Endothelial Cell Signaling and Microcirculatory Flow in Severe Sepsis

描述(由申请人提供)： 败血症是致命的、常见的和昂贵的。严重脓毒症(脓毒症加器官功能障碍)的住院病例死亡率为30%-50%；美国每年有75.1万例严重脓毒症，花费170亿美元。内皮反应正在成为脓毒症病理生理学的关键因素。临床前数据和小型人体研究表明，内皮细胞负责增加白细胞的黏附、炎症、激活凝血功能，并对内皮细胞介质血管内皮细胞生长因子(VEGFR)水平的升高做出反应。此外，内皮细胞在微循环内稳态和微血管血流的保存中起着积极的作用。我们建议通过测量内皮细胞生物标志物的循环水平以及用体内视频显微镜直接观察微循环流动来进行全面的内皮细胞“读出”来研究内皮。因此，该项目的广泛、长期目标是研究内皮细胞在一大群不同种类的患者中在败血症中的作用。为此，我们将研究两个特定的目标：1)研究脓毒症时内皮细胞激活的生物标志物；2)研究脓毒症时的微循环血流。该项目的总体假设是，严重的脓毒症与内皮功能障碍有关；内皮功能障碍反过来预示着随后的器官衰竭和死亡；早期有效的方案指导的复苏可以减轻内皮功能障碍，从而提高存活率。为了验证这一假设，我们将利用患者、辅助测量(特别是体内微循环血流评估)以及来自临床试验过程的额外样本和分析。Process是一项大型、多中心、随机、对照的临床试验，测试程序化目标导向复苏背后的有效性和机制。为了进行原始试验中没有涉及的内皮和微循环的这一系列调查，我们将选择8个过程研究地点参与这项辅助研究。我们将利用新的床边正交偏振显微镜技术，直接可视化和量化舌下微循环血流障碍的存在。此外，我们将开发一个多标记物小组，评估内皮细胞功能障碍的程度和随后的死亡风险。我们还将利用临床试验过程中随机分配的干预措施，观察不同复苏策略对内皮细胞反应的差异。对这些机制的更好理解可能会导致预测结果的策略，选择患者进行量身定制的(内皮导向)治疗，跟踪治疗反应，并开发针对脓毒症患者内皮功能障碍的新疗法。 这个项目的目标是研究因感染而危重的患者的内皮细胞。从这个项目中获得的信息可能会导致诊断和治疗这一重要患者群体的新方法。(摘要结束)

DESCRIPTION (provided by applicant): Sepsis is lethal, common, and expensive. The hospital case mortality rate for severe sepsis (sepsis plus organ dysfunction) is 30-50%; there are 751,000 cases of severe sepsis in the US annually at a cost of $17 billion. The endothelial response is emerging as a critical element of sepsis pathophysiology. Preclinical data and small human studies suggest that endothelial cells are responsible for increased leukocyte adhesion, inflammation, activation of coagulation, and respond to increased levels of the endothelial cell mediator Vascular Endothelial Cell Growth Factor (VEGF). Furthermore, the endothelium plays an active role in microcirculatory homeostasis and the preservation of microvascular flow. We propose to study the endothelium by performing a comprehensive endothelial cell "read-out" through the measurement of circulating levels of endothelial cell biomarkers as well as direct visualization of microcirculatory flow with in-vivo videomicroscopy. Accordingly, the broad, long-term objective of this project is to study the role of the endothelium in sepsis in a large, heterogeneous group of patients. To accomplish this, we will investigate two specific aims: 1) to study biomarkers of endothelial cell activation in sepsis; and, 2) to study microcirculatory flow in sepsis. The overall hypotheses of this project is that severe sepsis is associated with endothelial dysfunction; that endothelial dysfunction, in turn, is predictive of subsequent organ failure and death; and that early effective protocol-directed resuscitation attenuates endothelial dysfunction leading to improved survival. To test this hypothesis, we will utilize patients, ancillary measurements (notably in-vivo assessment of microcirculatory flow), and additional samples and assays from the ProCESS clinical trial. ProCESS is a large, multicenter, randomized, controlled clinical trial testing the efficacy and mechanisms behind protocolized goal-directed resuscitation. To conduct this line of investigation directed at the endothelium and microcirculation that was not addressed in the original trial, we will select 8 ProCESS study sites for participation in this ancillary study. We will directly visualize and quantify the presence of disturbances in sublingual microcirculatory flow utilizing the novel bedside technique of orthogonal polarization microscopy. Furthermore, we will develop a multi-marker panel that assesses degree of endothelial cell dysfunction and subsequent mortality risk. We will also capitalize on the randomly assigned interventions in the ProCESS clinical trial to observe differences in endothelial response across the alternative resuscitation strategies. Improved understanding of these mechanisms may lead to strategies to predict outcome, to select patients for tailored (endothelium-directed) therapies, to follow treatment response, and to develop novel therapies for endothelial dysfunction in sepsis. The goal of this project is to study the endothelium in patients who are critically ill from an infection. The information gained from this project may lead to new methods to diagnose and treat this important patient population. (End of Abstract)