Platelets and microvascular thrombosis in inflammation

炎症中的血小板和微血管血栓形成

• 批准号: 9262053
• 负责人: ROLANDO E RUMBAUT
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262053
• 关键词: Address; Adhesions; Adhesives; Admission activity; Adult; Blood Cells; Blood Platelets; Blood Vessels; Blood coagulation; Cause of Death; Cell Wall; Cellular Structures; Coagulation Process; Critical Illness; Data; Diagnosis; Disease; Endothelial Cells; Endotoxemia; Endotoxins; Functional disorder; Future; Goals; Gram-Negative Bacteria; Healthcare Systems; Hemostatic function; Histones; Immobilization; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intensive Care Units; Kinetics; Knowledge; Laboratories; Link; Mediating; Modeling; Nuclear Proteins; Organ; Patient-Focused Outcomes; Patients; Platelet Activation; Platelet aggregation; Property; Publishing; Reporting; Research; Role; Sepsis; Sickle Cell Anemia; System; TLR4 gene; Techniques; Therapeutic; Thrombosis; Thrombotic Thrombocytopenic Purpura; Thrombus; Time; United States; Veterans; Work; base; clinically significant; experimental study; extracellular; improved outcome; in vivo; interest; intravital microscopy; mortality; neutrophil; prevent; programs; public health relevance; release factor; response; von Willebrand Factor

 DESCRIPTION (provided by applicant): Microvascular thrombosis and inflammation are interrelated in a variety of illnesses including sepsis, the body's inflammatory response to an infection. Sepsis is the most common admission diagnosis in intensive care units in the VA system and the leading cause of death in adult intensive care units in the United States. Veterans with sepsis and organ dysfunction have >50% mortality and microvascular thrombosis is implicated in organ dysfunction in sepsis. Thus, understanding the mechanisms responsible for microvascular thrombosis has major clinical significance to the VA health care system. Platelets are increasingly recognized to be important mediators of the inflammatory response, in addition to their well-established role in hemostasis and thrombosis. Recent work from this laboratory demonstrates that endotoxin, a major component of the cell wall of gram-negative bacteria, promotes microvascular platelet thrombus formation in vivo via toll-like receptor 4 (TLR4) on platelets. Endotoxin and platelet TLR4 promote release of histones, nuclear proteins that may also link inflammation, platelet activation and thrombosis. Our preliminary data show that histones promote microvascular thrombosis, they activate platelets and they induce endothelial cells to release von Willebrand factor (VWF). This proposal will address the mechanisms by which platelet TLR4 and histones promote microvascular thrombosis. The central hypothesis is that platelet TLR4 mediates microvascular thrombosis in endotoxemia via microparticles and histone-induced VWF release. The proposal will utilize in vivo and in vitro techniques; in vivo it will utilize two intravital microscopy modls well established in our lab and others. These models allow assessment of the kinetics of microvascular thrombosis and platelet- endothelial adhesive interactions in real-time. In vitro experiments involve assessment of platelet adhesion to cultured endothelial cells and immobilized substrates under flow and platelet aggregation. Two aims are proposed: Aim 1 will determine the mechanisms by which platelet TLR4 promotes microvascular thrombosis in endotoxemia. Aim 2 will determine the mechanisms by which histones promote microvascular thrombosis. Completion of the proposed experiments will broaden understanding of the links between inflammation and microvascular thrombosis in sepsis, and will provide the basis for future work aimed at preventing microvascular thrombosis in inflammation. The long-term goal is to develop optimal therapeutic approaches for patients with sepsis and other inflammatory diseases.

 描述（由申请人提供）： 微血管血栓形成和炎症在包括脓毒症在内的多种疾病中相互关联，脓毒症是退伍军人管理局系统重症监护病房最常见的入院诊断，也是成人重症监护病房死亡的主要原因。美国，患有脓毒症和器官功能障碍的退伍军人的死亡率>50%，并且微血管血栓形成与脓毒症的器官功能障碍有关，因此，了解微血管血栓形成的机制对于 VA 医疗保健系统具有重要的临床意义。除了在止血和血栓形成中的明确作用外，人们越来越认识到内毒素是炎症反应的重要介质。该实验室最近的工作表明，内毒素是革兰氏阴性细菌细胞壁的主要成分，可促进微血管血小板的形成。体内血栓通过血小板上的 Toll 样受体 4 (TLR4) 形成，血小板 TLR4 促进组蛋白、核蛋白的释放，这些蛋白也可能与炎症、血小板活化和血栓形成有关。我们的初步数据表明，组蛋白促进微血管血栓形成，它们激活血小板并诱导内皮细胞释放血管性血友病因子（VWF）。该提案将解决血小板TLR4和组蛋白促进微血管血栓形成的机制。中心假设是血小板TLR4。通过微粒和组蛋白诱导的 VWF 释放介导内毒素血症中的微血管血栓形成该提案将利用体内和体外两种技术；我们的实验室和其他实验室已经建立了显微模型，这些模型可以实时评估微血管血栓形成和血小板-内皮粘附相互作用的动力学，包括评估血小板在流动和血小板下对培养的内皮细胞和固定基质的粘附。提出了两个目标：目标 1 将确定血小板 TLR4 促进内毒素血症中微血管血栓形成的机制。组蛋白促进微血管血栓形成的实验的完成将加深对脓毒症中炎症和微血管血栓形成之间联系的理解，并为未来旨在预防炎症中微血管血栓形成的工作奠定基础。败血症和其他炎症性疾病患者的最佳治疗方法。