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

项目摘要：严重伤害是世界范围内死亡和残疾的主要原因，主要 归因于损伤引起的致命并发症。虽然孤立的损伤会随着时间的推移而痊愈 在没有显著后果的情况下，严重损伤会引发全身炎症反应综合征。 (SIRS)和凝血功能障碍，这极大地增加了威胁生命的并发症的风险 如出血、多器官功能障碍综合症和血栓形成。复杂的分子 导致这些并发症发生的变化并不明显。因此，虽然医疗 先进的技术(如输血)使创伤患者得以存活下来，但很少有 治疗方法的存在是为了有效地预防这些患者的致命并发症并促进其康复。 纤溶酶是一种丝氨酸蛋白酶，负责纤维蛋白的降解(纤溶)，对组织至关重要 然而，在受伤后的恢复期，严重的损伤会在病理上改变 其活动的时间和规模。严重的损伤会引起早期的、过度的纤溶酶激活，导致 由于不适当的纤维蛋白降解(纤溶功能亢进)、出血和死亡风险增加。近期 对创伤和外科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 炎症及相关并发症。而其纤溶的典型作用使其成为关键的 凝血、纤溶酶的生理作用延伸到炎症信号的调节 和细胞迁移。因此，我们假设过量的纤溶酶活性是一个关键的分子驱动因素。 创伤性全身炎症反应综合征的发生，使患者容易出现急性和慢性炎症并发症。 这一建议的目的是研究纤溶酶过度激活的机制及其 在严重创伤后SIRS中的作用。将使用热损伤模型，在该模型中，过量的纤溶酶 激活时不会有出血的风险。虽然纤溶酶是减少出血的关键靶点 创伤患者，目前临床上用于预防出血的治疗方法和新的药理 该系统的调节剂也可用于减少或预防炎症相关 并发症，如果剂量适当的话。在拟议的研究中，我将实施遗传和 在烫伤动物模型中操纵纤溶酶活性的药理工具，这是可靠的 激发SIRS，以量化纤溶酶活性对炎症的影响。除了……之外 血清学测量细胞因子，我将使用NF-κB-荧光素酶报告鼠来跟踪全身变化 随着时间的推移，在器官和细胞水平上的急性和慢性炎症 受伤。这项工作的目标是确定治疗靶点和预测性诊断工具 可用于减少炎症并发症和改善创伤患者的预后。

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.