Lung disease is the fourth leading cause of death in the U.S. Lung transplant (LTX) could improve quality of life and enhance survival in many lung disease patients, but is severely constrained by an inadequate number of suitable lungs for transplant. Currently, lungs for transplant are retrieved from conventional organ donors - individuals who sustain a lethal brain injury, but who are intubated and ventilated before brain death occurs. Because most lungs from conventional organ donor are not suitable for transplant, only 1,400 LTX procedures are performed annually in the U.S. This Stage 1 Grand Opportunities project will test the hypothesis that the number of lung donors can be dramatically expanded to allow performance of substantially more LTX procedures. Increasing the number of lung donors is possible because the lung is unique among solid organs that are transplanted. Specifically, lungs remain viable for substantial periods of time after circulatory arrest because lung tissue does not rely on blood flow for cellular respiration. The PI has demonstrated in animal models that lungs can function well after transplant, even if retrieved hours after death. If lungs could be retrieved for LTX from some of the 3 million annual U.S. victims of sudden death - non-heart-beating donors (NHBDs) - then the lung donor shortage could be eliminated. To make NHBD lungs a viable option requires a reliable way to ensure safety of transplanting lungs retrieved after death. The aims of this proposal are: 1). to perfect a technique of lung perfusion and ventilation outside the body (ex-vivo) to reliably assess lung function and suitability for transplant;2). to perform a pilot/feasibility clinical study to demonstrate safety of transplanting human lungs after ex-vivo perfusion;3). to plan a multi-center prospective clinical trial to compare effectiveness of LTX from conventional brain-dead organ donors with LTX using lungs retrieved from NHBDs after death assessed in an ex-vivo perfusion circuit as a Stage 2 clinical trial;and 4). to develop an educational tool to enhance involvement of Emergency Medical Services (EMS) personnel to identify appropriate NHBDs for lung donation and facilitate lung donation from NHBDs. This ex-vivo perfusion approach will allow assessment of suitability for LTX of lungs retrieved from NHBDs, and importantly will also provide an opportunity to treat lungs before transplant to reduce ischemia-reperfusion injury. Thus, this new donor source and ex-vivo perfusion will not only provide many more lungs for transplant, but lungs that are better (less graft dysfunction and improved survival) than lungs currently being transplanted. This project addresses two major problems that plague LTX as a therapy for patients with end-stage lung disease - far too few suitable lungs for transplant, and graft failure after LTX. This project would revolutionize LTX and the treatment of end-stage lung disease. PUBLIC HEALTH RELEVANCE: This 2-year Stage 1 project will perfect a technique to perfuse and ventilate human lungs outside the body (ex- vivo) to determine if they are suitable for transplant, and will demonstrate safety of transplanting human lungs after ex-vivo perfusion in a pilot clinical study. This project will also plan a large multi-center clinical trial to use this ex-vivo lung perfusion/ventilation system to evaluate human lungs retrieved after death from non-heart- beating donors. This would provide much larger numbers of human lungs for transplant that may function better and last longer than lungs currently being transplanted from conventional brain-dead organ donors.