LGK974 suppresses the formation of deep vein thrombosis in mice with sepsis

Sepsis is a disorder characterized by host inflammation and is caused by systemic infection. The inflammatory cytokine storm results in platelet overactivation, leading to coagulation dysfunction and thrombosis, but the underlying mechanism remains poorly understood. Recent evidence has shown that the Wnt/β-catenin signaling pathway is related to sepsis, but its role and mechanism in sepsis complicated with deep vein thrombosis (DVT) are unclear. In this study, a cecal ligation and puncture (CLP)-induced sepsis model and DVT mouse model were constructed by inferior vena cava ligation. The levels of serum inflammatory factors and adhesion molecules were measured in each group, and the thrombus weight and size, hematoxylin-eosin staining, collagen fiber tissue, and transcriptome of the venous wall were analyzed. The activation of the Wnt/β-catenin signal was evaluated by quantitative real-time polymerase chain reaction, Western blotting, ELISA, and immunohistochemical and immunofluorescence methods. Sepsis significantly promoted the formation of venous wall collagen fibers and DVT. In addition, Porcn significantly upregulated and activated the Wnt/β-catenin signaling pathway in sepsis mouse models with DVT. In contrast, the Wnt signaling inhibitor LGK974 was found to improve the survival rate, decrease thrombosis, and inhibit the expression of inflammation and adhesion molecules in sepsis mice with DVT. Therefore, activation of the Wnt/β-catenin signal may promote the formation of DVT in sepsis mice. LGK974 protects against DVT formation in sepsis mice by inhibiting the activation of the Wnt/β-catenin signal and down-regulating the production of proinflammatory cytokines, PAI-1, and adhesion molecules. LGK974 may be a new candidate for the treatment of sepsis complicated with DVT.