The role of pathologic plasmin activity in trauma-induced systemic inflammatory response syndrome

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Project Summary: Severe injury is a leading cause of death and disability worldwide, largely attributed to fatal complications that arise from the injury. While an isolated injury heals over time without notable consequence, a severe injury provokes systemic inflammatory response syndrome (SIRS) and coagulation dysfunction, which greatly increase the risk of life-threatening complications such as bleeding, multiple organ dysfunction syndrome, and thrombosis. The complex molecular changes that drive the development of these complications are obscure. Consequently, while medical advances (such as blood transfusions) have allowed trauma patients to survive their injuries, few therapeutics exist to effectively prevent fatal complications and promote recovery in these patients. Plasmin, the serine protease responsible for fibrin degradation (fibrinolysis), is critical for tissue repair later in convalescence following an injury, however, a severe injury pathologically alters the timing and magnitude of its activity. Severe injuries provoke early, excess plasmin activation, leading to inappropriate fibrin degradation (hyperfibrinolysis), bleeding, and increased risk of death. Recent studies on the use of antifibrinolytic drugs in trauma and surgical patients have demonstrated that early inhibition of this inappropriate plasmin activation not only reduces bleeding but also reduces inflammation and associated complications. While its canonical role of fibrinolysis makes it a critical regulator of coagulation, plasmin's physiologic roles extend to modulation of inflammatory signaling and cell migration. Therefore, we hypothesized that excess plasmin activity is a key molecular driver of trauma-induced SIRS, predisposing patients to acute and chronic inflammatory complications. The purpose of this proposal is to investigate mechanisms of excess plasmin activation and its role in SIRS following severe injury. A model of thermal injury will be used in which excess plasmin activation occurs without risk of bleeding. While plasmin is a key target in the reduction of bleeding in trauma patients, therapeutics currently used in the clinic to prevent bleeding and novel pharmacologic modulators of this system may also be used to reduce or prevent inflammation-associated complications, if dosed appropriately. Within the proposed studies, I will implement genetic and pharmacologic tools to manipulate plasmin activity in an animal model of thermal injury, which reliably provokes SIRS, in order to quantify the effect of plasmin activity on inflammation. In addition to serologic measures of cytokines, I will use NF- κB-luciferase reporter mice to track systemic changes in both acute and chronic inflammation at the organ and cellular level over time following the thermal injury. The goal of this work is to identify both therapeutic targets and predictive diagnostic tools that may be used to reduce inflammatory complications and improve outcomes in trauma patients.