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

创伤后器官损伤和炎症的机制阐明和靶向治疗

• 批准号: 10409732
• 负责人: Matthew D Neal
• 金额: $ 39.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409732
• 关键词: Automobile Driving; Biological Assay; Blood Platelets; Blood Transfusion; Blood Vessels; Blood coagulation; Cause of Death; Cells; Coagulation Process; Critical Illness; Data; Defect; Endothelium; Event; Functional disorder; Goals; Immune; Immune system; Inflammation; Inflammatory; Injury; Innate Immune Response; Intervention; Kidney; Knowledge; Link; Lung; Modernization; Morbidity - disease rate; Multiple Organ Failure; Organ; Patients; Phase; Prevention; Research; Resuscitation; Risk; Role; Sentinel; Survivors; Techniques; Thrombosis; Tranexamic Acid; Trauma; Trauma patient; Whole Blood; Work; design; disability; immune activation; immune function; immunothrombosis; improved; mortality; organ injury; platelet function; post intervention; programs; targeted treatment; thrombotic; trauma induced coagulopathy

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

项目摘要/摘要：多器官功能障碍综合征（mods）是死亡的主要原因 严重的创伤，这是全球死亡率的主要原因。国防部被认为是 过度炎症和凝结异常的恶性级联 理解。创伤患者复苏的最新进展（例如全血输血和 使用曲霉素酸）导致最初的生存提高，但这些重症患者现在仍然活着 有发展MOD和其他免疫/炎症并发症的风险。这使得了解如何 国防部发生至关重要的创伤需求。人们认为在过度的情况下会出现mods 先天免疫激活，与创伤诱导的凝血病（TIC）的后期有关。 tic是 以内皮损伤为特征 这导致器官功能障碍以及致命的大型血管栓塞事件。有一个 确定过度炎症和先天免疫反应之间的机械联系的批判性需求 以及凝血中的缺陷以了解mod。 我们研究的总体目标是了解创伤如何通过 血管的炎症和凝结，或免疫骨骼病。我们的研究重点是核心角色 血小板功能在创伤后驱动免疫栓塞。我们的初步数据表明血小板是 受伤后对先天免疫反应至关重要。血小板是免疫功能的前哨细胞，并提供A 通过与其他炎症细胞相互作用，关键的调节功能，以这种方式是 炎症和血栓形成。此外，创伤引起的“功能失调”血小板是关键组成部分 驱动抽动和扩大炎症和器官损伤。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MOD的关键调节剂。迫在眉睫 开展研究重点是预防和管理器官损伤和并发症的研究 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改变，以包括挽救生命的新技术 受伤后。我们必须准确了解这些干预措施如何设计下一个巨大进步 复苏以及它们如何影响mod的风险。这是必不可少的 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）了解创伤后幸存者导致幸存者微栓性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）设计针对创伤后器官损伤和血栓形成的目标干预措施