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：严重伤害是全球死亡和残疾的主要原因，在很大程度上 归因于损伤引起的致命并发症。而孤立的伤害随着时间的流逝而治愈 没有明显的后果，严重伤害会引起全身炎症综合征 （SIRS）和凝血功能障碍，这大大增加了威胁生命并发症的风险 例如出血，多器官功能障碍综合征和血栓形成。复合物分子 推动这些并发症发展的变化是晦涩的。因此，医疗 进步（例如输血）使创伤患者能够在伤害中生存，很少 存在治疗剂可有效预防致命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）的系列蛋白，对于组织至关重要 损伤后后来在康复中进行修复，但是，严重损伤在病理上改变了 其活性的时间和大小。早期造成严重损伤，超过纤溶酶激活，领先 不适当的纤维蛋白降解（高纤维蛋白溶解），出血和死亡风险增加。最近的 关于在创伤和外科患者中使用抗纤维蛋白水解药物的研究表明， 早期抑制这种不适当的纤溶酶激活不仅会减少出血，而且还会减少 炎症和相关并发症。虽然其纤维蛋白溶解的规范作用使其成为关键 凝血调节剂，纤溶酶的生理作用扩展到炎症信号的调节 和细胞迁移。因此，我们假设超过纤溶酶活性是一个关键的分子驱动器 创伤引起的SIRS，使患者患有急性和慢性炎症并发症。 该建议的目的是研究过量纤溶酶激活及其的机制 严重受伤后的Sir中作用。将使用超过纤溶酶的热损伤模型 激活发生没有出血的风险。纤溶酶是减少出血的关键目标 创伤患者目前在诊所使用治疗来防止出血和新型药理学 该系统的调节器也可以用于减少或防止注射相关 并发症，如果做得适当。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工具，可靠 挑衅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值，我将使用NF-κB-荧光素酶报告基因小鼠跟踪系统变化 在热量之后，随着时间的流逝，在器官和细胞水平的急性和慢性感染中 受伤。这项工作的目的是确定治疗目标和预测性诊断工具 可用于减少炎症并发症并改善创伤患者的结局。