GRANULOPOIESIS REGULATION IN LUNG GRAFT ISCHEMIA-REPERFUSION INJURY

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DESCRIPTION (provided by applicant): Outcomes for lung transplant recipients remain significantly worse when compared to other organ recipients. Lung allograft injury in the first 72 hours post-transplant, also termed Primary Graft Dysfunction, is the leading cause for early mortality following lung transplantation and has also been shown to be a risk factor for chronic lung rejection. Ischemia-reperfusion injury is the leading cause of Primary Graft Dysfunction but the mechanisms that control this type of injury remain unclear. To address this problem we developed an orthotopic vascularized aerated lung transplant method that models Primary Graft Dysfunction in humans. New data from this model shows that a subset of IL-10+ TNF-¿- neutrophils accumulate in graft tissue shortly after transplantation and may protect against lung graft ischemia-reperfusion injury. We observed that IL-10+ TNF-¿ - neutrophils are the predominant IL-10+ cell type following lung transplantation and that their development is dependent on stress-induced or 'emergency granulopiesis'. In the absence of IL-10 expression in the recipient lung graft injury was severe indicating IL-10 is important to prevent lung graft ischemia reperfusion injury. We hypothesize that emergency granulopoiesis is required to generate IL-10+ neutrophils to prevent lung graft ischemia reperfusion injury. We have three specific aims. Our first aim is to examine factors that regulate the production of IL-10+ neutrophils in lung recipients. Our second aim is to develop IL-10+ neutrophil-based strategies to prevent or treat lung graft ischemia reperfusion injury. Our third aim is to assess patterns of IL-10 and TNF-¿ expression in the peripheral blood neutrophils of human lung recipients with varying degrees of primary graft dysfunction.