Severe Trauma Provokes Pathologic Continuum of Plasmin Activation

严重创伤引发纤溶酶激活的病理连续体

• 批准号: 10080741
• 负责人: Jonathan Schoenecker
• 金额: $ 45.84万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080741
• 关键词: Ablation; Activities of Daily Living; Acute-Phase Reaction; Alteplase; Antisense Oligonucleotides; Attenuated; Biological Assay; Biological Markers; Biomechanics; Blood Coagulation Disorders; Blood Platelets; Bolus Infusion; Bone Injury; Bone Regeneration; Bone Tissue; Burn injury; Cause of Death; Cells; Cessation of life; Coagulation Process; Complex; Convalescence; Data; Diagnostic radiologic examination; Dorsal; Due Process; Elements; Endothelial Cells; Event; Femoral Fractures; Fibrin; Fibrin split products; Fibrinogen; Fibrinolysis; Fracture; Fracture Healing; Functional disorder; Generations; Genetic; Growth Factor; Hemorrhage; Heterotopic Ossification; Histologic; Histological Techniques; Homeostasis; Impairment; Individual; Inflammation; Inflammatory; Injury; Knowledge; Life; Measures; Mediating; Methods; Modeling; Molecular; Monitor; Mus; Muscle; Musculoskeletal; Mutation; Organ; Osteoporosis; Outcome; Pathologic; Pathologic Processes; Pathology; Patients; Peptide Hydrolases; Pharmacology; Phase; Plasmin; Plasmin Inhibitor; Plasminogen; Plasminogen Activator; Pre-Clinical Model; Protease Inhibitor; Recombinants; Resuscitation; Serine Protease; Site; Skeletal muscle injury; Syndrome; System; Systemic Inflammatory Response Syndrome; Testing; Therapeutic; Thrombosis; Tissues; Trauma; Trauma patient; Work; bone; bone health; bone preservation; bone quality; burn model; chronic pain; disability; early experience; exhaust; heat injury; in vivo; long bone; lysine analog; macrophage; microCT; novel; platelet function; prevent; repaired; severe burns; soft tissue; stem cells; tissue repair; tool; trauma induced coagulopathy; wound

1 Project Summary: Severe trauma is a significant cause of death and disability. Early in convalescence, it causes 2 bleeding, thrombosis and multi-organ dysfunction syndrome; later in convalescence, it instigates pathologic 3 tissue repair and homeostasis, which prevents return to activities of daily living. Severe trauma related death 4 and disability is directly correlated with the degree of activation of pathologic activation of coagulation (trauma- 5 induce coagulopathy (TIC)) and inflammation (systemic inflammatory response syndrome (SIRS)) suggesting 6 that mitigating TIC and/or SIRS would reduce complications caused by severe trauma. There is a key knowledge 7 gap regarding the molecular instigators of TIC and SIRS following severe trauma. Our preliminary data support 8 a transformative hypothesis that implicates inappropriate early activation of plasmin, the principle protease of 9 the fibrinolytic system essential for tissue repair and homeostasis, as a key event that initiates TIC and SIRS, 10 that also results in a prolonged loss of plasmin activity that disrupts tissue repair and homeostasis. Premise: 11 Following an isolated trauma, plasminogen activation is tightly regulated and restricted to the wound site. 12 However, following a severe trauma, plasmin is systemically activated (hyperfibrinolysis) followed by a prolonged 13 deficit of plasmin activity (hypofibrinolysis), both of which are associated with poor outcomes. Our central 14 hypothesis is that (i) early hyperfibrinolysis following severe trauma is a primary accelerant of TIC and SIRS, 15 (ii) early hyperfibrinolysis causes hypofibrinolysis by exhausting plasminogen, and that (iii) the acquired 16 plasminogen deficiency is a driver of pathologic tissue homeostasis and repair. Methods & Approach: 17 Employing a murine burn injury as a representative model of severe trauma, we will determine in Aim 1 whether 18 early hyperfibrinolysis accelerates TIC and SIRS and in Aim 2 whether early hyperfibrinolysis causes late 19 sustained hypofibrinolysis. Plasmin activity will be pharmacologically inhibited/enhanced and measured using 20 novel molecular tools. TIC and SIRS will be assessed with serial analysis of established biomarkers, platelet 21 function, and organ specific NF-κB quantification as a surrogate measure of multiorgan dysfunction syndrome. 22 The fibrinolytic system will be assessed by quantifying its individual elements, protease-inhibitor complexes, 23 fibrin degradation products, and activity assays. Next, in Aim 3 we will combine the murine burn model with a 24 femur fracture and skeletal muscle injury model to assess whether late hypofibrinolysis causes bone-related 25 pathologies; specifically impaired fracture healing, heterotopic ossification in muscle, and trauma-induced 26 osteoporosis. At the molecular level, we will determine if restoring plasmin activity prevents these bone 27 complications and to what extent of the bone pathologic processes are due to fibrin, or fibrin mediated 28 inflammation. Taken together, if true, these findings would provide support for 1) inhibition of plasminogen 29 activation during the early convalescence to prevent, in part, TIC and SIRS and 2) resuscitation of plasminogen, 30 or alternative means of promoting fibrinolysis, during late convalescence, to preserve bone health.

