Restoring Endothelial Function After Traumatic Injury to Reduce ARDS and Multi-Organ Dysfunction

项目摘要 创伤是全球45岁以下人群的主要死因，出血性休克 仍然是创伤后早期死亡的主要原因。后来的创伤死亡往往归因于 创伤性内皮病（EOT），一种对活化内皮细胞的全身反应，其特征在于受损的 血流、屏障完整性和凝血。临床上，EOT表现为一种促炎状态， 微循环渗漏和组织水肿，导致急性呼吸窘迫综合征（ARDS），多 器官功能障碍最终导致死亡纤维蛋白原替代体外修复内皮糖萼 以及在小鼠中通过稳定多配体蛋白聚糖-1（一种基于糖萼的蛋白聚糖）。纤维蛋白原稳定 多配体蛋白聚糖-1然后减轻EOT并恢复微循环屏障完整性。然而，目前尚不清楚， 基于纤维蛋白原的内皮完整性的恢复转化为人类临床结果的改善。 此外，目前创伤中的输血方案提供的纤维蛋白原太少或太晚。这是一个问题 因为创伤后出现EOT的患者死亡的可能性是没有EOT的患者的两倍。因此，我们认为， 恢复内皮屏障的完整性对于减轻创伤中的晚期发病率和死亡率至关重要。 因此，迫切需要确定早期纤维蛋白原替代对内皮和血管内皮细胞的影响， 严重创伤患者的器官功能障碍。我们的初步数据表明，以患者为中心的 在到达医院后6小时内更换纤维蛋白原的结果。然而，我们不知道是否 内皮修复是主要机制。为了弥补这一差距，我们将测试我们的总体 早期纤维蛋白原替代保护内皮功能可预防ARDS和多器官功能衰竭 创伤后器官功能障碍我们将测试这个假设与以下具体目标：1）确定 早期纤维蛋白原替代与多器官功能障碍之间的关系; 2）确定早期纤维蛋白原替代的影响， 纤维蛋白原替代对内皮功能的影响;以及3）确定内皮病对内皮功能的累积影响。 补充无氧天数。为了实现这些目标，候选人，医学博士大卫杜因，将利用他的 临床研究背景和现有的研究基础设施在急诊医学，创伤 外科和麻醉科。作为一名麻醉师和外科重症监护医生，杜恩博士是独一无二的 定位于实现拟议的K23研究和职业发展目标。他的长期目标是 成为预防和治疗多器官功能障碍并改善 重症创伤患者。Douin博士组建了一个多学科的导师团队， 以及创伤性损伤、重症监护、临床试验方面的转化研究经验和专题专业知识， 内皮功能和肺损伤，以确保他成功地实现所述的具体目标和职业生涯 目标.这项提议将使杜安博士过渡到一个独立的医生，科学家，并为他做好准备， 未来的NIH R61/R33资助，最终，NIH UG 3/UH 3或R 01资助。

PROJECT SUMMARY Trauma is the leading cause of death worldwide for people under 45 years old, and hemorrhagic shock remains the primary cause of early death after trauma. Later trauma deaths are frequently attributable to endotheliopathy of trauma (EOT), a systemic response to activated endothelial cells characterized by impaired blood flow, barrier integrity, and coagulation. Clinically, EOT manifests as a pro-inflammatory state of microcirculation leak and tissue edema, contributing to acute respiratory distress syndrome (ARDS), multi- organ dysfunction, and, eventually, death. Fibrinogen replacement restores the endothelial glycocalyx in vitro and in mice via stabilization of syndecan-1, a glycocalyx-based proteoglycan. Fibrinogen stabilization of syndecan-1 then mitigates EOT and restores microcirculation barrier integrity. However, it is unclear if fibrinogen-based restoration of endothelial integrity translates to improved clinical outcomes in humans. Further, current transfusion protocols in trauma provide fibrinogen too little or too late. This is a problem because trauma patients who develop EOT are twice as likely to die than those who do not. Therefore, restoring endothelial barrier integrity is essential to mitigating late morbidity and mortality in trauma. Accordingly, there is a critical need to determine the effect of early fibrinogen replacement on endothelial and organ dysfunction in critically ill trauma patients. Our preliminary data indicate improved patient-centered outcomes when fibrinogen is replaced within 6 hours of hospital arrival. However, we do not know whether endothelial restoration was the primary mechanism. To address this gap, we will test our overarching hypothesis that preserving endothelial function with early fibrinogen replacement will prevent ARDS and multi- organ dysfunction after trauma. We will test this hypothesis with the following specific aims: 1) determine the association between early fibrinogen replacement and multi-organ dysfunction; 2) determine the effect of early fibrinogen replacement on endothelial function; and 3) determine the cumulative effect of endotheliopathy on supplemental oxygen-free days. To achieve these aims, the candidate, David Douin, MD, will leverage his background in clinical research and the existing research infrastructure within the emergency medicine, trauma surgery, and anesthesiology departments. As an anesthesiologist and surgical intensivist, Dr. Douin is uniquely positioned to accomplish the proposed K23 research and career development aims. His long-term goal is to become an expert in novel interventions to prevent and treat multi-organ dysfunction and improve outcomes in critically ill trauma patients. Dr. Douin has assembled a multidisciplinary team of mentors with extensive clinical and translational research experience and topical expertise in traumatic injury, critical care, clinical trials, endothelial function, and lung injury to ensure his success in achieving the stated specific aims and career goals. This proposal will allow Dr. Douin to transition to an independent physician-scientist and prepare him for future NIH R61/R33 funding and, eventually, NIH UG3/UH3 or R01 funding.