Inflammatory Signalling Associated with Brain Dead Organ Donation: From Brain Injury to Brain Stem Death and Posttransplant Ischaemia Reperfusion Injury

Abstract

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.

Pediatric and adult dilated cardiomyopathy represent distinct pathological entities

“…With respect to this study, we excluded donors with hepatitis C, HIV, and preexisting cardiac disease. Importantly, brain death itself has been demonstrated to increase inflammation within the heart (27,28). Thus, donor specimens obtained from brain-dead individuals are unlikely to represent normal cardiac tissue.…”

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“…Hemodynamic instability, the potential for ischemia/reperfusion injury, and concomitant organ failure may result from both the original cause of brain death and the series of events associated with the inflammatory state induced by brain injury. [1][2][3] Donor brain death is a significant risk factor in liver transplant outcomes because marginal liver utilization is associated with higher risk of primary nonfunction of the organ. 4,5 In deceased-donor organ transplant, clinicians attempt life-saving procedures by retrieving organs from deceased donors whose activated inflammatory systems can lead to graft dysfunction.…”

The implications of brain death in donor lung injury: investigation and blockade of the endothelin axis

“…Brain death then independently causes inflammatory, haemodynamic and endocrine effects that cause further injury. [20][21][22][23][24] Finally, ischaemia-reperfusion injury (IRI) generates reactive oxygen species (ROS), which are responsible for complement activation and cytokine release, further driving inflammation. [24][25][26] …”

“…[238,240] Impaired perfusion pressure leads to tissue ischaemia, local inflammation, necrosis and microthrombus formation. [24] Interventions are therefore necessary to support blood pressure and augment tissue perfusion. Central to this is recognition that prior management efforts (for example mannitol to manage intracranial hypertension) and development of diabetes insipidus may result in intravascular fluid depletion.…”

“…[318,319] These findings have lead to the conclusion that resident tissue inflammatory cells, including pulmonary macrophages, may be primed prior to transplantation, and that these cell populations may be the initiators of early lung injury after transplant. [24,318] The selection of a dual endothelin receptor antagonist was therefore based on the observations that alveolar macrophages express both endothelin receptors after brain death [88] and that they contribute significantly to post-transplant pulmonary injury. [318] Endothelin antagonists have been investigated in a wide variety of conditions, including pulmonary hypertension, [108] sepsis, [74] pain, [80] cancer, [84,111] meconium aspiration, [320] heart failure, [321,322] and cerebral vasospasm amongst others.…”