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

 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（由申请人提供）：在体外膜肺氧合（ECMO）和心肺转流（CPB）期间接受肝素治疗的重症儿童，发生严重毛细血管渗漏综合征（CLS）和出血过多（EB）的风险较高。这些事件可归因于多因素原因，包括炎性细胞因子和肝素的抗凝活性。然而，关于肝素结合血管紧张生长因子（HBGFs）与肝素样药物协同作用在此过程中的作用知之甚少。需要一种能有效控制术后血管渗漏和出血的非手术干预。这一建议是基于我们的新观察，即成纤维细胞生长因子-2（FGF-2），一种肝素结合的血管生成生长因子，在用肝素样药物治疗的小鼠中起着促成致命出血疾病的关键作用。此外，我们发现血管生成素-1（Ang-1），一种抗渗透性抗炎性血管生成生长因子，可以预防小鼠致命的出血并发症，而不使其抗凝状态正常化。基于这些发现，我们假设FGF-2和其他HBGF通过与肝素样药物联合诱导血管张力和渗透性的变化来平衡沉淀CLS和EB。此外，我们建议阻断肝素+ FGF-2诱导的渗透性信号通路将预防这些并发症。最后，我们假设FGF-2和其他HBGF将成为可靠的生物标志物，以确定儿童在发展CLS和EB的高风险。将探讨三个目标。在目的1中，将检验肝素与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）的血管活性而诱导血管渗漏和出血并发症的假设。在目标2中，我们将鉴定通过Ang-1预防由肝素+ FGF-2诱导的严重出血并发症的发展的基本机制，并测试阻断Rho-A、Src、Tek（Tie-2）和其他信号传导-炎症途径将预防小鼠中的致命出血并发症的假设。在目标3中，我们将跟踪接受ECMO和CPB治疗的儿童的临床结果，并定义FGF-2和其他HBGFs作为生物标志物的临床价值，以识别有发生严重CLS和EB风险的儿童。这些实验将产生新的知识和治疗方法，以预防ECMO和CPB治疗的儿童中的CLS和EB，并建立新的概念，即阻断肝素+ FGF-2诱导的早期毛细血管通透性变化将预防这些患者中的CLS和EB，而不会使其抗凝状态正常化。