Red blood cell microparticles and lung inflammation after hemorrhage and resuscit

描述（由申请方提供）：我们提案的长期目标是了解输注较旧pRBC单位对出血复苏后患者结局的影响机制。出血性休克是创伤后潜在可预防死亡的最常见原因。目前用于严重失血患者的复苏策略包括使用浓缩红细胞（pRBC）和新鲜冷冻血浆。虽然使用pRBC复苏受伤的患者对于存活是必不可少的，但是输注pRBC单位是必要的。 储存期间老化的药物与患者临床结局恶化相关，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。我们最近证明，老化的pRBC单位含有红细胞微粒。我们以前的研究和初步数据强烈表明，这些微粒是出血复苏后炎症反应和肺部炎症的关键介质。在目前的提议中，我们假设来自储存的pRBC的微粒本质上是促炎性的，并且在从出血复苏后促进炎症后果，例如肺部炎症的发展。为了验证这一假设，我们提出了以下具体目标。目的1：确定pRBC单位储存期间微粒形成和生化组成的性质。目的2：探讨红细胞来源微粒激活细胞的分子机制。目标3：确定RBC微粒促进多细胞相互作用的方式，从而导致出血和复苏后的器官炎症。拟议的研究将产生关于微粒在由于使用储存的pRBC从出血中复苏而引起的炎症后遗症中的作用的新数据，并将提供重要的新信息，以指导开发减轻出血和复苏后器官损伤的治疗策略。

DESCRIPTION (provided by applicant): The long term goal of our proposal is to understand the mechanisms by which transfusion of older pRBCs 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 packed RBCs (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 recently demonstrated that aged pRBC units contain red blood cell microparticles. Our previous studies and preliminary data strongly indicate that these microparticles are critical mediators of the inflammatory response and lung inflammation after resuscitation from hemorrhage. In the current proposal, we hypothesize that microparticles from stored pRBCs are pro-inflammatory in nature and promote inflammatory consequences, such as the development of lung inflammation, after resuscitation from hemorrhage. To test this hypothesis, we propose the following specific aims. Aim 1: Determine the nature of the formation and biochemical composition of microparticles during storage of pRBC units. Aim 2: Determine the molecular mechanisms of cellular activation by RBC derived microparticles. Aim 3: Determine the manner in which RBC microparticles promote multi-cellular interactions leading to organ inflammation after hemorrhage and resuscitation. The proposed studies will generate novel data concerning the role of microparticles in the inflammatory sequelae due to the use of stored pRBCs for resuscitation from hemorrhage and will provide important new information to guide the development of therapeutic strategies to mitigate organ injury after hemorrhage and resuscitation.