Possible contribution of the STAT3 signaling pathway to disseminated intravascular coagulation (DIC) in mice with cecal ligation and puncture-induced sepsis.

Abstract

Disseminated intravascular coagulation (DIC) is a serious disorder characterized by the systemic activation of blood coagulation and is a frequent complication in sepsis. Once septic patients develop DIC, it leads to a poor outcome. Appropriate DIC prevention strategies will be helpful for the management of sepsis. In this study, we attempted to identify coagulation disorder in mice with cecal ligation and puncture (CLP)-induced sepsis, a clinically relevant animal model of sepsis, and to provide pharmacological approaches for preventing the occurrence of DIC in sepsis. In CLP-induced septic mice, the blood platelet count was significantly declined, prothrombin time was significantly prolonged, the coagulation blood markers D-dimer and thrombin-antithrombin complex were significantly elevated, microvascular fibrin deposition and thrombus formation were detected in liver and kidney tissues, and thrombin levels in liver tissues were prominently up-regulated in comparison with sham-operated controls, implying that coagulation was developed in this animal model of sepsis. These changes were almost entirely abrogated when the signal transducers and activators of transcription 3 (STAT3) pathway was inhibited by transfection of STAT3 decoy oligodeoxynucleotides (ODNs) or pharmacological intervention with stattic. CLP-induced septic mice exhibited significant increases in tissue expression of plasminogen activator inhibitor (PAI-1) and tissue factor (TF), both of which play a crucial role in thrombogenesis. STAT3 ODN transfection strikingly suppressed overproduction of PAI-1 and TF after CLP. Nuclear factor-κB inhibition also reduced the PAI-1 and TF up-regulation but was without effect on prolonged prothrombin time in CLP mice. Our results suggest that inhibition of the STAT3 signaling pathway provides a potential benefit for preventing the development of DIC in sepsis.