Abstract
Approximately 20-25 percent of Traumatic Brain Injury (TBI) subjects develop Acute Lung Injury (ALI), but the pathomechanisms of TBI-induced ALI remain poorly defined. In my thesis, I investigated whether (Extracellular Vesicle) EV-mediated inflammasome signalling contributed to the etiology of TBI-induced ALI. C57/BL6 male mice were subjected to Controlled Cortical Impact, and the brains and lungs were examined for inflammasome activation and ALI at 4 hours and 24 hours after TBI. I show that TBI releases EV containing inflammasome proteins into serum that target the lung to cause ALI. Administration of a Low Molecular Weight Heparin (Enoxaparin, a blocker of EV uptake) or treatment with a monoclonal antibody against apoptosis speck-like staining protein containing a caspase recruitment domain (anti-ASC) after adoptive transfer of EV isolated from TBI-injured mice significantly inhibited inflammasome activation in the lungs of recipient mice resulting in improved ALI scores. In addition, treatment with Enoxaparin reduced inflammasome activation and lung injury in TBI-injured mice and anti-ASC reduced inflammasome activation after TBI in the brain of injured mice. Furthermore, serum-derived EVs from severe TBI patients were isolated and analyzed for particle size, concentration, origin, and levels of ASC. Severe TBI patients with lung injury had a significantly higher level of ASC in serum and serum-derived EVs compared to individuals without lung injury. EVs were co-cultured with lung human microvascular endothelial cells (HMVEC-L) and induced inflammasome activation and endothelial cell pyroptosis. My results demonstrate that serum-derived EVs and inflammasome proteins play a critical role in the pathogenesis of TBI-induced lung injury, and provide evidence for activation of an EV-mediated Neural-Respiratory Inflammasome Axis in TBI-induced lung injury.