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.

项目摘要/摘要 创伤是死亡的第三大原因。在这些死亡中，出血仍然是 早期的创伤死亡，尽管现代复苏策略已经降低了早期死亡率。 早期死亡的进一步减少和后来减少多器官失败（MOF）的出血生存 代表了出血性休克（HS）后进一步改善护理的机会。我们的努力专注于逆转 遵循创伤和HS的功能失调的内皮，创造了“创伤的内皮病”（EOT）。我们 是第一个在患者中表现出的患者，Syndecan-1（SDC1）是一种细胞表面蛋白聚糖，在创伤后脱落 脱落与结果不佳有关。但是，关于SDC1表达的知之甚少 以及它对内皮的影响，代表了我们所知的差距。为了定义机制 对于SDC1下调，我们发现MicroRNA-19b（miR-19b）靶向SDC1，表op骨的影响 HS减少SDC1表达，并有助于EOT，新的观察结果。我们的数据也证明了 MiR-19b可能是一个治疗靶标，因为Antagomirs逆转了SDC1下调的有害作用。 我们还将证明纤维蛋白原是血浆中的关键成分，作为孤立的治疗，共定位了 并在内皮细胞表面接合SDC1以增强SDC1表达，降低miR-19b表达和 恢复障碍完整性。创伤后全身性纤维蛋白原的低浓度与增加有关 受伤的严重程度，可以预测死亡率。尽管如此，在美国的标准实践中是替代纤维蛋白原 （使用冷冻沉淀）仅在大规模输血期间降低水平和晚期。这项研究的结果 将支持实践的重大变化，包括早期使用纤维蛋白原作为内皮保护剂来减少 MOF并降低死亡率。 我们的初步数据支持miRNA-19b诱导SDC1下调的新假设。 HS导致内皮细胞屏障完整性的分解。我们进一步假设纤维蛋白原还原 内皮细胞SDC1表达通过抑制miR-19b，在细胞表面与SDC1接合并激活 PAK1恢复障碍完整性并减轻肺部损伤。我们将通过追求以下内容来检验我们的假设 目的：SA 1。确定miR-19b在出血性休克后下调内皮细胞SDC1下调的作用 以及miR-19b antagomirs和SA2的肺部保护作用。检查的机制 纤维蛋白原增强了内皮细胞SDC1的表达，并在出血性休克后减轻肺损伤。我们的 提案提出了创新的概念和新型机制，这些机制为逆转的新范式提供了新的范式 eot。这与出血性休克发病机理和治疗具有重要意义，miRNA生物学 除了改善结果并减少出血性休克后死亡的潜力。