Endothelial injury and repair following hemorrhagic shock

失血性休克后的内皮损伤与修复

• 批准号: 9767269
• 负责人: Rosemary A Kozar
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767269
• 关键词: Binding; Biology; Blood Vessels; Caring; Cause of Death; Cell surface; Cessation of life; Coin; Data; Depressed mood; Down-Regulation; Early-life trauma; Endothelial Cells; Endothelium; Failure; Fibrinogen; Functional disorder; Glycocalyx; Hemorrhage; Hemorrhagic Shock; Heparitin Sulfate; Impairment; Inflammation; Injury; Knowledge; Lung; MicroRNAs; Modernization; Mus; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Phenocopy; Plasma; Proteoglycan; Reporting; Research; Resuscitation; Role; Severities; Shock; Signal Pathway; Structure; Survivors; Testing; Therapeutic; Time; Transfusion; Trauma; United States National Institutes of Health; Vertebral column; age group; burden of illness; experimental study; human study; improved; improved outcome; injured; injury and repair; innovation; insight; loss of function; lung injury; mortality; novel; protective effect; syndecan; therapeutic target

Project Summary/Abstract Trauma is the third leading cause of death. Of these deaths, hemorrhage remains the number one cause of early trauma deaths, though reductions in early mortality have occurred from modern resuscitation strategies. Further reductions in early deaths and later reductions in multi-organ failure (MOF) in survivors of hemorrhage represent opportunities to further improve care after hemorrhagic shock (HS). Our efforts are focused on reversal of the dysfunctional endothelium that follows trauma and HS, coined the “endotheliopathy of trauma” (EoT). We were the first to demonstrate in patients that syndecan-1 (Sdc1), a cell surface proteoglycan, is shed after trauma and that shedding was associated with poor outcomes. However, much less is known about Sdc1 expression and its effect on the endothelium, representing a gap in our knowledge. In our efforts to define the mechanisms for Sdc1 downregulation, we discovered that microRNA-19b (miR-19b) targets Sdc1, phenocopies the effects of HS in reducing Sdc1 expression, and contributes to the EoT, novel observations. Our data also demonstrates that miR-19b may be a therapeutic target, as antagomiRs reverse the deleterious effects of Sdc1 downregulation. We will also show that fibrinogen, as a key component in plasma and as an isolated therapeutic, co-localizes and engages Sdc1 on the endothelial cell surface to enhance Sdc1 expression, reduce miR-19b expression, and restore barrier integrity. Low systemic concentrations of fibrinogen after trauma are associated with increased severity of injury and are predictive of mortality. Nonetheless, in the US standard practice is to replace fibrinogen (using cryoprecipitate) only once levels are depressed and late during massive transfusion. Results of this study will support a major change in practice to include the early use of fibrinogen as an endothelial protector to lessen MOF and decrease mortality. Our preliminary data support the novel hypothesis that miRNA-19b-induced downregulation of Sdc1 following HS leads to breakdown of endothelial cell barrier integrity. We further hypothesize that fibrinogen restores endothelial cell Sdc1 expression by inhibiting miR-19b, engaging with Sdc1 on the cell surface, and activating PAK1 to restore barrier integrity and mitigate lung injury. We will test our hypotheses by pursuing the following aims: SA 1. Determine the role of miR-19b on endothelial cell Sdc1 downregulation following hemorrhagic shock and the pulmonary protective effects of miR-19b antagomiRs and SA2. Examine the mechanism by which fibrinogen enhances endothelial cell Sdc1 expression and mitigates lung injury after hemorrhagic shock. Our proposal puts forth innovative concepts and novel mechanisms that offer a new paradigm for the reversal of the EOT. This has significant implication to hemorrhagic shock pathogenesis and treatment, and miRNA biology along with the potential to improve outcomes and reduce deaths after hemorrhagic shock.

项目概要/摘要 创伤是第三大死因。在这些死亡中，出血仍然是第一大原因 早期创伤死亡，尽管现代复苏策略已经降低了早期死亡率。 进一步减少出血幸存者的早期死亡和后期多器官衰竭（MOF） 代表了进一步改善失血性休克（HS）后护理的机会。我们的努力集中在逆转 创伤和 HS 后出现的功能失调的内皮细胞，创造了“创伤性内皮病”(EoT)。我们 第一个在患者身上证明 Syndecan-1 (Sdc1)（一种细胞表面蛋白聚糖）在创伤后会脱落 并且脱落与不良结果相关。然而，人们对 Sdc1 表达知之甚少 及其对内皮细胞的影响，代表了我们的知识空白。在我们努力定义机制的过程中 对于 Sdc1 下调，我们发现 microRNA-19b (miR-19b) 靶向 Sdc1，表型复制了 HS 减少 Sdc1 表达，并有助于 EoT，新颖的观察结果。我们的数据还表明 miR-19b 可能是一个治疗靶点，因为 antagomiR 可以逆转 Sdc1 下调的有害影响。 我们还将证明纤维蛋白原作为血浆中的关键成分和作为一种单独的治疗剂，共定位 并与内皮细胞表面的 Sdc1 结合，增强 Sdc1 表达，减少 miR-19b 表达， 恢复屏障完整性。创伤后纤维蛋白原的全身浓度低与纤维蛋白原增加有关 损伤的严重程度并可预测死亡率。尽管如此，在美国，标准做法是替代纤维蛋白原 （使用冷沉淀）仅在水平下降且在大量输血期间晚期时才进行。本研究结果 将支持实践中的重大改变，包括早期使用纤维蛋白原作为内皮保护剂，以减少 MOF 并降低死亡率。 我们的初步数据支持以下新假设：miRNA-19b 诱导 Sdc1 下调 HS 会导致内皮细胞屏障完整性破坏。我们进一步假设纤维蛋白原恢复 通过抑制 miR-19b、与细胞表面的 Sdc1 结合并激活内皮细胞 Sdc1 表达 PAK1 可恢复屏障完整性并减轻肺损伤。我们将通过以下方式检验我们的假设 目的：SA 1.确定miR-19b对失血性休克后内皮细胞Sdc1下调的作用 以及 miR-19b antagomirs 和 SA2 的肺保护作用。检查其机制 纤维蛋白原增强内皮细胞 Sdc1 表达并减轻失血性休克后的肺损伤。我们的 提案提出了创新概念和新颖机制，为扭转现状提供了新范式 环氧乙烷。这对失血性休克的发病机制和治疗以及 miRNA 生物学具有重要意义 以及改善失血性休克后的结果和减少死亡的潜力。