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: 8079099
• 负责人: NATHAN I SHAPIRO
• 金额: $ 40.83万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079099
• 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; United States National Institutes of Health; 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）： 败血症是致命的，常见的，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751，000例严重脓毒症病例，费用为170亿美元。内皮反应是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粘附、炎症、凝血激活，并对内皮细胞介质血管内皮细胞生长因子（VEGF）水平升高作出反应。此外，内皮细胞在微循环稳态和微血管流量的维持中起着积极的作用。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，本项目的广泛、长期目标是在一个大的、异质性的患者组中研究内皮在脓毒症中的作用。为了实现这一目标，我们将研究两个具体目标：1）研究脓毒症中内皮细胞活化的生物标志物; 2）研究脓毒症中的微循环流量。该项目的总体假设是严重脓毒症与内皮功能障碍相关;内皮功能障碍反过来预测随后的器官衰竭和死亡;早期有效的方案指导的复苏减轻内皮功能障碍，从而改善生存率。为了检验这一假设，我们将利用患者、辅助测量（特别是微循环流量的体内评估）以及来自ProCESS临床试验的其他样本和测定。ProCESS是一项大型、多中心、随机、对照临床试验，旨在测试协议目标导向复苏背后的疗效和机制。为了进行针对原始试验中未涉及的内皮和微循环的研究，我们将选择8家ProCESS研究中心参与本辅助研究。我们将直接可视化和量化的干扰舌下微循环流动的存在，利用正交偏振显微镜的新床边技术。此外，我们将开发一个多标志物面板，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ProCESS临床试验中随机分配的干预措施，观察替代复苏策略中内皮反应的差异。对这些机制的进一步理解可能会导致预测结果的策略，选择患者进行定制（内皮导向）治疗，跟踪治疗反应，并开发败血症内皮功能障碍的新疗法。 该项目的目标是研究因感染而病情危重的患者的内皮细胞。从该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。(End摘要）

项目成果

Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis*.

• DOI: 10.1097/ccm.0b013e31825fdc31
• 发表时间: 2012-11
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: David S;Mukherjee A;Ghosh CC;Yano M;Khankin EV;Wenger JB;Karumanchi SA;Shapiro NI;Parikh SM
• 通讯作者: Parikh SM

Leukocyte Transcriptional Response in Sepsis.

脓毒症中的白细胞转录反应。

• DOI: 10.1097/shk.0000000000001258
• 发表时间: 2019
• 期刊: Shock (Augusta, Ga.)
• 作者: Skibsted,Simon;Bhasin,ManojK;Henning,DanielJ;Jaminet,ShouChing;Lewandowski,Jeffrey;Kirkegaard,Hans;Aird,WilliamC;Shapiro,NathanI
• 通讯作者: Shapiro,NathanI

A guide to human in vivo microcirculatory flow image analysis.

• DOI: 10.1186/s13054-016-1213-9
• 发表时间: 2016-02-10
• 期刊: Critical care (London, England)
• 作者: Massey MJ;Shapiro NI
• 通讯作者: Shapiro NI

Serial Procalcitonin Predicts Mortality in Severe Sepsis Patients: Results From the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study.

• DOI: 10.1097/ccm.0000000000002321
• 发表时间: 2017-05
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Schuetz P;Birkhahn R;Sherwin R;Jones AE;Singer A;Kline JA;Runyon MS;Self WH;Courtney DM;Nowak RM;Gaieski DF;Ebmeyer S;Johannes S;Wiemer JC;Schwabe A;Shapiro NI
• 通讯作者: Shapiro NI

Age-related differences in biomarkers of acute inflammation during hospitalization for sepsis.

• DOI: 10.1097/shk.0000000000000182
• 发表时间: 2014-08
• 期刊: Shock (Augusta, Ga.)
• 作者: Ginde AA;Blatchford PJ;Trzeciak S;Hollander JE;Birkhahn R;Otero R;Osborn TM;Moretti E;Nguyen HB;Gunnerson KJ;Milzman D;Gaieski DF;Goyal M;Cairns CB;Rivers EP;Shapiro NI
• 通讯作者: Shapiro NI