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Project

Dynamic preservation and reconditioning to improve organ quality in lung transplantation: from basic science to clinical implementation

Lung transplantation (LTx) is the only treatment option for well-selected patients with end-stage pulmonary disease. However, the number of available donor organs is still inadequate leading to a reported mortality of 15-30% on the waiting list. Moreover, the success of LTx is not solely dependent on the number of available organs, but also on their quality, which has a significant impact on early and late outcome after LTx. During the last decade, the profile of the lung donor is dramatically changing (from Donation after Brain Death (DBD) to Donation after Cardiac Death (DCD) and more use of organs from extended-criteria donors (ECD)) which might also impact outcome after LTx. As the selection process for donor organs is crucial, extending donor criteria have forced the community to implement novel ways to assess, preserve and optimize these grafts. A promising strategy is to make use of Ex Vivo Lung Perfusion (EVLP). EVLP is a form of isolated lung perfusion in normothermic conditions where a perfusion machine recirculates a preservation solution through the pulmonary vasculature while the lungs are mechanically ventilated and metabolically active. Our research group has been pioneering EVLP since its first description in 2001. EVLP offers the opportunity to evaluate and preserve lung grafts in a dynamic manner and can serve as a platform for active reconditioning and treatment of potential donor organs. Currently, EVLP has been introduced in clinical practice, but its wider use and implementation is rather limited. Up to date, this approach is still experimental, limited by the uncertainty regarding the translation and validation of EVLP physiology to the in vivo setting, and the impact of EVLP on graft quality is incompletely understood. However, if this technology could be further refined and if specific therapies could be applied to improve graft quality and transform initially rejected lungs into acceptable lungs, EVLP might change the landscape of clinical lung transplantation.

The objective of this research project is to improve the number of transplantable donor organs by using EVLP as a central platform to assess lung grafts and to prevent or repair organ damage at the early stages in the transplantation process.

In the first part, we will improve our insights in the current donor lung profile and identify those lungs that might benefit from EVLP. Therefore, we will investigate the interaction between blood biomarkers and graft performance in order to identify blood markers reflecting organ quality. We will also perform a prospective national donor registry analysis to define potential indications for EVLP in Belgium.

In the second part, we aim for an improvement of EVLP technology to prevent graft injury. In a large animal (pigs) research model we will investigate the impact of rotation of the graft during EVLP to modify distribution of graft perfusion. Next, we will use the same animal model to investigate the role of temperature and composition of the perfusate during EVLP. Therefore, metabolic profiling will be performed in close collaboration with the metabolomics lab.

In the third part, we will address the potential of ferroptosis inhibitors to reduce ischemia-reperfusion injury as an active treatment strategy. In a large animal DCD model (pigs), lungs will be exposed to 90 minutes of warm ischemia and subsequently being exposed to 5 hours of EVLP. The compound (a 3rd generation ferrostatin analogue) will be administered during reperfusion of the lung graft. Results will be compared with a control group without ferroptosis inhibition. Specific panels for ferroptosis will be investigated on parenchymal and perfusate samples.

In a final part, and based on the findings of the previous parts, we will be able to formulate an innovative EVLP protocol that will be validated in declined human donor lungs. This will be designed as a pilot experiment.

The ultimate goal of this research project is to better understand the mechanism behind EVLP reconditioning and to widely implement this technology in clinical practice.

Date:18 Jan 2022 →  Today
Keywords:lung transplantation, organ donor, ex vivo lung perfusion, EVLP, anesthesia, respiratory physiology, ferroptosis, donor lung injury
Disciplines:Cell death, Respiratory medicine not elsewhere classified, Transplantation surgery, Organ physiology
Project type:PhD project