Inflammatory Signalling Associated with Brain Dead Organ Donation: From Brain Injury to Brain Stem Death and Posttransplant Ischaemia Reperfusion Injury
Brain death is associated with dramatic and serious pathophysiologic changes that adversely affect both the quantity and quality of organs available for transplant. To fully optimise the donor pool necessitates a more complete understanding of the underlying pathophysiology of organ dysfunction associated with transplantation. These injurious processes are initially triggered by catastrophic brain injury and are further enhanced during both brain death and graft transplantation. The activated inflammatory systems then contribute to graft dysfunction in the recipient. Inflammatory mediators drive this process in concert with the innate and adaptive immune systems. Activation of deleterious immunological pathways in organ grafts occurs, priming them for further inflammation after engraftment. Finally, posttransplantation ischaemia reperfusion injury leads to further generation of inflammatory mediators and consequent activation of the recipient’s immune system. Ongoing research has identified key mediators that contribute to the inflammatory milieu inherent in brain dead organ donation. This has seen the development of novel therapies that directly target the inflammatory cascade. 1. Introduction Organ transplantation is the gold standard treatment for patients with end stage solid organ failure. An ever increasing disparity between available organs and potential recipients is the cause of avoidable morbidity and mortality [1–4]. Ongoing efforts are being made to increase the quantity and quality of organs available for transplant. Although outcomes from non-heart-beating donors have become increasingly successful [5], the majority of organs are still donated from donors after brain death (BD). Significant brain injury of any aetiology will cause a systemic response [6], creating a proinflammatory environment prior to the occurrence of brain death itself. BD then also creates a variety of inflammatory, haemodynamic and endocrine effects, which induce adverse sequelae in distant organs [7–10]. Finally, ischaemia-reperfusion injury (IRI), inherent in transplantation, generates reactive oxygen species (ROS), activates complement, and independently drives cytokine release and inflammation [11, 12]. Every transplanted organ from a BD donor will face these stages of potential injury. Consequently, donor management must consider each step from donor to recipient in order to maximise recipient outcomes. The purpose of this paper is to explore the current understanding of the three main contributors to injury that an organ will travel through from donor to
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