Role of heparin binding growth factors in vascular leakage and fatal bleeding

肝素结合生长因子在血管渗漏和致命性出血中的作用

• 批准号: 9111036
• 负责人: PATRICIO E RAY
• 金额: $ 43万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111036
• 关键词: ANGPT1 gene; Affect; Angiotensin II; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Arteries; Biological Assay; Biological Markers; Blood Circulation; Blood Coagulation Disorders; Blood Pressure; Blood Vessels; Capillary Leak Syndrome; Capillary Permeability; Cardiopulmonary Bypass; Child; Clinical; Coagulants; Critically ill children; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Data; Development; Early identification; Early treatment; Endothelial Cells; Equilibrium; Event; Extracorporeal Membrane Oxygenation; Extravasation; FGF2 gene; Functional disorder; Growth; Health; Hemorrhage; Heparin; Heparin Binding; Heparin Binding Growth Factor; Hypotension; Inflammatory; Intervention; Intestines; Knowledge; Mesentery; Mus; Nitric Oxide; Organ; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Permeability; Pharmaceutical Preparations; Plasma; Play; Postoperative Period; Procedures; Process; Regulation; Resistance; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Testing; Urine; Vascular Endothelial Growth Factors; Vascular Permeabilities; base; candidate marker; cytokine; high risk; improved; inhibitor/antagonist; mouse model; novel; prevent; prospective; research study; rho; ANGPT1 gene; Affect; Angiotensin II; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Arteries; Biological Assay; Biological Markers; Blood Circulation; Blood Coagulation Disorders; Blood Pressure; Blood Vessels; Capillary Leak Syndrome; Capillary Permeability; Cardiopulmonary Bypass; Child; Clinical; Coagulants; Critically ill children; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Data; Development; Early identification; Early treatment; Endothelial Cells; Equilibrium; Event; Extracorporeal Membrane Oxygenation; Extravasation; FGF2 gene; Functional disorder; Growth; Health; Hemorrhage; Heparin; Heparin Binding; Heparin Binding Growth Factor; Hypotension; Inflammatory; Intervention; Intestines; Knowledge; Mesentery; Mus; Nitric Oxide; Organ; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Permeability; Pharmaceutical Preparations; Plasma; Play; Postoperative Period; Procedures; Process; Regulation; Resistance; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Testing; Urine; Vascular Endothelial Growth Factors; Vascular Permeabilities; base; candidate marker; cytokine; high risk; improved; inhibitor/antagonist; mouse model; novel; prevent; prospective; research study; rho

 DESCRIPTION (provided by applicant): Critically ill children treated with heparin during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB), are at high risk of developing severe capillary leak syndromes (CLS) and excessive bleeding (EB). These events are attributed to multifactorial causes, including inflammatory cytokines and the anti-coagulant activity of heparin. Very little is known, however, about the role that heparin-binding angiotenic growth factors (HBGFs), acting in synergy with heparin-like drugs, play in this process. A nonsurgical intervention that can effectively control postoperative vascular leakage and bleeding is needed. This proposal is based on our novel observation that Fibroblast Growth Factor-2 (FGF-2), a heparin binding angiogenic growth factor, plays a critical role precipitating lethal bleeding disorders in mice treated with heparin-like drugs. In addition, we found that Angiopoietin-1 (Ang-1), an anti-permeability-anti-inflammatory angiogenic growth factor, can prevent lethal bleeding complications in mice without normalizing their anticoagulant status. Based on these findings, we hypothesize that FGF-2 and other HBGFs, tip the balance to precipitate CLS and EB by inducing changes in vascular tone and permeability in combination with heparin-like drugs. Furthermore, we propose that blocking the permeability signaling pathways induced by heparin + FGF-2 will prevent these complications. Finally, we hypothesize that FGF-2 and other HBGFs will become reliable biomarkers to identify children at high risk of developing CLS and EB. Three aims will be explored. In aim 1, will test the hypothesis that heparin, in synergy with FGF-2, induce vascular leakage and bleeding complications by affecting the vascular activity of Angiotensin II (Ang II), VEGF-A, and nitric oxide (NO). In aim 2 we will identify the basic mechanisms through with Ang-1 prevents the development of severe bleeding complications induced by heparin + FGF-2, and test the hypothesis that blocking the Rho-A, Src, Tek (Tie-2) and other signaling - inflammatory pathways will prevent lethal bleeding complications in mice. In aim 3, we will follow the clinical outcome of children treated with ECMO and CPB, and define the clinical value of FGF-2 and other HBGFs as biomarkers to identify children at risk of developing severe CLS and EB. These experiments will generate new knowledge and treatments to prevent CLS and EB in children treated with ECMO and CPB, and establish the new notion that blocking the early capillary permeability changes induced by heparin + FGF-2 will prevent CLS and EB in these patients without normalizing their anti-coagulant status.

 描述（由适用提供）：在体外膜氧合（ECMO）和心肺旁路（CPB）期间接受肝素治疗的重症儿童患有严重毛细血管泄漏综合征（CLS）和多余的出血（EB）的高风险。这些事件归因于多因素原因，包括炎症细胞因子和肝素的抗凝蛋白活性。然而，关于与肝素样药物的作用在此过程中起着肝素结合的血管融合生长因子（HBGF）的作用，知之甚少。需要一种非外科干预措施，可以有效控制术后血管泄漏和出血。该建议基于我们的新观察结果，即成纤维细胞生长因子2（FGF-2）是一种肝素结合血管生长生长因子，在用肝素样药物治疗的小鼠中促成致命性出血疾病的关键作用。此外，我们发现Angiopietin-1（Ang-1）是一种抗渗透性 - 抗炎性血管生长因子，可以防止小鼠的致死性出血并发症而不使其抗凝状态归一化。基于这些发现，我们假设FGF-2和其他HBGF会通过诱导的血管张力变化和与肝素样药物结合诱导的血管张力变化和渗透性，使平衡促进CLS和EB。此外，我们建议阻止肝素 + FGF-2引起的渗透性信号通路将阻止这些并发症。最后，我们假设FGF-2和其他HBGF将成为可靠的生物标志物，以确定患有CLS和EB的高风险的儿童。将探索三个目标。在AIM 1中，将检验以下假设：肝素与FGF-2协同作用，通过影响血管紧张素II（ANG II），VEGF-A和一氧化氮（NO）的血管活性来诱导血管泄漏和出血并发症。在AIM 2中，我们将通过ANG-1确定基本机制，以防止肝素 + FGF-2引起的严重出血并发症的发展，并检验以下假设：阻止Rho-A，SRC，TEK，TIE-2（TIE-2）和其他信号传导 - 炎症途径 - 炎症途径将阻止小鼠的致死性出血。在AIM 3中，我们将遵循ECMO和CPB治疗的儿童的临床结果，并将FGF-2和其他HBGF的临床价值定义为生物标志物，以鉴定有患有严重CLS和EB的风险的儿童。这些实验将产生新的知识和治疗方法，以防止接受ECMO和CPB治疗的儿童中的CLS和EB，并确定新的观念，即阻止肝素 + FGF-2引起的早期毛细血管渗透率变化会阻止这些患者的CLS和EB，而不会使他们的抗凝结状态正常化。