GRANULOPOIESIS REGULATION IN LUNG GRAFT ISCHEMIA-REPERFUSION INJURY

描述(由申请人提供)：与其他器官接受者相比，肺移植接受者的结果仍然明显更差。同种异体肺移植后72小时内的损伤，也称为原发移植物功能障碍，是肺移植术后早期死亡的主要原因，也是慢性肺排斥反应的危险因素。缺血再灌注损伤是移植物功能障碍的主要原因，但控制这种损伤的机制尚不清楚。为了解决这个问题，我们开发了一种原位带血管充气肺移植方法，模拟人类的原发移植物功能障碍。来自该模型的新数据显示，移植后不久，IL-10、肿瘤坏死因子-β-中性粒细胞亚群在移植组织中积聚，可能对移植肺缺血-再灌注损伤具有保护作用。我们观察到，肺移植后IL-10的主要细胞类型是IL-10的肿瘤坏死因子-中性粒细胞，它们的发育依赖于应激诱导或“紧急粒细胞生成”。在受体缺乏IL-10表达的情况下，移植肺损伤严重，提示IL-10在预防移植肺缺血再灌注损伤中具有重要作用。我们假设需要紧急粒系造血来产生IL-10中性粒细胞，以防止肺移植缺血再灌注损伤。我们有三个具体目标。我们的第一个目标是研究调节肺移植受者IL-10中性粒细胞产生的因素。我们的第二个目标是开发基于IL-10中性粒细胞的策略来预防或治疗肺移植缺血再灌注损伤。我们的第三个目标是评估有不同程度原发移植物功能障碍的人肺移植受者外周血中性粒细胞中IL-10和TNF-β的表达模式。

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.