Red blood cell microparticles and lung inflammation after hemorrhage and resuscitation

项目摘要 我们建议的长期目标是了解输血的机制， 红细胞（pRBC）单位可评估出血复苏后患者的预后。出血性 休克是创伤后潜在可预防死亡的最常见原因。当前复苏 对于大量失血的患者的策略包括使用pRBC和新鲜冷冻血浆。而 使用pRBC对受伤患者进行复苏对于存活至关重要，输注pRBC单位 在储存期间老化与患者的临床结局恶化相关，包括 多系统器官衰竭、肺炎、肾衰竭、败血症和死亡的风险增加。我们有 证明来自老化pRBC单位的微粒含有介导 输血后的炎症事件。我们之前的研究和初步数据强烈表明， 微粒形成是pRBC储存过程中的关键事件， 出血复苏后肺部炎症介质。在目前的提案中，我们假设 来自储存的浓缩红细胞的微粒本质上是急性促炎性的， 炎症后果，如内皮细胞活化、肺微血栓形成，以及 出血复苏后肺部炎症的发展。为了验证这一假设，我们建议 目标1：测试减少pRBC微粒生成的机制策略 目的2：确定pRBC单位在储存过程中的促炎作用，并减轻储存的pRBC单位的促炎潜力;目的2：确定pRBC单位的促炎作用。 来自储存的pRBC单位的微粒激活内皮细胞的分子机制;目的3： 确定pRBC微粒促进多细胞相互作用的机制， 出血复苏后肺微血栓形成。拟议的研究将一般新的数据 关于来自储存的pRBC单位的微粒和内皮细胞发育的作用， 出血复苏后功能障碍。如果成功，这些研究将发现新的治疗方法， 靶点允许使用储存的pRBC单位改善出血和复苏后的临床结局。

Project Summary The long term goal of our proposal is to understand the mechanisms by which transfusion of older packed red blood cell (pRBC) units worsens patient outcomes after resuscitation from hemorrhage. Hemorrhagic shock is the most common cause of potentially preventable death after trauma. Current resuscitation strategies for patients with significant blood loss include the use pRBCs and fresh-frozen plasma. While the use of pRBCs for resuscitation of the injured patient is essential for survival, transfusion of pRBC units that have aged during storage is associated with worsened clinical outcomes in patients, including increased risk of multisystem organ failure, pneumonia, renal failure, sepsis, and death. We have demonstrated that microparticles from aged pRBC units contain red blood cell microparticles that mediate inflammatory events after transfusion. Our previous studies and preliminary data strongly indicate that microparticle formation is a key event during pRBC storage and that pRBC microparticles are critical mediators of lung inflammation after resuscitation from hemorrhage. In the current proposal, we hypothesize that microparticles from stored packed red blood cells are acutely pro-inflammatory in nature and promote inflammatory consequences, such as endothelial cell activation, formation of pulmonary microthrombi, and development of lung inflammation after resuscitation from hemorrhage. To test this hypothesis, we propose the following specific aims: Aim 1: Test mechanistic strategies to reduce pRBC microparticle generation during storage and mitigate pro-inflammatory potential of stored pRBC units; Aim 2: Determine the molecular mechanisms of endothelial cell activation by microparticles from stored pRBC units; Aim 3: Determine the mechanisms by which pRBC microparticles promote multi-cellular interactions leading pulmonary microthrombi after hemorrhage and resuscitation. The proposed studies will general novel data concerning the role of microparticles from stored pRBC units and the development of endothelial cell dysfunction after hemorrhage and resuscitation. If successful, these studies will identify new therapeutic targets allowing improved clinical outcomes after hemorrhage and resuscitation with stored pRBC units.