Red blood cell microparticles and lung inflammation after hemorrhage and resuscit

描述(由申请人提供)：我们建议的长期目标是了解输注较老的pRBC单位在出血复苏后恶化患者预后的机制。失血性休克是创伤后可能可预防的死亡的最常见原因。目前对大量失血患者的复苏策略包括使用填充红细胞(PRBC)和新鲜冰冻血浆。虽然使用pRBC对受伤患者的复苏是生存所必需的，但输注pRBC单位 在储存过程中老化与患者的临床结局恶化有关，包括多系统器官衰竭、肺炎、肾功能衰竭、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有力地表明，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，我们假设储存的pRBC中的微粒本质上是促炎的，并在出血复苏后促进炎症后果，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：确定红细胞单位储存过程中微粒形成的性质和生化组成。目的2：探讨红细胞来源微粒激活细胞的分子机制。目的3：确定红细胞微粒促进多细胞相互作用的方式，导致出血和复苏后器官炎症。这项拟议的研究将产生有关微粒在使用储存的红细胞复苏出血后的炎性后遗症中的作用的新数据，并将为指导制定治疗策略以减轻出血和复苏后的器官损伤提供重要的新信息。

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.