Lung disease is the third leading cause of death in the United States. Lung transplant could improve quality of life and enhance survival in many lung disease patients. However, lung transplantation is severely limited by an inadequate number of suitable lungs for transplant from conventional organ donors - individuals who sustain a lethal brain injury, but who are incubated and ventilated before brain death occurs. Because most lungs from conventional organ donors are not suitable for transplant, only 1,700 lung transplants are performed annually in the U.S. However, lung tissue remains viable after circulatory arrest. In animal models, the PI of this project showed that lungs can function well after transplant, even if retrieved hours after death. Each year, more than 750,000 people in the U.S. are victims of sudden death; if lungs could be retrieved for transplant from some of these people - non-heart-beating donors (NHBDs) - the lung donor shortage could be eliminated. The PI has performed ex-vivo lung perfusion (EVLP) to determine suitability of human lungs initially turned down for transplant from conventional organ donors. Safety of transplanting these lungs after EVLP has recently been demonstrated. This proposed Phase 2 clinical trial will demonstrate safety and efficacy of transplant of lungs retrieved from NHBDs after death, assessed by EVLP, We will accomplish this Specific Aim: To demonstrate non-inferiority of lung transplant using lungs retrieved from NHBDs assessed by EVLP compared to lung transplant from conventional brain dead organ donors. We will obtain lungs from Maastricht Category 1 and 2 NHBDs in a large-population North Carolina county (Wake) and from targeted emergency rooms. We will apply established methods of EVLP and ex-vivo CT scan to evaluate suitability for transplant. Acceptable lungs will be transplanted at UNC and Duke under IRB-approved protocols. Outcomes will be compared to patients contemporaneously transplanted with lungs from conventional organ donors. Because lungs from NHBDs have not been injured by a prolonged interval of brain death, lungs retrieved from NHBDs may not only be much more plentiful; they may be superior to lungs currently being transplanted from conventional brain-dead donors. Timely retrieval of lungs from NHBDs requires coordination of EMS, law enforcement, medical examiners, and OPO personnel. Through the Office of the N.C. Secretary of Health and Human Services, we commenced a dialogue with leadership of state agencies to facilitate timely lung retrieval from NHBDs. We will use experts at Lung Banks of America, a not-for-profit corporation, to analyze time flow metrics from declaration of death to lung retrieval. With N.C. state government agencies, we will develop practices and policies to improve the yield of successful lung retrieval from NHBDs that can be implemented in N.C. and across the U.S. An ancillary project will determine metabolomic biomarkers for suitability of NHBD lungs for EVLP assessment, and biomarkers associated with poor function after lung transplant. Successful study completion will revolutionize lung transplant and the care of patients with end-stage lung disease.