Abstract: Pulmonary dysfunction often occurs in patients with severe Traumatic Brain Injury (TBI). Acute lung injury (ALI) is seen in 20-25% of patients with TBI. Mechanisms of TBI-induced ALI are unclear but may be mediated by inflammasome activation. The role of Extracellular Vesicles (EV) in inflammasome signaling mechanisms has been investigated as a biomarker in TBI. The pathomechanisms of EV in inflammasome signaling after TBI- induced ALI has never been examined. The goal of this project is to study the role of EV in inflammasome signaling after TBI-induced ALI.
Specific aims : 1) to establish the effects of inflammasome activation after TBI on the pathology of ALI after injury; 2) to test the effects of genetic deletion of the inflammasome protein ASC on inflammasome signaling, histopathological and functional pulmonary outcomes after TBI. Methods and Techniques: I will use a Controlled Cortical Impact (CCI) model to induce TBI in wild-type mice and measure inflammasome activation. I will examine inflammatory lung cell infiltration and perform physiological pulmonary function studies to determine ALI outcome. My preliminary data uses an in-vitro model where I have delivered serum-derived EV from TBI patients to human lung cells and have found significant activation of inflammasome proteins. My preliminary data also presents an in-vivo experiment where I have injected serum-derived EV from injured mice into un-injured mice and measured inflammasome activation in lung tissue as well as evidence of ALI. In addition I will induce TBI in ASC-/- mice in order to confirm that inhibition of the inflammasome pathway reduces ALI after brain trauma. The overall goal of this study is to determine an inflammatory signaling mechanism that may reduce development of ALI and severe pulmonary dysfunction after TBI.
Patients who suffer from severe Traumatic Brain Injury (TBI) often develop pulmonary dysfunction and either die or have severe long-term neurological and/or respiratory problems. The goal of this project is to understand the inflammatory signaling mechanisms in TBI-induced pulmonary dysfunction. These findings have long-term medical benefits that will allow for the discovery of potential biomarker for early diagnosis and novel treatment options for multiple-organ failure after TBI.
