MECHANISMS OF MICROVASCULAR THROMBOSIS IN ENDOTOXEMIA

内毒素血症中微血管血栓形成的机制

• 批准号: 7091768
• 负责人: ROLANDO E RUMBAUT
• 金额: $ 30.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091768
• 关键词: abdomen; cell adhesion molecules; genetically modified animals; glycoproteins; hemodynamics; laboratory mouse; lipopolysaccharides; microcirculation; platelet aggregation; receptor expression; septicemia; thrombosis; toll like receptor; vascular endothelium; video microscopy

DESCRIPTION (provided by applicant): This project will study the mechanisms responsible for microvascular thrombosis in experimental models of sepsis. Sepsis, a systemic response to an infection, is the main cause of death in adult intensive care units in the United States, and microvascular thrombosis is a severe complication of the disease. The main model we will use involves bacterial endotoxin (lipopolysaccharide, LPS), which mediates many manifestations of patients with a common form of sepsis. In addition, we will use a clinically relevant model of human polymicrobial sepsis of abdominal origin, cecal ligation and perforation (CLP). Our preliminary data demonstrate that both sepsis models enhance microvascular thrombosis in vivo; in this project, we will explore the molecular mechanisms involved. Our central hypothesis is that LPS-induced stimulation of toll-like receptor 4 (TLR4) on endothelial cells mediates microvascular thrombosis in endotoxemia, by a mechanism dependent on the platelet adhesive molecule, glycoprotein Ibct. We propose four aims: in aim 1, we will identify which LPS receptors mediate enhancement of microvascular thrombosis in vivo. In aim 2, we will determine whether bone marrow- or non-bone marrow-derived cells mediate LPS- induced responses in vivo. In aim 3, we will use an ex vivo flow system to examine the effects of endotoxemia and CLP on platelet activation and adhesion to specific adhesion molecules (e.g.-vWf, P- selectin, fibrinogen) under physiologic flow. In aim 4, we will use the in vivo model to define the platelet and endothelial adhesion molecules responsible for LPS- and CLP-enhanced microvascular thrombosis. Completion of these aims will broaden our understanding of the mechanisms of microvascular thrombosis in models of human sepsis. This will allow identification of novel therapeutic targets for microvascular thrombosis in this disease. Our long-term goal is to apply the knowledge gained from these studies to allow optimal management of patients with sepsis and their associated microvascular alterations. Relevance to public health: Sepsis, the body's response to an infection, is a major cause of death in the U.S. Our goal is to understand the causes of a severe complication of this illness, clots in tiny blood vessels. This information would help develop new treatments for patients with this devastating illness.

描述（由申请人提供）：该项目将研究脓毒症实验模型中微血管血栓形成的机制。脓毒症是对感染的全身反应，是美国成人重症监护病房的主要原因，而微血管血栓形成是该疾病的严重并发症。我们将使用的主要模型涉及细菌内毒素（脂多糖，LPS），它介导常见脓毒症患者的许多表现。此外，我们将使用腹部起源的人类多种微生物败血症、盲肠结扎和穿孔（CLP）的临床相关模型。我们的初步数据表明，两种脓毒症模型都会增强体内微血管血栓形成。在这个项目中，我们将探索所涉及的分子机制。我们的中心假设是，LPS 诱导的内皮细胞 Toll 样受体 4 (TLR4) 的刺激通过依赖于血小板粘附分子糖蛋白 Ibct 的机制介导内毒素血症中的微血管血栓形成。我们提出了四个目标：在目标 1 中，我们将确定哪些 LPS 受体介导体内微血管血栓形成的增强。在目标 2 中，我们将确定骨髓来源的细胞还是非骨髓来源的细胞是否介导 LPS 诱导的体内反应。在目标 3 中，我们将使用离体流动系统来检查生理流动下内毒素血症和 CLP 对血小板活化和对特定粘附分子（例如-vWf、P-选择素、纤维蛋白原）的粘附的影响。在目标 4 中，我们将使用体内模型来定义负责 LPS 和 CLP 增强的微血管血栓形成的血小板和内皮粘附分子。这些目标的完成将拓宽我们对人类脓毒症模型中微血管血栓形成机制的理解。这将有助于确定该疾病的微血管血栓形成的新治疗靶点。我们的长期目标是应用从这些研究中获得的知识，对脓毒症患者及其相关的微血管改变进行最佳管理。与公共卫生的相关性：脓毒症是人体对感染的反应，是美国的一个主要原因。我们的目标是了解这种疾病的严重并发症（微小血管凝块）的原因。这些信息将有助于为患有这种毁灭性疾病的患者开发新的治疗方法。