Mechanistic Elucidation and Targeted Therapy of Organ Injury and Inflammation following Trauma

Project Summary/Abstract: Multiple organ dysfunction syndrome (MODS) is a leading cause of death after severe trauma, which is a leading cause of mortality worldwide. MODS is thought to be a consequence of a vicious cascade of excessive inflammation and coagulation abnormalities but remains incompletely understood. Recent advances in the resuscitation of trauma patients (such as whole blood transfusion and the use of tranexamic acid) have led to improved initial survival, yet these critically ill patients now stay alive to be at risk to develop MODS and other immune/inflammatory complications. This makes understanding how MODS occurs a critical and an immediate need in trauma. MODS is thought to arise in the setting of excessive innate immune activation and is associated with the late phase of trauma-induced coagulopathy (TIC). TIC is characterized by endothelial injury, excessive thrombosis manifesting as both severe small vessel thrombosis, which contributes to organ dysfunction, as well as deadly large vessel thromboembolic events. There is a critical need to identify a mechanistic link between the excessive inflammatory and innate immune responses and the defects in coagulation in order to understand MODS. The overarching goal of our research is to understand how trauma leads to organ injury through inflammation and clotting of blood vessels, or immunothrombosis. Our research focus is the central role of platelet function in driving immunothrombosis after trauma. Our preliminary data demonstrate that platelets are critical to the innate immune response after injury. Platelets are sentinel cells in immune function and serve a critical regulatory function by interacting with other inflammatory cells, and in this way are a major link between inflammation and thrombosis. Furthermore, trauma-induced `dysfunctional' platelets are key components to both drive TIC and to amplify inflammation and organ injury. Thus, we hypothesize that dysfunctional platelets and their interactions with other immune cells are critical regulators of MODS. There is an imminent need to develop research focusing on the prevention and management of organ injury and complications of inflammation/thrombosis, and this represents the key theme of the present proposal and research program. Furthermore, modern trauma resuscitation is rapidly changing to include new techniques which saves lives after injury. We must understand exactly how these interventions work to design the next great advance in resuscitation and also how they impact the risk of MODS. Essential to this is the need to develop targeted therapeutic strategies to treat the overwhelming morbidity after trauma. We propose to tackle the following key knowledge gaps in the field: 1) Understand the cellular mechanisms leading to micro-thrombotic organ injury in survivors after trauma 2) Unravel the immune and inflammatory consequences of modern trauma resuscitation 3) Design targeted interventions for post-traumatic organ injury and thrombosis