Mechanisms underlying immune dysfunction after severe injury

Traumatic injuries are the leading cause of death for people under the age of 45 and can lead to long-term disability in patients. Severe trauma causes multi-modal immune dysfunction that can lead to sepsis, organ failure, and even death. There are few therapeutic options that exist to improve immune function after injury and clinical trials that target individual mediators have been unsuccessful. While there are numerous types of traumatic injuries (traumatic brain injury, blunt or penetrating trauma, etc.), severe burn injuries and burn-related polytraumas will be the main focus of this dissertation. Burn injuries are a classic example of how a traumatic injury can lead to systemic effects throughout the body. These injuries cause systemic immune dysfunction that contribute to impaired wound healing, susceptibility to infection, and multi-organ failure. The topics covered here shed light on the many different mechanisms that contribute to immune dysregulation following burn injury and explores a variety of different treatments that improve immune and cytokine signaling. The first part of this dissertation discusses the role of brain-derived microvesicles in promoting peripheral immune responses following burn injury. The second portion evaluates the effectiveness of activating the master transcription factor, Nuclear Factor erythroid 2-related factor 2, after combined burn and inhalation injury. Lastly, the final studies explored here describe the potential use of extracellular vesicles as biomarkers and therapeutic agents in the setting of radiation exposure and radiation combined burn injury. By gaining a better understanding of the immune dysregulation that develops following burn injury, we can hopefully develop new multi-modal therapies that improve clinical outcomes in patients.