Endothelial Cell Signaling and Microcirculatory Flow in Severe Sepsis

严重脓毒症中的内皮细胞信号传导和微循环流动

• 批准号: 7839461
• 负责人: NATHAN I SHAPIRO
• 金额: $ 34.55万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7839461
• 关键词: Address; Adhesions; Affect; Ancillary Study; Animals; Attenuated; Biological Assay; Biological Markers; Biological Preservation; Caring; Cell Adhesion; Cell Hypoxia; Cell physiology; Cessation of life; Clinical Trials; Coagulation Process; Critical Illness; Data; Defect; Diagnosis; Diagnostic; Elements; Endothelial Cells; Endothelium; Fibroblast Growth Factor; Foundations; Functional disorder; Funding; Future; Goals; Growth Factor Inhibition; Homeostasis; Hospitals; Human; Imagery; Infection; Inflammation; Intervention; Investigation; Lead; Leukocytes; Measurable; Measurement; Measures; Mediator of activation protein; Methods; Microcirculation; Morbidity - disease rate; Nature; Organ; Organ failure; Outcome; Oxidative Stress; Participant; Pathway interactions; Patients; Peripheral; Physiological; Play; Polarization Microscopy; Protocols documentation; Randomized; Randomized Controlled Clinical Trials; Reading; Research; Resuscitation; Risk; Role; Sampling; Sepsis; Signal Transduction; Site; Techniques; Testing; Therapeutic; Thrombosis; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular Permeabilities; Venous; Video Microscopy; abstracting; bench to bedside; cost; efficacy testing; improved; in vivo; insight; mortality; mouse model; novel; patient population; pre-clinical; response; treatment response; trial comparing; vascular bed

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)

描述（由申请人提供）：