Targeting brain death-induced injury

The global shortage of donor organs leaves over 117.00 people in the United States and almost 15.000 people in Europe on the organ waiting list. These numbers highlight the need to increase the number of transplantable organs. One strategy to enlarge the donor organ pool is to improve the quality of suboptimal donor organs. However, in order to achieve this, we first must expand our understanding of what harms these organs prior to transplantation. Most organs worldwide are obtained from brain-dead donors. Despite extensive efforts to treat the pathophysiological effects of donor brain death, these grafts remain suboptimal when compared to living donor grafts. The aim of this thesis was to expand on the current knowledge of brain death pathophysiology and to use this knowledge to target brain death-induced injury. In the first part of this thesis, we provided an update on the current status of deceased donor management in the clinical setting and investigated the effects of two different interventions targeting brain death-induced inflammation and hormonal perturbances. In attempt to broaden our understanding of brain death pathophysiology, we then investigated two novel aspects of donor brain death: metabolism and autophagy. Our results portrayed a distinct, organ-specific metabolic response as well as autophagy dysregulation during brain death. Altogether, this thesis expands on the currently available knowledge and identifies novel pathways that can be targeted to improve brain death- induced injury.