Understanding and modulating primary graft dysfunction following lung transplantation

The success of lung transplantation (LTx) is hampered by cytotoxic and immunological effects of ischemia-reperfusion injury (IRI) on lung allografts causing primary graft dysfunction (PGD). During the window between organ procurement and LTx, ex-vivo lung perfusion (EVLP) offers the opportunity for lung graft modulation (LGM) that targets IRI and reduces PGD. We aim to assess the effect of biological and genetic LGM on PGD through analysis of lung graft injury and function in an experimental rat EVLP and transplant model and a human discarded lung graft EVLP model. Firstly, we will test biological LGM by enriching the EVLP perfusate with polyethylene glycol (PEG). Secondly, we will explore genetic LGM by means of CRISPR-technology, transfected by adeno-associated virus (AAV) during EVLP. After assessment in the rat model, we aim to test the effect of biological and genetic LGM in the human discarded lung graft EVLP model. The aforementioned models and LGM strategies will provide additional insight in the pathophysiology of PGD and the associated cytotoxic and immunological effects of IRI. Development of the EVLP and transplant experiments will be an important step to implement modulatory strategies in the clinical practice in order to tackle the challenge of PGD and improve outcome after LTx.