Role of RAGE and Necroptosis in Transfusion Mediated Lung Inflammation

 描述(申请人提供)：最近的流行病学研究表明，在危重患者中，与输血红细胞(RBC)相关的急性呼吸窘迫综合征(ARDS)的发病率、死亡率和发展趋势都有所增加，但这种联系背后的机制仍不清楚。我们的数据表明，储存的红细胞诱导肺内皮细胞的坏死性下垂(一种受调控的坏死性细胞死亡)，并增强对后续损伤的敏感性。我们先前已经证明，晚期糖基化终末产物的前炎性受体(RAGE)介导了红细胞输注后的肺内皮细胞功能障碍。这项建议的总体目标是阐明RAGE在红细胞诱导的坏死性下垂中的作用。在特定的目标1中，将在体外和在人肺的微型工程模型中检验RAGE在感觉坏死性刺激中的作用。具体目标2将探讨细胞内RAGE在坏死性下垂执行中的作用。最后，《特殊目的3》将通过动物模型检测RBC诱导的坏死性下垂对肺损伤的体内影响。从这些研究中获得的知识将阐明红细胞增强肺损伤易感性的一些机制，并有望导致预防与红细胞输注相关的发病率的新疗法。

 DESCRIPTION (provided by applicant): Recent epidemiologic studies have demonstrated increased morbidity, mortality, and the development of Acute Respiratory Distress Syndrome (ARDS) associated with red blood cell (RBC) transfusions in the critically ill, yet the mechanisms underlying this association remain unknown. Our data demonstrate that banked RBCs induce necroptosis (a form of regulated necrotic cell death) of lung endothelial cells and enhance susceptibility to subsequent injury. We have previously demonstrated that the proinflammatory receptor for advanced glycation endproducts (RAGE) mediates lung endothelial dysfunction following RBC transfusion. The overall goal of this proposal is to elucidate the role of RAGE in RBC-induced necroptosis. In Specific Aim 1 the role of RAGE in sensing necroptotic stimuli will be examined in vitro and in a micro-engineered model of human lung. Specific Aim 2 will explore the role of intracellular RAGE in necroptosis execution. Lastly, Specific Aim 3 will examine the in vivo effects of RBC- induced necroptosis on lung injury using animal models. Knowledge derived from these studies will elucidate some of the mechanisms by which RBCs enhance susceptibility to lung injury and hopefully lead to novel therapies to prevent the morbidity associated with RBC transfusions.