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注旧包装物的机制。 红细胞(PRBC)单位在出血复苏后会恶化患者的预后。出血性 休克是创伤后可能可预防的死亡的最常见原因。当前复苏 对于大量失血的患者，治疗策略包括使用红细胞和新鲜冰冻血浆。而当 使用pRBC对受伤患者进行复苏对于存活、输注pRBC是必不可少的 在储存过程中老化与患者的临床结果恶化有关，包括 增加多系统器官衰竭、肺炎、肾功能衰竭、败血症和死亡的风险。我们有 证明了来自老化的pRBC单位的微粒含有红细胞微粒， 输血后的炎性事件。我们之前的研究和初步数据强烈表明， 微粒的形成是pRBC储存过程中的一个关键事件，pRBC微粒是至关重要的 失血复苏后肺部炎症的介质。在目前的提案中，我们假设 来自储存的压缩红细胞的微粒在本质上是强烈的促炎作用，并促进 炎症后果，如内皮细胞激活，肺微血栓形成，以及 失血复苏后肺部炎症的发展。为了检验这一假设，我们建议 以下具体目标：目标1：测试减少pRBC微粒产生的机械策略 在储存期间，并减轻储存的pRBC单位的促炎潜力；目标2：确定 来自储存的红细胞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。拟议的研究将概括出新颖的数据。 关于储存红细胞单位中微粒的作用和内皮细胞的发育 出血和复苏后的功能障碍。如果成功，这些研究将确定新的治疗方法 利用储存的pRBC单位改善出血和复苏后的临床结果的目标。

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.