Cytosporone B ameliorates hypercoagulability in sepsis by agonizing the Nur77-thrombomodulin pathway

Sepsis-induced coagulopathy (SIC) is often a sign of high mortality and poor prognosis in patients with sepsis. Thrombomodulin (TM) plays an important anticoagulant role by activating protein (AP)C.

Our previous study has shown that the overexpression of Nur77 upregulates TM expression in human umbilical vein endothelial cells (HUVECs). This study aimed to investigate whether upregulation of Nur77 using cytosporone (Csn)-B could ameliorate SIC.

A mouse model of SIC was prepared by cecum ligation and puncture (CLP) operation. Five hours after CLP, coagulation-related indicators and histopathologic injury of the liver, lungs, and kidneys were investigated. The effect of Csn-B on the clotting time of HUVECs transfected with Nur77 or TM small-interfering RNA in response to tumor necrosis factor α stimulation was observed. The effects of Csn-B on survival, organ damage, microthrombosis, coagulation factors, TM activated protein C anticoagulant system, fibrinolytic system, and complement system were observed in vascular endothelial conditional knockout Nur77 mice after CLP.

Sepsis-induced upregulation of Nur77 in vascular endothelial cells. Knockout of Nur77 in vascular endothelium exacerbated organ damage and early coagulation dysfunction in sepsis. Csn-B attenuated the procoagulant response of HUVEC to tumor necrosis factor α stimulation, which is dependent on the activation of Nur77-TM pathway. Furthermore, Csn-B relied on activation of vascular endothelial Nur77 to inhibit the increase of coagulation factors, enhance activation of TM activated protein C, restore fibrinolysis homeostasis, and inhibit C3 and C5 activation to ameliorate hypercoagulability in SIC.

Csn-B improves early coagulopathy in sepsis by increasing endogenous TM through upregulating Nur77 in the vascular endothelium.