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: 10649442
• 负责人: Matthew D Neal
• 金额: $ 39.75万
• 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/10649442
• 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

多器官功能障碍综合征（MODS）是一种主要的死亡原因， 严重创伤，这是全世界死亡的主要原因。MODS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 明白创伤患者复苏的最新进展（如全血输注和 使用氨甲环酸）已经改善了最初的生存率，但这些重症患者现在仍然活着， 有发生MODS和其他免疫/炎症并发症的风险。这使得理解如何 多器官功能障碍综合征（MODS）是创伤后的一种危重病. MODS被认为是在过度的环境中出现的。 先天性免疫激活，并与创伤诱导的凝血病（TIC）的晚期相关联。TIC是 其特征在于内皮损伤，过度血栓形成表现为严重的小血管血栓形成， 导致器官功能障碍以及致命的大血管血栓栓塞事件。有一个 迫切需要确定过度炎症和先天免疫反应之间的机制联系， 以及凝血功能的缺陷，以了解MODS。 我们研究的首要目标是了解创伤如何通过以下途径导致器官损伤： 炎症和血管凝结，或免疫血栓形成。我们的研究重点是 血小板在创伤后驱动免疫血栓形成中的作用我们的初步数据表明， 对受伤后的先天免疫反应至关重要。血小板是免疫功能的前哨细胞， 通过与其他炎性细胞相互作用，发挥重要的调节功能，并以这种方式成为 炎症和血栓形成。此外，创伤诱导的“功能障碍”血小板是 都是TIC的驱动器，并放大炎症和器官损伤。因此，我们假设功能障碍的血小板 它们与其他免疫细胞的相互作用是MODS的关键调节因子。迫切需要 开展研究，重点是预防和管理器官损伤和并发症， 炎症/血栓形成，并且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，包括挽救生命的新技术 伤后我们必须确切地了解这些干预措施是如何工作的，以设计下一个重大进展， 以及它们如何影响MODS的风险。为此，必须制定有针对性的 治疗创伤后的绝大多数发病率的治疗策略。 我们建议解决该领域的以下主要知识差距： 1)了解创伤后幸存者微血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)为创伤后器官损伤和血栓形成设计有针对性的干预措施

项目成果

Missingness matters: a secondary analysis of thromboelastography measurements from a recent prehospital randomized tranexamic acid clinical trial.

缺失很重要：对最近一项院前随机氨甲环酸临床试验的血栓弹力图测量结果进行二次分析。

• DOI: 10.1136/tsaco-2023-001346
• 发表时间: 2024
• 期刊: Trauma surgery & acute care open
• 影响因子: 2
• 作者: Donohue,JackK;Iyanna,Nidhi;Lorence,JohnM;Brown,JoshuaB;Guyette,FrancesX;Eastridge,BrianJ;Nirula,Raminder;Vercruysse,GaryA;O'Keeffe,Terence;Joseph,Bellal;Neal,MatthewD;Sperry,JasonL
• 通讯作者: Sperry,JasonL

Whole Blood Resuscitation and Association with Survival in Injured Patients with an Elevated Probability of Mortality.

• DOI: 10.1097/xcs.0000000000000708
• 发表时间: 2023-08-01
• 期刊: Journal of the American College of Surgeons
• 影响因子: 5.2

Accelerating availability of clinically-relevant parameter estimates from thromboelastogram point-of-care device.

• DOI: 10.1097/ta.0000000000002608
• 发表时间: 2020-05
• 期刊: The journal of trauma and acute care surgery
• 作者: Pressly MA;Parker RS;Neal MD;Sperry JL;Clermont G
• 通讯作者: Clermont G

Heme Oxygenase-2 Localizes to Mitochondria and Regulates Hypoxic Responses in Hepatocytes.

血红素加氧酶 2 定位于线粒体并调节肝细胞的缺氧反应。

• DOI: 10.1155/2018/2021645
• 发表时间: 2018
• 期刊: Oxidative medicine and cellular longevity
• 作者: Waltz,PaulK;Kautza,Benjamin;Luciano,Jason;Dyer,Mitch;Stolz,DonnaBeer;Loughran,Patricia;Neal,MatthewD;Sperry,JasonL;Rosengart,MatthewR;Zuckerbraun,BrianS
• 通讯作者: Zuckerbraun,BrianS

Prehospital tranexamic acid is associated with a dose-dependent decrease in syndecan-1 after trauma: A secondary analysis of a prospective randomized trial.

• DOI: 10.1097/ta.0000000000003955
• 发表时间: 2023-11-01
• 期刊: The journal of trauma and acute care surgery