Alpha-Defensins in perioperative thrombosis

围手术期血栓形成中的α-防御素

基本信息

批准号：
8903553
负责人：
Abd Alroof HIGAZI
金额：
$ 40万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903553
关键词：
Address Adherence Alteplase Anticoagulants Attenuated Biological Markers Bone Marrow Transplantation Carotid Arteries Clinical Clinical Medicine Coagulation Process Colchicine Complex Confocal Microscopy Cytolysis Cytoplasmic Granules Data Defensins Deposition Disease Dose Drug usage Embolism Enzymes Equilibrium Femoral vein Fibrin Fibrinogen Fibrinolysis Gene Dosage Gene Expression Genetic Guidelines Health Hemorrhage Hemostatic function Human In Vitro Individual Infection Infection prevention Inflammation Investigation Link Lung Measures Mechanics Mediator of activation protein Medical Methods Mus Natural Immunity Nature Neutrophil Activation Operative Surgical Procedures Outcome Patients Peptides Perioperative Permeability Plasma Plasma Cells Platelet Activation Play Populations at Risk Postoperative Period Postphlebitic Syndrome Prevention Process Property Prophylactic treatment Proteins Publishing Resistance Risk Risk Estimate Risk Factors Risk Reduction Role Scanning Electron Microscopy Structure Thromboembolism Thrombosis Thrombus Transgenic Mice Venous Venous Thrombosis Wound Healing alpha-Defensins antimicrobial peptide base biophysical techniques crosslink effective intervention in vivo inhibitor/antagonist injured insight meetings neutrophil novel novel strategies polymerization prevent prophylactic protein expression reconstitution research study

项目摘要

DESCRIPTION (provided by applicant): Surgery increases the risk of thrombosis but prevention and management of thromboembolic disease in the perioperative period is complicated by the risk of hemorrhage. Neutrophils (PMNs) play a vital role in wound healing, but their contribution to perioperative thrombosis and implications for thromboprophylaxis are unclear. Adherence of PMNs to wounds and to the vasculature generates a unique localized sequestrum enriched in enzymes and antimicrobial peptides protected from plasma inhibitors that contribute to innate immunity in part through the orderly formation and dissolution of fibrin. We posit that post-operative and persistent inflammation disrupt this balance, predisposing to thrombosis by promoting formation and persistence of fibrin. We have previously observed that alpha-defensins (α-def), antimicrobial peptides that constitute 5% of total human PMN protein that are released upon activation, promote clotting and inhibit fibrinolysis. The absence of α-def in murine PMNs has hindered a better understanding of how these peptides contribute to thromboembolic disease in the perioperative setting. Using a novel transgenic mouse that expresses PMN α-def (Def++), we show that α-def circulates in a complex with fibrinogen and promotes polymerization and retraction of fibrin in vitro, deposits in the vasculature, induces occlusive arterial and venous thrombosis, and inhibits lysis of pulmonary emboli in vivo. These pathogenic properties can be prevented and possibly reversed by preventing α-def release using colchicine. We now propose an integrated approach to understanding the mechanism and implications of PMN α-def on perioperative thrombosis by examining: a) The biophysical effects of α-def on clot formation and structure~ b) The mechanism of accelerated thrombosis and impaired fibrinolysis in Def++ mice and the salutary effect of blocking α-def release~ and c) The utility of α-def gene and protein expression as biomarkers of risk for venous thrombosis and post-thrombotic syndrome. These studies will provide insight into an unappreciated contribution of PMN α-def to arterial and venous thrombosis, identify novel genetic and protein biomarkers of patients at risk for surgery related thrombosis and provide evidence for the use of a safe and effective intervention to prevent thrombosis in the perioperative period.

描述（由适用提供）：手术增加了血栓形成的风险，但在周期期间预防和治疗血小板疾病的风险因出血风险而复杂。中性粒细胞（PMN）在伤口愈合中起着至关重要的作用，但是它们对周期性血栓形成的贡献及其对血栓预防的影响尚不清楚。 PMN遵守胜利和脉管系统会产生一种独特的局部锁骨，富集于酶和抗菌胡椒中受到的抗菌辣椒剂的侵害，这些粘液剂免受了血浆抑制剂的保护，这些粘液抑制剂通过纤维蛋白的有序形成和溶解。我们先前已经观察到α-防御素（α-脱Fef），抗菌肽，构成在激活，促进服装并抑制纤维蛋白溶解后释放的人类PMN蛋白的5％。在鼠PMN中没有α-DEF的缺乏阻碍了对这些肽在周期性环境中如何促进血栓疾病的方法。使用一种表达PMNα-DEF（DEF ++）的新型转基因小鼠，我们表明，α-二氧化碳圆圈与纤维蛋白原相结合，并促进纤维蛋白在体外的聚合和缩回，在脉管系统中沉积，诱导闭塞的人工锻炼和静脉血栓形成，并抑制肺炎植物溶液的静脉内。可以通过防止秋水仙碱释放α-DEF，可以预防这些致病性能。现在，我们提出了一种综合方法来理解PMNα-DEF对周期性血栓形成的机制和含义：有静脉血栓形成和栓性后综合征风险的生物标志物。这些研究将洞悉PMNα-DEF对动脉和静脉血栓形成的未经批准的贡献，确定具有与手术相关的血栓形成风险的患者的新型遗传和蛋白质生物标志物，并为使用安全有效的干预提供了证据，以防止在周期性期间预防血栓形成。