The role of pathologic plasmin activity in trauma-induced systemic inflammatory response syndrome

病理性纤溶酶活性在创伤引起的全身炎症反应综合征中的作用

• 批准号: 10059140
• 负责人: Breanne Helen Yvonne Gibson
• 金额: $ 3.02万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059140
• 关键词: Acute; Acute-Phase Reaction; Age; Alteplase; Animal Model; Animals; Antifibrinolytic Agents; Antiplasmin; Automobile Driving; Blood Coagulation Disorders; Blood Transfusion; Cause of Death; Cessation of life; Chronic; Clinic; Clinical; Coagulation Process; Cohort Studies; Complex; Convalescence; Development; Diagnostic; Disease; Elements; Enzymes; Event; Fibrin; Fibrinolysis; Functional disorder; Genetic; Goals; Hemorrhage; Human; Individual; Inflammation; Inflammatory; Injury; Life; Luciferases; Measures; Mediating; Medical; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mus; Operative Surgical Procedures; Organ; Organ failure; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Plasmin; Plasminogen; Plasminogen Activator; Play; Process; Recombinants; Recovery; Reporter; Risk; Role; Serine Protease; Serological; Signal Transduction; Survival Rate; System; Systemic Inflammatory Response Syndrome; Testing; Therapeutic; Thrombosis; Time; Tranexamic Acid; Trauma; Trauma patient; Treatment Efficacy; Urokinase; Work; angiogenesis; appropriate dose; burn model; cell motility; cytokine; diagnostic biomarker; disability; experimental study; functional restoration; genetic manipulation; healing; heat injury; improved; improved outcome; inflammatory modulation; inhibitor/antagonist; injured; knock-down; mortality; mortality risk; mouse model; novel; premature; prevent; response; severe injury; therapeutic evaluation; therapeutic target; tissue regeneration; tissue repair; tool

Project Summary: Severe injury is a leading cause of death and disability worldwide, largely attributed to fatal complications that arise from the injury. While an isolated injury heals over time without notable consequence, a severe injury provokes systemic inflammatory response syndrome (SIRS) and coagulation dysfunction, which greatly increase the risk of life-threatening complications such as bleeding, multiple organ dysfunction syndrome, and thrombosis. The complex molecular changes that drive the development of these complications are obscure. Consequently, while medical advances (such as blood transfusions) have allowed trauma patients to survive their injuries, few therapeutics exist to effectively prevent fatal complications and promote recovery in these patients. Plasmin, the serine protease responsible for fibrin degradation (fibrinolysis), is critical for tissue repair later in convalescence following an injury, however, a severe injury pathologically alters the timing and magnitude of its activity. Severe injuries provoke early, excess plasmin activation, leading to inappropriate fibrin degradation (hyperfibrinolysis), bleeding, and increased risk of death. Recent studies on the use of antifibrinolytic drugs in trauma and surgical patients have demonstrated that early inhibition of this inappropriate plasmin activation not only reduces bleeding but also reduces inflammation and associated complications. While its canonical role of fibrinolysis makes it a critical regulator of coagulation, plasmin's physiologic roles extend to modulation of inflammatory signaling and cell migration. Therefore, we hypothesized that excess plasmin activity is a key molecular driver of trauma-induced SIRS, predisposing patients to acute and chronic inflammatory complications. The purpose of this proposal is to investigate mechanisms of excess plasmin activation and its role in SIRS following severe injury. A model of thermal injury will be used in which excess plasmin activation occurs without risk of bleeding. While plasmin is a key target in the reduction of bleeding in trauma patients, therapeutics currently used in the clinic to prevent bleeding and novel pharmacologic modulators of this system may also be used to reduce or prevent inflammation-associated complications, if dosed appropriately. Within the proposed studies, I will implement genetic and pharmacologic tools to manipulate plasmin activity in an animal model of thermal injury, which reliably provokes SIRS, in order to quantify the effect of plasmin activity on inflammation. In addition to serologic measures of cytokines, I will use NF- κB-luciferase reporter mice to track systemic changes in both acute and chronic inflammation at the organ and cellular level over time following the thermal injury. The goal of this work is to identify both therapeutic targets and predictive diagnostic tools that may be used to reduce inflammatory complications and improve outcomes in trauma patients.

项目摘要：严重伤害是全世界死亡和残疾的主要原因 归因于受伤引起的致命并发症。虽然孤立的伤害会随着时间的推移而愈合 在没有明显后果的情况下，严重损伤会引发全身炎症反应综合征 （SIRS）和凝血功能障碍，大大增加了危及生命的并发症的风险 例如出血、多器官功能障碍综合征和血栓形成。复杂的分子 导致这些并发症发生的变化尚不清楚。因此，在医疗的同时 进步（例如输血）使创伤患者得以幸存，但很少有 现有的治疗方法可以有效预防致命的并发症并促进这些患者的康复。 纤溶酶是负责纤维蛋白降解（纤维蛋白溶解）的丝氨酸蛋白酶，对于组织至关重要 在受伤后的恢复期进行修复，然而，严重的损伤会在病理上改变 其活动的时间和规模。严重损伤会导致早期纤溶酶过度激活，导致 纤维蛋白过度降解（纤溶亢进）、出血和死亡风险增加。最近的 对创伤和手术患者使用抗纤溶药物的研究表明， 早期抑制这种不适当的纤溶酶激活不仅可以减少出血，还可以减少 炎症和相关并发症。虽然其纤维蛋白溶解的典型作用使其成为关键 作为凝血调节剂，纤溶酶的生理作用延伸至炎症信号传导的调节 和细胞迁移。因此，我们假设过量的纤溶酶活性是关键的分子驱动因素 创伤引起的 SIRS，使患者容易出现急性和慢性炎症并发症。 本提案的目的是研究纤溶酶过度激活的机制及其 严重损伤后 SIRS 中的作用。将使用热损伤模型，其中过量的纤溶酶 激活不会有出血风险。虽然纤溶酶是减少出血的关键目标 创伤患者、目前临床上用于预防出血的治疗方法和新药理 该系统的调节剂也可用于减少或预防炎症相关的 如果剂量适当的话，会出现并发症。在拟议的研究中，我将实施遗传和 在热损伤动物模型中操纵纤溶酶活性的药理学工具，可靠地 激发 SIRS，以量化纤溶酶活性对炎症的影响。此外 细胞因子的血清学测量，我将使用 NF-κB-荧光素酶报告小鼠来跟踪全身变化 随着时间的推移，在器官和细胞水平的急性和慢性炎症中 受伤。这项工作的目标是确定治疗靶点和预测诊断工具 可用于减少炎症并发症并改善创伤患者的预后。