The Role of Ischemia Reperfusion Injury in Lung Allograft Rejection

项目摘要 肺移植后的生存率继续大大落后于那些观察到的， 其他实体器官移植。肺移植成功的主要障碍是原发性 移植物功能障碍，一种由缺血再灌注损伤介导的急性肺损伤形式。 原发性移植物功能障碍不仅导致早期发病率和死亡率的增加， 易患慢性肺移植功能障碍我们开发了新的临床相关的 小鼠肺移植模型和新的活体成像方法来检查 原发性移植物功能障碍和排斥反应之间的机械联系。在我们的上一个融资期， 我们已经发现单核细胞在介导原发性移植物功能障碍中起中心作用， 调节中性粒细胞进入再灌注肺移植物。此外，我们还描述了 从损伤的肺释放的内源性配体的嗜酸性摄取的机制 传播原发性移植物功能障碍。在本申请中，我们提出检查 导致肺移植物中单核细胞和嗜中性粒细胞的活化， 这些细胞如何促进同种免疫和移植排斥。在目标1中，我们将定义机制 在移植物浸润时激活中性粒细胞。在目标2中，我们将分析介导 肺移植物中单核细胞的活化和分化。在目标3中，我们将研究相互作用 单核细胞和T细胞之间的相互作用会引发移植排斥

PROJECT SUMMARY Survival rates after lung transplantation continue to lag substantially behind those observed after transplantation of other solid organs. A major barrier to success of lung transplantation is primary graft dysfunction, a form of acute lung injury that is mediated by ischemia reperfusion injury. Primary graft dysfunction not only results in an increase in early morbidity and mortality, but it also predisposes to chronic lung allograft dysfunction. We have developed new clinically relevant mouse models of lung transplantation and novel intravital imaging approaches to examine mechanistic links between primary graft dysfunction and rejection. In our previous funding period we have discovered that monocytes play a central role in mediating primary graft dysfunction by regulating neutrophil entry into the reperfused lung graft. Furthermore, we have described mechanisms how neutrophilic uptake of endogenous ligands that are released from injured lungs propagates primary graft dysfunction. In this application we propose to examine pathways that result in the activation of monocytes and neutrophils in lung grafts and to uncover mechanisms how these cells promote alloimmunity and graft rejection. In Aim 1 we will define mechanisms that activate neutrophils upon graft infiltration. In Aim 2 we will analyze pathways that mediate the activation and differentiation of monocytes in lung grafts. In Aim 3 we will examine interactions between monocytes and T cells that can trigger graft rejection.