Prevention and management of perioperative pulmonary embolism

围手术期肺栓塞的预防和处理

基本信息

批准号：
8723275
负责人：
Douglas Brock Cines
金额：
$ 39.38万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/8723275
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 radiotracer receptor receptor binding risk benefit ratio urokinase inhibitor vasoconstriction

项目摘要

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）是一种常见的手术后并发症，管理为次优。在术后期间，使用纤溶酶原激活剂（PA）仅限于具有下辅助或大规模PE的患者，否则有资格进行栓塞切除术，因为它缺乏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和新的手段来避免此问题。我们最近的研究有助于解释我们称之为“肺纤维蛋白水解悖论”的内容。我们的发现暗示脂蛋白受体相关的激活蛋白受体（LRP1）和N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）在UPA（和TPA）的肺脉管系统中（和TPA）中破坏了肺动脉EC屏障功能，并消除了血管张力，从而抵消了纤维氨基溶解的北极溶解益处。我们假设UPA通过LRP1信号在部分阻塞的低氧血管中诱导血管收缩，同时激活良好的段中的NMDAR，这会产生导致血管舒张的压倒信号。这使血液中的血液不足，并加剧通风/灌注不匹配。幸运的是，我们已经成功地隔离了UPA的有益的非纤维蛋白水解血管活性效应，UPA的纤维蛋白水解活性是由不同的区域介导的，这些域可能被特定的肽和受体拮抗剂阻止，并被特定的UPA突变体绕开。 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血管收缩通过评估低氧和体外正常氧条件下LRP和NMDAR的贡献，并评估新型“血管鼻” UPA变体的疗效。在AIM 2中，我们将在亚质量PE模型中评估血管活性，纤维蛋白溶解和临床结果之间的关系，并提出了“ vasoneutral” UPA变体的提高有效性。在AIM 3中，我们将探索靶向RBC靶向的血管中性UPAS的血栓性蛋白质潜能，这些脉管中性UPA会形成纤维蛋白内通道，这些通道允许在不影响术后术后止血止血细胞的情况下快速运输红细胞到拯救缺血组织。因此，我们的研究具有直接的转化相关性，因为它们：1）确定一种损害PAS临床功效的新型受体，激动剂，受体和抑制剂，2）可以通过重新设计UPA来绕过的过程，3）描述一种新的方法，我们希望对安全性和有效的血栓性甲基动物进行新的方法，希望我们能够改善毛骨动管计治疗和PEERESERATIC PERESERTIC PERESERTIC PERESERTION PERESERTION PERESERTION PERESERTIC PERESERTIC PERESERTION PEERESTION fRECERTION PERESERTION PEREDICTION PEESERTION cORETICTY pEPERTION和PEE。