Resuscitation Strategies for Achieving Thrombo-inflammatory Homeostasis

摘要 在美国，每年有4万人死于意外创伤，死于出血后潜在的可预防的并发症 令人震惊。早期黄金时间内的引导性损伤控制复苏(DCR)可改善止血和 代谢稳态(Gonzalez，Ann Surg.2016；263：1051-9)。我们对这项提议的长期愿景是 发展必要的知识基础设施，使DCR在5-10年内更上一层楼，以减少员额 创伤发病率和死亡率急剧上升(25%)。这种RM1的目的是限制血栓炎症 而不会失去止血或先天免疫防御。中心假设是，血浆可以被定制成 实现血栓-炎症动态平衡。我们的理论基础是血浆中含有可溶性的先天免疫 完全正常但可促进致命性血栓炎症和创伤后器官损伤的成分 病人。我们的特定目标验证了创伤和失血性休克(T/HS)目标1 复苏失血性凝血和免疫炎症：将探讨激活 血栓炎症丝氨酸蛋白酶级联增加血管通透性，目标2别构 纤溶介质的调节：多结构域丝氨酸蛋白水解酶(纤溶酶相互作用组)：将定义和 鉴定已发布的调节纤溶进入血浆的化合物，靶向3 LXR信号和出血 休克迅速改变纤溶表型：将确定参与肝细胞核反应调节 动物止血和AIM 4代谢重编程驱动错乱的止血和炎症 T/HS后的反应：将表征扰乱先天免疫的代谢物。这一贡献是 意义重大，因为它提供了未来FDA批准所需的动物和人类数据，同时考虑 性别差异的作用。拟议的方法在以下几个方面具有创新性：第一，我们评估 补体病和运动病，这两种病在创伤、酸中毒和 凝血障碍。其次，我们发现了新的纤溶酶调节因子。第三，纤溶功能的转变。 通过激活或拮抗特定的核受体而将表型转变为另一种表型是一种新的方法。最后，我们有 确定了一些与器官损伤/功能障碍有关并导致器官损伤/功能障碍的代谢物，特别是肺 目前正在研究抑制其积累和影响的方法。我们已经建立了一个多学科的 工作组自2010年以来一直在研究DCR的范围。多年来，我们一直在聘请和支持专家 蛋白质组学、代谢组学和生物信息学分析最早的患者血浆，发现止血 预测结果的表型。我们是第一批在现场测试院前DCR的公司之一，也是第一家 获取创伤后休克患者的TEG和生化的详细数据。多年来，我们精益求精 最佳团队动态1)招聘和维持合适的专家，2)根据以下条件分配职责 具体的专业知识，以及3)通过强调个人成长来建立信任和解决冲突。

ABSTRACT Annually 40,000 die of unintentional trauma in USA, from potentially preventable complications after hemorrhagic shock. Guided damage control resuscitation (DCR) within the early golden hours improves hemostasis and metabolic homeostasis (Gonzalez, Ann Surg. 2016; 263:1051-9). Our long term vision for this proposal is to develop the knowledge infrastructure necessary to take DCR to the next level in 5-10 years to reduce post traumatic morbidity and mortality drastically (25%). The objective of this RM1 is to restrict thrombo inflammation without losing hemostasis or innate immune defense. The central hypothesis is that plasma can be tailored to achieve thrombo-inflammatory homeostasis. Our rationale is that plasma contains soluble, innate immune components that while perfectly normal can promote lethal thrombo-inflammation and organ injury in trauma patients. Our specific aims test the hypotheses that Trauma and Hemorrhagic shock (T/HS) Aim 1 Resuscitating hemorrhage-induced coagulopathy and immuno-inflammation: will explore the activation of thrombo-inflammatory serine protease cascades that increase vascular permeability, Aim 2 Allosteric modulation of fibrinolysis mediators: multi-domain Ser-proteases (plasmin interactome): will define and identify the released novels regulators of fibrinolysis into the plasma, Aim 3 LXR signaling and hemorrhagic shock rapidly alter the fibrinolytic phenotype: will define the involvement of liver nuclear responses regulating hemostasis in animals and Aim 4 Metabolic reprogramming drives deranged hemostatic and inflammatory responses after T/HS: will characterize the metabolites that perturb innate immunity. This contribution is significant because it provides animal and human data necessary for future FDA approvals while considering the role of sex differences. The proposed approaches are innovative on a number of areas: First, we evaluate complementopathy and kininopathy, which have not been well studied in the context of trauma, acidosis and coagulopathy. Secondly, we identify new regulators of plasmin. Thirdly, the switching of fibrinolysis from one phenotype to another through activation or antagonism of specific nuclear receptors is novel. Lastly, we have identified a number of metabolites that are associated with and induce organ injury/dysfunction, especially lung injury, and are investigating methods to inhibit their accumulation and effects. We have built a multidisciplinary team to study the scope of DCR since 2010. Over the years, we have engaged and supported experts in proteomics, metabolomics, and bioinformatics to analyze earliest patient plasma, discovering hemostatic phenotypes that predict outcomes. We have been amongst the first to test prehospital DCR in the field, and first to obtain detailed TEG and biochemistry of humans in post-traumatic shock. Over the years, we have refined optimal team dynamics 1) recruiting and sustaining suitable experts, 2) assigning responsibility according to specific expertise, and 3) building trust and resolving conflict by emphasizing personal growth.