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

基本信息

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
项目类别：
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

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

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项目摘要

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项目摘要：严重的创伤是死亡和残疾的重要原因。在康复的早期，它会导致 2出血，血栓形成和多器官功能障碍综合征；后来在康复中促进了病理学 3组织修复和体内平衡，可防止恢复日常生活的活动。严重的创伤与死亡有关 4和残疾与凝血的病理激活的激活程度直接相关（创伤 5诱导凝血病（TIC））和炎症（系统性炎症综合征（SIRS））提示 6减轻TIC和/或SIRS会减少因严重创伤引起的并发症。有关键知识 7关于TIC和SIRS的分子刺激的差距严重创伤。我们的初步数据支持 8一种变革性假设，它实现了不适当的纤溶酶早期激活，这是主要蛋白酶的早期激活 9纤维蛋白水解系统对于组织修复和稳态必不可少，是启动TIC和SIRS的关键事件， 10还导致纤溶酶活性长期丧失，破坏了组织修复和稳态。前提： 11孤立的创伤后，纤溶酶原活化受到严格调节，并限于伤口部位。 12然而，在严重的创伤之后，纤溶酶被系统地激活（高纤维蛋白溶解），然后延长 13纤溶酶活性（低纤维蛋白溶解）的缺陷，这两种溶解都与不良预后有关。我们的中心 14假设是（i）严重创伤后的早期过度纤维蛋白溶解是由TIC和SIRS的主要加速， 15（ii）早期高纤维蛋白溶解通过耗尽纤溶酶原质会导致低纤维蛋白溶解，而（iii）获得的 16纤溶酶原缺乏是病理组织稳态和修复的驱动力。方法和方法： 17采用鼠烧伤作为严重创伤的代表性模型，我们将在AIM 1中确定是否是否 18早期高纤维蛋白溶解加速了TIC和SIRS，在AIM 2中，早期高纤维蛋白溶解是否会引起晚期 19持续的低纤维蛋白溶解。纤溶酶活性将在药理学上抑制/增强和测量 20种新型分子工具。 TIC和SIRS将通过既定生物标志物，血小板的序列分析进行评估 21功能和器官特异性NF-κB定量作为多器官功能障碍综合征的替代度量。 22纤维蛋白水解系统将通过量化其各个元素，蛋白酶抑制剂复合物，即评估 23纤维蛋白降解产物和活动测定。接下来，在AIM 3中，我们将将鼠燃烧模型与 24股骨骨折和骨骼肌损伤模型，以评估晚期低纤维蛋白溶解是否引起骨相关 25种病理；特别受损的骨折愈合，肌肉中的异位骨化和创伤引起的 26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阻止了这些骨骼 27并发症以及骨病理过程的多大程度是由于纤维蛋白或纤维蛋白介导的 28炎症。如果是真的，这些发现将提供支持1）抑制纤溶酶原 29早期康复期间的激活，部分预防TIC和SIRS，以及2）纤溶酶原复苏， 30或在恢复后期促进纤维蛋白溶解的替代方法，以保留骨骼健康。