Platelet/Mast Cell Interactions as Determinants of End-Organ Injury in Cardiac Surgery

血小板/肥大细胞相互作用作为心脏手术终末器官损伤的决定因素

• 批准号: 9130438
• 负责人: Jorn Karhausen
• 金额: $ 41.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-14 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130438
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adoptive Transfer; Age; Animal Model; Animals; Blood; Blood Platelets; Blood specimen; Bypass; Cade; Cardiac; Cardiac Surgery procedures; Cardiopulmonary; Cardiopulmonary Bypass; Cardiovascular Surgical Procedures; Cell Communication; Cerebrum; Chymase; Clinical; Complication; Coronary Artery Bypass; Cromoglicic Acid; Data; Development; Disease; Distant; Epidemiology; Event; Foundations; Health; Health Care Costs; Healthcare; Human; Immunologics; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Intestines; Ischemia; Ischemic Bowel Disease; Kidney; Label; Lead; Link; Mast Cell Stabilizer; Measures; Medical; Methods; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nature; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Perfusion; Perioperative; Physiology; Plasma; Platelet Activating Factor; Platelet Activation; Platelet aggregation; Preventive; Procedures; Proteomics; Rattus; Reading; Regulation; Reperfusion Injury; Reperfusion Therapy; Risk Assessment; Rodent Model; Role; Sampling; Signal Transduction; Source; Specimen; Stimulus; Testing; Therapeutic; Time; Tissues; Work; base; chemokine; clinically relevant; improved; in vitro Assay; in vitro testing; in vivo; in vivo Model; inflammatory marker; innovation; mast cell; mortality; novel; novel strategies; primary outcome; repaired; repository; research study; response; secondary outcome; statistics

 DESCRIPTION (provided by applicant): Cardiac surgery requiring cardiopulmonary bypass perfusion elicits powerful inflammatory and tissue injurious responses. As a consequence, significant distant organ damage - such as acute kidney injury - occurs, and is the principal cause of the considerable morbidity and mortality associated with these procedures. Currently, suitable concepts on the origins of the tissue injurious stimuli in this setting are lacking. This constitutes a major obstacle to the development of effective organ protection strategies. Based on provocative preliminary data, we propose a novel role for activated platelets as important inflammatory regulators through activation of perivascular mast cells at the microvascular/tissue interface. In the proposed studies, we will define the mechanisms of this interaction and its implications for end-organ injury in cardiac surgery. Our aims are: (1) Investigate the role of platelet/mast cell interactions in tissue injurious and inflammatory responses. Using rodent models of ischemia/reperfusion injury and of cardiopulmonary bypass, we will study the nature and functional relevance of platelet/mast cell interactions to early inflammatory responses and tissue injury. (2) Identify the mast cell-activating platelet factor(s) and establish their pathophysiologic relevance. Preliminary experiments based on platelet secretome analysis indicate a role of platelet-CXCL4 in mast cell activation. We will define the molecular foundations of this pathway and its impact in relevant animal models. (3) Determine the relevance of the platelet and mast cell activation to end-organ injury in cardiac surgery patients. We will investigate the link between mast cell and platelet activation and markers of inflammation and end-organ injury using our large sample repository and prospectively collected patient samples. In summary, we propose to define, for the first time, platelet/mast cell interactions as a potentially decisive mechanism of inflammatory propagation and comprehensively develop its clinical implications for improvement of organ protection strategies in cardiac surgical patients. A team of experts in the fields of mast cell (Abraham), and platelet (Bergmeier) physiology, animal models of cardiopulmonary bypass (Qing) and clinical statistics and epidemiology (Kertai) provide strong support for successful completion.

 描述（由申请人提供）：需要体外循环灌注的心脏手术会引发强烈的炎症和组织损伤反应。因此，会发生显著的远端器官损伤，如急性肾损伤，并且是与这些手术相关的相当大的发病率和死亡率的主要原因。目前，在这种情况下，组织伤害性刺激的起源缺乏适当的概念。这是制定有效的器官保护战略的主要障碍。 基于挑衅性的初步数据，我们提出了一个新的作用，激活血小板作为重要的炎症调节因子，通过激活血管周围肥大细胞在微血管/组织界面。在拟议的研究中，我们将定义这种相互作用的机制及其对心脏手术中终末器官损伤的影响。我们的目的是：（1）研究血小板/肥大细胞相互作用在组织损伤和炎症反应中的作用。使用缺血/再灌注损伤和心肺转流的啮齿动物模型，我们将研究血小板/肥大细胞相互作用与早期炎症反应和组织损伤的性质和功能相关性。(2)鉴定肥大细胞活化血小板因子并确定其病理生理相关性。基于血小板分泌组分析的初步实验表明血小板-CXCL 4在肥大细胞活化中的作用。我们将定义这一途径的分子基础及其在相关动物模型中的影响。(3)确定血小板和肥大细胞活化与心脏手术患者终末器官损伤的相关性。 我们将使用我们的大型样本库和前瞻性收集的患者样本，研究肥大细胞和血小板活化与炎症和终末器官损伤标志物之间的联系。 总之，我们建议首次将血小板/肥大细胞相互作用定义为炎症传播的潜在决定性机制，并全面发展其临床意义，以改善心脏手术患者的器官保护策略。肥大细胞（Abraham）和血小板（Bergmeier）生理学，体外循环动物模型（Qing）以及临床统计学和流行病学（Kertai）领域的专家团队为成功完成提供了强有力的支持。

项目成果

Platelet Counts and Postoperative Stroke After Coronary Artery Bypass Grafting Surgery.

• DOI: 10.1213/ane.0000000000002187
• 发表时间: 2017-10
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7
• 作者: Karhausen JA;Smeltz AM;Akushevich I;Cooter M;Podgoreanu MV;Stafford-Smith M;Martinelli SM;Fontes ML;Kertai MD
• 通讯作者: Kertai MD