1项目概述：严重创伤是导致死亡和残疾的重要原因。在康复初期， 2出血、血栓形成和多器官功能障碍综合征;恢复期后期， 3组织修复和体内平衡，阻止恢复日常生活活动。严重创伤相关死亡 4和残疾是直接相关的程度激活的病理激活凝血（创伤- 5诱导凝血病（TIC））和炎症（全身炎症反应综合征（SIRS）），表明 6减轻TIC和/或SIRS将减少严重创伤引起的并发症。有一个关键的知识 7关于严重创伤后TIC和SIRS的分子煽动者的差距。我们的初步数据支持 图8是一个变革性的假设，它暗示纤溶酶的早期激活不适当，纤溶酶是纤溶酶的主要蛋白酶。 纤维蛋白溶解系统是组织修复和体内平衡所必需的，是引发TIC和SIRS的关键事件， 10，这也导致纤溶酶活性的长期丧失，从而破坏组织修复和体内平衡。前提条件： 11.在孤立创伤后，纤溶酶原激活受到严格调节并局限于伤口部位。 12然而，在严重创伤后，纤溶酶被全身激活（纤溶亢进），随后是长时间的 13纤溶酶活性缺陷（纤溶功能减退），两者均与不良结局相关。我们的中央 14假设是（i）严重创伤后的早期纤维蛋白溶解亢进是TIC和SIRS的主要促进剂， 15（ii）早期纤溶亢进通过耗尽纤溶酶原引起纤溶减退，以及（iii）获得性纤溶亢进， 16纤溶酶原缺乏是病理组织稳态和修复的驱动因素。方法和途径： 17采用鼠烧伤作为严重创伤的代表性模型，我们将在目标1中确定是否 18早期纤溶亢进加速TIC和SIRS，目的2是否早期纤溶亢进导致晚期 19例持续性低纤溶。纤溶酶活性将被显著抑制/增强，并使用 20种新型分子工具。TIC和SIRS将通过对已建立的生物标志物、血小板和血小板计数的系列分析进行评估。 21功能，以及器官特异性NF-κB定量作为多器官功能障碍综合征的替代指标。 22纤溶系统将通过量化其单个元素、蛋白酶-抑制剂复合物、 23纤维蛋白降解产物和活性测定。接下来，在目标3中，我们将联合收割机将鼠烧伤模型与 24股骨骨折及骨骼肌损伤模型评估是否迟发性纤溶低下引起骨相关性 25种病理;特别是骨折愈合受损、肌肉异位骨化和创伤诱导 26例骨质疏松症。在分子水平上，我们将确定恢复纤溶酶活性是否能阻止这些骨 27并发症和骨病理过程的程度是由于纤维蛋白或纤维蛋白介导的 28炎症综合起来，如果是真的，这些发现将支持1）抑制纤溶酶原 29在早期恢复期激活以部分预防TIC和SIRS，和2）纤溶酶原的复苏， 30或促进纤维蛋白溶解的替代手段，以保持骨骼健康。