Resuscitation Strategies for Achieving Thrombo-inflammatory Homeostasis

摘要 在美国，每年有40，000人死于意外创伤，死于出血后可能可预防的并发症。 冲击.在早期黄金时间内引导损伤控制复苏（DCR）可改善止血效果， 代谢稳态（Gonzalez，Ann Surg. 2016; 263：1051-9）。我们对这一建议的长期愿景是 发展必要的知识基础设施，在5-10年内将DCR提升到一个新的水平， 创伤发病率和死亡率急剧上升（25%）。该RM 1的目的是限制血栓炎症 而不会失去止血或先天免疫防御。核心假设是等离子体可以被定制为 实现血栓炎性稳态。我们的理论是血浆中含有可溶性先天免疫物质 这些成分虽然完全正常，但可以促进致命的血栓炎症和创伤中的器官损伤 患者我们的具体目标是检验创伤和出血性休克（T/HS）的假设 复苏性脑出血诱导的凝血功能障碍和免疫炎症：将探讨 血栓炎性丝氨酸蛋白酶级联增加血管通透性，Aim 2变构 纤溶介质的调节：多结构域丝氨酸蛋白酶（纤溶酶相互作用组）：将定义和 确定释放到血浆中的新型纤溶调节剂，Aim 3 LXR信号传导和出血性 休克迅速改变纤溶表型：将定义肝细胞核反应调节的参与 动物止血和目标4代谢重编程驱动紊乱的止血和炎症 T/HS后的反应：将表征干扰先天免疫的代谢物。这种贡献 重要的是，它提供了未来FDA批准所需的动物和人类数据， 性别差异的作用。所提出的方法在许多方面是创新的：首先，我们评估 补体病和激肽病，这还没有得到很好的研究，在创伤，酸中毒和 凝血病其次，我们确定了新的纤溶酶调节剂。第三，纤溶系统从单一纤溶系统 通过激活或拮抗特异性核受体将表型转化为另一种表型是新颖的。最后，我们有 鉴定了许多与器官损伤/功能障碍相关并诱导器官损伤/功能障碍的代谢物，尤其是肺 伤害，并正在研究抑制其积累和影响的方法。我们建立了一个多学科的 自2010年以来，该团队一直在研究DCR的范围。多年来，我们聘请并支持专家， 蛋白质组学、代谢组学和生物信息学分析最早期患者血浆，发现止血 预测结果的表型。我们是最早在现场测试院前DCR的公司之一， 以获得详细的TEG和生物化学的人在创伤后休克。多年来，我们不断完善 最佳团队动态1）招募和维持合适的专家，2）根据 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.