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，常见的且昂贵的。严重败血症的医院病例死亡率（败血症加器官功能障碍）为30-50％；美国每年有751,000例严重的败血症病例，耗资170亿美元。内皮反应是脓毒症病理生理学的关键要素。临床前数据和小型人类研究表明，内皮细胞负责增加白细胞粘附，炎症，凝结激活，并响应内皮细胞介体血管血管内皮细胞生长因子（VEGF）的水平增加。此外，内皮在微循环稳态和微血管流动的保存中起着积极作用。我们建议通过测量内皮细胞生物标志物的循环水平，以及使用体内视频镜检查的微循环流直接可视化微循环流，从而研究内皮细胞“读出”。因此，该项目的广泛长期目标是研究内皮在败血症中的作用，在大型，异质的患者组中。为此，我们将研究两个具体目标：1）研究败血症内皮细胞激活的生物标志物； 2）研究败血症的微循环流。该项目的总体假设是严重的败血症与内皮功能障碍有关。反过来，这种内皮功能障碍可预测随后的器官衰竭和死亡。该早期有效方案指导的复苏减弱了内皮功能障碍，从而改善了生存率。为了检验这一假设，我们将利用患者，辅助测量（尤其是对微循环流的体内评估），以及该过程临床试验中的其他样本和测定。过程是一个大型，多中心，随机，受控的临床试验，可测试协议定向的复苏背后的功效和机制。为了进行针对原始试验中未解决的内皮和微循环的调查线，我们将选择8个过程研究地点以参与这项辅助研究。我们将直接对正交极化显微镜的新型床边技术进行可视化和量化舌下微循环流中的干扰。此外，我们将开发一个多标记面板，该小组评估内皮细胞功能障碍的程度和随后的死亡率风险。我们还将利用该过程临床试验中随机分配的干预措施，以观察替代复苏策略中内皮反应的差异。对这些机制的了解的提高可能会导致预测结果，选择患者的量身定制（内皮方向性）疗法，遵循治疗反应，并开发败血症内皮功能障碍的新型疗法。 该项目的目的是研究因感染而患病的患者的内皮。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人群的新方法。 （抽象的结尾）

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

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

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