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

• Published in: Cells (Basel, Switzerland) Switzerland), 2022-03, Vol.11 (7), p.1148
• Main Authors: La Mura, Vincenzo, Gagliano, Nicoletta, Arnaboldi, Francesca, Sartori, Patrizia, Procacci, Patrizia, Denti, Luca, Liguori, Eleonora, Bitto, Niccolò, Ristagno, Giuseppe, Latini, Roberto, Dondossola, Daniele, Salerno, Francesco, Tripodi, Armando, Colombo, Massimo, Peyvandi, Flora
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibodies; Anticoagulants; Biopsy; coagulation; Disease Models, Animal; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Endotoxemia; Endotoxemia - drug therapy; Eosinophilia; Fibrin; Fibrin - metabolism; Hemostatics - therapeutic use; Hepatocytes; Immunohistochemistry; Infections; Ischemia; Laboratory animals; Light; Lipopolysaccharides; Liver; Liver Diseases; Male; Microscopy; Mortality; Necrosis; Peripheral blood; Rats; Rats, Wistar; Sepsis; Sepsis - complications; Simvastatin; Simvastatin - therapeutic use; sinusoidal endothelial cells; thrombomodulin; Thrombosis - prevention & control; Von Willebrand factor
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11071148

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