagulopathy and hepatic failure elicited by endotoxemia

High plasma soluble thrombomodulin levels indicated poor prognosis of decompensated liver cirrhosis: a prospective cohort study

“…As Kume et al [27] reported that TM antigen and activity levels were significantly decreased in sinusoidal cells isolated from LPS-treated rats and recombinant TM protects against LPSinduced liver dysfunction, which indicates that decreased sinusoidal TM levels may result in liver dysfunction. And La Mura et al [28] also found that TM immunoreactivity was almost totally lost in endothelial cells 24 h after LPS injection, thus further confirming the involvement of the endothelium in the pathogenesis of liver damage induced by endotoxemia. Other researches also demonstrated that tumor necrosis factor [29] and other cytokines also aggravate vascular endothelial injury in liver cirrhosis, which can lead to the continuous increase of sTM level.…”

“…And La Mura et al . [ 28 ] also found that TM immunoreactivity was almost totally lost in endothelial cells 24 h after LPS injection, thus further confirming the involvement of the endothelium in the pathogenesis of liver damage induced by endotoxemia. Other researches also demonstrated that tumor necrosis factor [ 29 ] and other cytokines also aggravate vascular endothelial injury in liver cirrhosis, which can lead to the continuous increase of sTM level.…”

Effect of statins on sepsis and inflammatory factors: A Mendelian randomization study

“…Many animal experiments have also proved the beneficial effect of statins on animal sepsis. [31][32][33] Therefore, statins may have a protective effect on sepsis and this may provide a new idea for the treatment of sepsis.…”

The evolving role of liver sinusoidal endothelial cells in liver health and disease

“…In the setting of lipopolysaccharide-induced endotheliopathy in an animal model with increased microvascular thrombosis and vWF expression by liver ECs, statin treatment upregulates KLF2 and decreases thrombosis in the liver. [140] New research has built on this approach utilizing nanotechnology that enhances simvastatin delivery to LSECs to augment KLF2. [141] This field is developing, and given that the nanotechnology in this study relied on targeting the mannose receptor on LSECs with mannan-containing nanoparticles, which while demonstrating preferential LSEC uptake lack total specificity, [142] more specialized technology should be used for further precision therapy.…”

“…Recent studies demonstrated that statins ameliorate prothrombotic endotheliopathy in the liver as well. In the setting of lipopolysaccharide-induced endotheliopathy in an animal model with increased microvascular thrombosis and vWF expression by liver ECs, statin treatment upregulates KLF2 and decreases thrombosis in the liver 140 . New research has built on this approach utilizing nanotechnology that enhances simvastatin delivery to LSECs to augment KLF2 141 .…”