In the field of organ transplantation, cyclosporin A (CsA) is a well-established immunosuppressant that has an outstanding track record since its initiation of use in the 1970s. Four decades later, CsA has continued to be an important drug option in the controlling immune system of selected pre- and posttransplant patients. Mechanistically, CsA confers the potent immunosuppression effect via inhibition of calcineurin in T cells.1 Despite decades of experience, this old drug may have new tricks that are underappreciated. That is, CsA may have another contribution in potentially improving clinical outcomes by impacting issue which is ischemia-reperfusion (I/R) injury.
In this issue of Transplantation, Gao et al2 successfully describe the significance of CsA as a potential graft preconditioning reagent by suggesting to us a role for of CsA in preventing I/R injury in transplant setting. The authors performed Langendorff normothermic reperfusion assessment on cardiac grafts after 6 hours of cold ischemia and found CsA protection on graft function when they administered CsA in preservation solution and at initial 15 minutes of reperfusion and rewarming time. However, CsA failed to protect the graft and promoted I/R damage when they prolonged CsA exposure for 45 minutes after reperfusion. Consistent data of tissue damage was shown as higher release of lactate dehydrogenase during reperfusion time with prolonged exposure to CsA. Also, mitochondrial integrity confirmed by intragraft cytostome c was stabilized by CsA administration during cold preservation and at initiating reperfusion, while it was disturbed by CsA prolonged exposure. Their molecular analysis of “Reperfusion Injury Salvage Kinase and Survivor activating factor enhancement” elements did not retrieve this phenomenon well, but only adenosine monophosphate kinase and endothelial nitric oxide synthase signaling responded in their experiments, suggesting potential mechanisms. These findings suggest the importance of timing and duration of CsA administration as well as the graft temperature during exposure to obtain the beneficial effects.
CsA is known as having an inhibitory act against mitochondrial permeability transition pore opening which has an important role in cellular death.3,4 The effect of CsA to minimize I/R injury has been confirmed in various organ systems including brain, liver, kidney, and heart. In heart studies, preclinical and clinical work has been conducted and confirmed the CsA protective effect on cardiac surgery–related I/R injury and minimizing infract size.4 On the basis of these findings, the authors attempted to clarify the administration timing of CsA into the cardiac transplant setting. The I/R process is biphasic, and this sequential event play priming and trigger roles, respectively, to create insult.5 Ischemia is a priming stage for causing reperfusion injury and makes mitochondria susceptible progressively with time through discharging their membrane potential, energy depletion, as well as intracellular calcium overload; thus, mitochondria are an important therapeutic target, and CsA can delay this priming. Subsequently, reperfusion triggers mitochondrial permeability transition pore opening and the pursuant injury pathway which CsA may not attenuate, but exacerbate as the authors observed.
Since organ transplantation has been established as the only option for patients with irreversible organ failure, multiple groups have been focused to develop novel strategies to minimize I/R injury in hopes of reducing allograft injury in early posttransplant period.6 The grafts must be kept in cooler box during transportation after they are flushed and packed with preservation solution at donor hospital, until reperfusion occurs in the recipient body. This preservation method is well supported clinically; however, it is still suboptimal for keeping graft quality, transportation time, and posttransplant outcomes.7 In such circumstances, the heart graft is one of the most susceptible transplantable organs against insult related to ischemia, hypoxia, and reperfusion due to its central nature of supporting oxygen delivery.7 I/R-associated acute graft damage could cause primary graft failure which remains major cause of morbidity and mortality. Complex mechanisms underlie the process of transplant-related I/R injury; however, this process typically generates excess reactive oxygen species that can activate inflammatory processes and subsequent cell death. Thus, various reagents which have antioxidant, anti-inflammatory, or antiapoptotic properties have been investigated as potential therapeutic molecules to protect against I/R injury.8,9 In this situation, inclusion of any therapeutic reagent which can disrupt I/R process will improve the organ preservation techniques allowing to prolonged graft ischemic time and better posttransplant outcomes.
We have options in how to best approach and potentially prevent I/R injury—donor intervention, preconditioning, and postconditioning.10 One such more modern approach could be with the use of an ex vivo machine perfusion system in which therapeutic molecules are mixed and circulated in the preservation solution. Ex vivo organ perfusion provides a theoretically ideal graft preservation for next generation and is a powerful tool for evaluation and conditioning of the grafts before transplant. However, the authors give us some caution about the application of CsA for normothermic ex vivo organ perfusion preservation on the basis of their findings. This study makes a strategic move for graft preconditioning with CsA to prevent I/R injury in cardiac transplantation and has important findings that should be translated into clinical practice.
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2. Gao L, Hicks M, Villanueva JE, et al. Cyclosporine A as a cardioprotective agent during donor heart retrieval, storage or transportation - benefits and limitations. Transplantation. 2019;103:1140–1151.
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