Exploring the mechanism of Pim-1 upregulation of tissue factor to initiate hypercoagulable state in sepsis

Background During sepsis-induced coagulopathy (SIC), the balance of coagulation, anticoagulation, and fibrinolysis is disrupted, and endothelial dysfunction plays a key role in the disease progression. Current studies have indicated that the Proviral integration site for Moloney murine leukemia virus 1 (Pim-1) can promote thrombosis and activate an autoimmune response. This study aimed to assess the relevance of inhibiting Pim-1 as a potential therapeutic target for SIC. Methods Wild-type, Pim-1-KO, and TLR4-KO mice were categorized into the sham and cecal ligation and puncture (CLP) groups. Human umbilical vein endothelial cells were classified into the control, lipopolysaccharide (LPS) stimulation, and intervention groups. Enzyme-linked immunosorbent assay was used to detect plasma coagulation index in mice. Western blotting and immunofluorescence were employed to examine protein expression in tissues or cells. Additionally, immunohistochemistry and hematoxylin and eosin staining were conducted to detect liver/lung tissue damage. Tissue factor (TF) promoter activity was detected using a dual-luciferase reporter assay. Moreover, the correlation between variables was determined using Pearson correlation analysis. Results Pim-1 inhibition can decrease the coagulation response of sepsis mice and improve the survival rate. Pim-1 administration activated LPS-induced endothelial injury via mTOR/Sp1/TF signaling pathways, and Pim-1 acts in endothelial cells via the TLR4 pathway. Conclusions These findings indicated that Pim-1 promotes TF upregulation, leading to the initiation of a hypercoagulable state in sepsis. Therefore, inhibiting Pim-1 activity may be a therapeutic approach for SIC.