The majority of potential donor lungs are rejected for transplantation and thus many patients die while waiting for a suitable donor. Donor lungs are typically retrieved from individuals after brain death;however, there is renewed interest in utilizing non-heart- beating donor (NHBD) lungs retrieved after cardiac death. The major challenge for utilization of NHBD lungs is the difficulty in assessing function after a warm ischemic period which results in significant injury. Two novel approaches show promise to greatly expand the utilization of NHBD lungs: 1) use of a "lung box" for ex vivo lung perfusion (EVLP) to assess and rehabilitate lungs prior to transplantation, and 2) use of adenosine 2A receptor (A2AR) agonist to rehabilitate lungs and prevent ischemia-reperfusion (IR) injury. This proposal combines these two approaches to perfect a lung box-based method of EVLP to assess and therapeutically rehabilitate NHBD lungs for successful transplantation. We have demonstrated the rehabilitation and successful transplantation of NHBD porcine lungs after EVLP with an A2AR agonist, and we have demonstrated that an adenosine 2B receptor (A2BR) antagonist attenuates IR injury. Thus our proposed studies will test the hypothesis that NHBD lungs can be rehabilitated for successful transplantation by EVLP-mediated therapy using an A2AR agonist or A2BR antagonist. We will test this hypothesis with three aims.
Aim 1 will use a porcine lung transplant model to determine if EVLP with A2AR agonist can safely extend both warm and cold ischemic times of NHBD lungs.
Aim 2 will determine if EVLP with A2AR agonist therapy will rehabilitate marginal and previously rejected human donor lungs to an acceptable state for transplantation.
Aim 3 will determine if EVLP with A2BR antagonist will rehabilitate porcine and human NHBD lungs. Within each aim, we will also determine if the rehabilitation of NHBD lungs by EVLP entails the inhibition of NKT cell activation, epithelial cell activation and neutrophil infiltration. This project addresses two major problems that plague lung transplantation: far too few suitable lungs for transplant and primary graft failure after transplat due to IR injury. If NHBD lungs can be safely rehabilitated for transplantation, then the lung donor shortage could be eliminated. Thus this project will provide a means to greatly extend the donor lung pool size and support clinical trials aimed at saving many more lives of those patients on the lung transplant waiting list.
The majority of potential donor lungs are rejected for transplantation and thus many patients die while waiting for a suitable donor. The objective of this proposal is to develop methods to increase the availability of donor lungs by developing and perfecting a lung box technique for ex vivo lung perfusion (EVLP) and adenosine 2A receptor (A2AR) agonist therapy to assess and rehabilitate non-heart-beating donor (NHBD) lungs for successful transplantation. If successful, our studies will provide a means to greatly extend the donor lung pool size and support clinical trials aimed at saving many more lives of those patients on the lung transplant waiting list.
|Wagner, Cynthia E; Pope, Nicolas H; Charles, Eric J et al. (2016) ExÂ vivo lung perfusion with adenosine A2A receptor agonist allows prolonged cold preservation of lungs donated after cardiac death. J Thorac Cardiovasc Surg 151:538-46|
|Huerter, Mary E; Sharma, Ashish K; Zhao, Yunge et al. (2016) Attenuation of Pulmonary Ischemia-Reperfusion Injury by Adenosine A2B Receptor Antagonism. Ann Thorac Surg 102:385-93|
|Laubach, Victor E; Sharma, Ashish K (2016) Mechanisms of lung ischemia-reperfusion injury. Curr Opin Organ Transplant 21:246-52|
|Charles, Eric J; Huerter, Mary E; Wagner, Cynthia E et al. (2016) Donation After Circulatory Death Lungs Transplantable Up to Six Hours After ExÂ Vivo Lung Perfusion. Ann Thorac Surg 102:1845-1853|
|Sharma, Ashish K; LaPar, Damien J; Stone, Matthew L et al. (2016) NOX2 Activation of Natural Killer T Cells Is Blocked by the Adenosine A2A Receptor to Inhibit Lung Ischemia-Reperfusion Injury. Am J Respir Crit Care Med 193:988-99|
|Stone, Matthew L; Sharma, Ashish K; Mas, Valeria R et al. (2015) Ex Vivo Perfusion With Adenosine A2A Receptor Agonist Enhances Rehabilitation of Murine Donor Lungs After Circulatory Death. Transplantation 99:2494-503|