Prevention and management of perioperative pulmonary embolism

围手术期肺栓塞的预防和处理

• 批准号: 8421570
• 负责人: Douglas Brock Cines
• 金额: $ 39.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8421570
• 关键词: Address; Adverse effects; Affect; Agonist; Alteplase; Alveolar; Animals; Antibodies; Attenuated; Binding; Binding Sites; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Blood flow; Bypass; Caliber; Chimeric Proteins; Clinical; Clinical effectiveness; Coagulation Process; Coronary; Coupling; Cytolysis; Development; Dose; Echocardiography; Effectiveness; Embolectomy; Embolism; Endothelial Cells; Engineering; Environmental air flow; Epitopes; Erythrocytes; Fibrinolysis; Fluorescein-5-isothiocyanate; Gases; Hemorrhage; Hemostatic Agents; Human; Hypoxemia; Hypoxia; Imaging Techniques; Immunoglobulin Variable Region; In Vitro; Intravenous; Lipoprotein Receptor; Lipoproteins; Low-Density Lipoproteins; Lung; Lung diseases; Magnetic Resonance Imaging; Mediating; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Odds Ratio; Outcome; Oxygen measurement, partial pressure, arterial; Pathway interactions; Patients; Penetration; Peptide Receptor; Perfusion; Perioperative; Permeability; Plasminogen Activator; Postoperative Period; Prevention; Process; Pulmonary Embolism; Recombinants; Reperfusion Therapy; Risk; Safety; Series; Signal Transduction; Slice; Smooth Muscle Myocytes; Surgical complication; System; Testing; Thrombus; Tissues; Urokinase; Variant; Vascular Permeabilities; Vasodilation; Venous; clinical efficacy; clinical risk; improved; in vivo; inhibitor/antagonist; insight; minimal risk; mutant; novel; novel strategies; prevent; public health relevance; radiotracer; receptor; receptor binding; risk benefit ratio; urokinase inhibitor; vasoconstriction

DESCRIPTION (provided by applicant): Pulmonary embolism (PE) is a common post-surgical complication for which management is suboptimal. Use of plasminogen activators (PA) in the post-operative period is restricted to patients with submassive or massive PE otherwise eligible for embolectomy because of its lack of proven clinical effectiveness and risk of hemorrhage. There is a pressing need to better understand why lysis of PE fails to generate better outcomes and new means to circumvent this problem. Our recent studies help to explain what we term the "pulmonary fibrinolytic paradox". Our findings implicate activation of lipoprotein receptor-related protein receptor (LRP1) and N-methyl-D-aspartate (NMDA) receptors (NMDARs) in the pulmonary vasculature by uPA (and tPA) which disrupts pulmonary arterial EC barrier function and deregulates vascular tone, offsetting the salutary benefits of fibrinolysis. We hypothesize that uPA signals through LRP1 to induce vasoconstriction in partially occluded hypoxic vessels, while activating NMDARs in well-perfused segments, which generates an overriding signal that leads to vasodilation. This diverts blood from underperfused ischemic segments and exacerbates ventilation/perfusion mismatch. Fortunately, we have successfully segregated the deleterious non-fibrinolytic vasoactive effects from the salutary fibrinolytic activity of uPA, sho each is mediated by distinct domains that can be blocked by specific peptides and receptor antagonists and bypassed with specific uPA mutants. We will elucidate the receptor-mediated pathways activated by uPA that disrupt pulmonary endothelial barrier function and increase vascular tone and use these insights to develop novel fibrinolytics and delivery systems with a greater benefit to risk ratio for use to prevent and manage PE in the perioperative period through three interrelated Aims: In Aim 1, we will delineate the mechanism of uPA-induced transendothelial self-transport and pulmonary vasoconstriction by assessing of contributions of LRP and NMDAR under hypoxic vs normoxic conditions in vitro and in vivo and assess the efficacy of novel "vasoneutral" uPA variants. In Aim 2, we will assess the relationship between vasoactivity, fibrinolysis and clinical outcome in a model of sub-massive PE and the proposed enhanced effectiveness of "vasoneutral" uPA variants. In Aim 3, we will explore the thromboprophylactic potential of RBC-targeted vasoneutral uPAs that form intrafibrin channels that permit rapid transport of erythrocytes to salvage ischemic tissues prior to complete clot lysi without affecting post-operative hemostatic clots. Thus, our studies are of direct translational relevance because they: 1) identify a novel class of receptors, agonists, receptors and inhibitors that impair the clinical efficacy of PAs, 2) a process that can be bypassed by re-engineering uPA, and 3) describe a new approach to safe and effective thromboprophylaxis that we hope will improve perioperative prevention and treatment of PE.

描述（由申请人提供）：肺栓塞（PE）是一种常见的术后并发症，其治疗效果不佳。术后使用纤溶酶原激活剂 (PA) 仅限于亚大块或大块 PE 患者，否则适合进行取栓术，因为其缺乏经证实的临床有效性和出血风险。迫切需要更好地理解为什么 PE 裂解无法产生更好的结果以及解决这一问题的新方法。我们最近的研究有助于解释我们所说的“肺纤溶悖论”。我们的研究结果表明脂蛋白受体相关的激活 uPA（和 tPA）通过 uPA（和 tPA）作用于肺血管系统中的蛋白受体（LRP1）和 N-甲基-D-天冬氨酸（NMDA）受体（NMDAR），破坏肺动脉 EC 屏障功能并放松血管张力，抵消纤溶的有益益处。我们假设 uPA 通过 LRP1 发出信号，在部分闭塞的缺氧血管中诱导血管收缩，同时在灌注良好的节段中激活 NMDAR，从而产生导致血管舒张的压倒性信号。这会使血液从灌注不足的缺血部位转移，并加剧通气/灌注不匹配。幸运的是，我们已经成功地将有害的非纤溶血管活性作用与有益的uPA纤溶活性分开，每个作用都由不同的结构域介导，这些结构域可以被特定的肽和受体拮抗剂阻断，并被特定的uPA突变体绕过。我们将阐明 uPA 激活的受体介导途径，破坏肺内皮屏障功能并增加血管张力，并利用这些见解开发新型纤溶药物和递送系统，其具有更大的获益风险比，用于通过三个相互关联的目标来预防和管理围手术期 PE：在目标 1 中，我们将描述 uPA 诱导的跨内皮自转运和肺动脉栓塞的机制。 通过在体外和体内低氧与常氧条件下评估 LRP 和 NMDAR 的贡献来评估血管收缩，并评估新型“血管中性”uPA 变体的功效。在目标 2 中，我们将评估次大面积 PE 模型中血管活性、纤维蛋白溶解和临床结果之间的关系，以及“血管中性”uPA 变体的拟议增强有效性。在目标 3 中，我们将探索红细胞靶向血管中性 uPA 的血栓预防潜力，这些 uPA 形成纤维蛋白内通道，允许红细胞在完全血栓溶解之前快速转运至抢救缺血组织，而不影响术后止血凝块。因此，我们的研究具有直接的转化相关性，因为它们：1）确定了一类新的受体、激动剂、受体和抑制剂，这些受体、激动剂、受体和抑制剂会损害 PA 的临床疗效，2）可以通过重新设计 uPA 来绕过这一过程，3）描述一种安全有效的血栓预防新方法，我们希望这种方法能够改善 PE 的围手术期预防和治疗。