Mechanistic Elucidation and Targeted Therapy of Organ Injury and Inflammation following Trauma

项目摘要/摘要：多器官功能障碍综合征(MODS)是以下疾病的主要死亡原因 严重创伤，这是世界范围内死亡的主要原因。多器官功能障碍被认为是一种 过度炎症和凝血异常的恶性级联反应，但仍不完全 明白了。创伤患者复苏的最新进展(如全血输注和 氨甲环酸的使用)提高了最初的存活率，但这些危重病人现在仍能活到 有发生MODS和其他免疫/炎症并发症的风险。这使得我们能够理解如何 多器官功能障碍综合征在创伤中是一种危急和迫切的需要。MODS被认为是在过度的环境下发生的 先天免疫激活，并与创伤所致凝血障碍(TIC)的晚期有关。TiC是 以内皮损伤、血栓形成过度为特征，表现为严重的小血管血栓形成， 这会导致器官功能障碍，以及致命的大血管血栓形成事件。有一个 迫切需要确定过度炎症反应和先天免疫反应之间的机制联系 以及凝血功能的缺陷，以期了解MODS。 我们研究的首要目标是了解创伤是如何通过 血管发炎和凝血，或免疫血栓形成。我们的研究重点是 血小板在创伤后免疫血栓形成中的作用。我们的初步数据表明，血小板 对损伤后的先天免疫反应至关重要。血小板是免疫功能中的哨兵细胞，起着 通过与其他炎性细胞相互作用发挥关键的调节功能，并且通过这种方式是 炎症和血栓形成。此外，创伤引起的“功能失调”的血小板是 两者都会导致TIC，并放大炎症和器官损伤。因此，我们假设功能失调的血小板 它们与其他免疫细胞的相互作用是MODS的关键调节因素。迫切需要 开展以预防和处理器官损伤和并发症为重点的研究 炎症/血栓形成，这代表了本提案和研究计划的关键主题。 此外，现代创伤复苏正在迅速变化，包括拯救生命的新技术 受伤后。我们必须准确地了解这些干预措施是如何工作的，以设计下一步的重大进展 复苏以及它们如何影响MODS的风险。这一点的关键是需要制定有针对性的 治疗创伤后压倒性发病率的治疗策略。 我们建议解决该领域的以下关键知识差距： 1)了解创伤后幸存者微血栓器官损伤的细胞机制 2)揭示现代创伤复苏的免疫和炎症后果 3)针对创伤后器官损伤和血栓形成设计针对性的干预措施

Project Summary/Abstract: Multiple organ dysfunction syndrome (MODS) is a leading cause of death after severe trauma, which is a leading cause of mortality worldwide. MODS is thought to be a consequence of a vicious cascade of excessive inflammation and coagulation abnormalities but remains incompletely understood. Recent advances in the resuscitation of trauma patients (such as whole blood transfusion and the use of tranexamic acid) have led to improved initial survival, yet these critically ill patients now stay alive to be at risk to develop MODS and other immune/inflammatory complications. This makes understanding how MODS occurs a critical and an immediate need in trauma. MODS is thought to arise in the setting of excessive innate immune activation and is associated with the late phase of trauma-induced coagulopathy (TIC). TIC is characterized by endothelial injury, excessive thrombosis manifesting as both severe small vessel thrombosis, which contributes to organ dysfunction, as well as deadly large vessel thromboembolic events. There is a critical need to identify a mechanistic link between the excessive inflammatory and innate immune responses and the defects in coagulation in order to understand MODS. The overarching goal of our research is to understand how trauma leads to organ injury through inflammation and clotting of blood vessels, or immunothrombosis. Our research focus is the central role of platelet function in driving immunothrombosis after trauma. Our preliminary data demonstrate that platelets are critical to the innate immune response after injury. Platelets are sentinel cells in immune function and serve a critical regulatory function by interacting with other inflammatory cells, and in this way are a major link between inflammation and thrombosis. Furthermore, trauma-induced `dysfunctional' platelets are key components to both drive TIC and to amplify inflammation and organ injury. Thus, we hypothesize that dysfunctional platelets and their interactions with other immune cells are critical regulators of MODS. There is an imminent need to develop research focusing on the prevention and management of organ injury and complications of inflammation/thrombosis, and this represents the key theme of the present proposal and research program. Furthermore, modern trauma resuscitation is rapidly changing to include new techniques which saves lives after injury. We must understand exactly how these interventions work to design the next great advance in resuscitation and also how they impact the risk of MODS. Essential to this is the need to develop targeted therapeutic strategies to treat the overwhelming morbidity after trauma. We propose to tackle the following key knowledge gaps in the field: 1) Understand the cellular mechanisms leading to micro-thrombotic organ injury in survivors after trauma 2) Unravel the immune and inflammatory consequences of modern trauma resuscitation 3) Design targeted interventions for post-traumatic organ injury and thrombosis