Pig lung transplant
Protection from Post-Transplant Lung Injury by Adenosine A2A Receptor Activation
During ischemia-reperfusion (IR) injury, adenosine can serve both pro- or anti-inflammatory functions, mediating its effects through four adenosine receptors (ARs): A1AR, A2AR, A2BR and A3R. Distinguishing pro- and anti-inflammatory functions of adenosine thus requires an understanding of the actions of each AR in lung IR injury. We have shown that A2AR activation attenuates IR injury. The objective of this project is to expand on our experience with A2AR to further test A2AR activation in a clinically relevant porcine lung transplant model. The overall hypothesis is that A2AR activation in the donor lung or in combination with other AR agonists will provide superior protection from IR injury. Aim 1 tests if specific, pharmacologic activation of A2AR in the donor lung prior to harvest will provide better protection against post-transplant lung IR injury. This aim will utilize a porcine lung transplant model which is most relevant to the clinical transplant setting. Aim 2 tests if A2AR agonist in combination with other AR agonists will provide enhanced protection from lung IR injury. The mouse model of lung IR injury will be used here, and if positive results are obtained, then the porcine lung transplant model will be employed for further testing. This project will provide critical data to support the initiation of clinical trials using pharmacologic A2AR agonists for the prevention of post-transplant IR injury. Beyond lung transplantation, A2AR agonists could also be valuable for the prevention of IR injury in other solid organs.