Platelet- mast cell interactions as determinants of the vascular pathology in septic shock.

血小板-肥大细胞相互作用作为败血性休克血管病理学的决定因素。

• 批准号: 10343476
• 负责人: Soman N Abraham
• 金额: $ 46.35万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343476
• 关键词: Adhesions; Anaphylaxis; Animals; Behavior; Biological; Biological Assay; Biological Markers; Biology; Blood Cells; Blood Platelets; Blood Pressure; Blood Pressure Monitors; Blood Vessels; Blood capillaries; Blood flow; Caliber; Cardiac Surgery procedures; Cell Communication; Cell Degranulation; Cell Shape; Cessation of life; Chymase; Clinical; Complex; Data; Deterioration; Development; Disease; Disease Progression; Drops; Edema; Effector Cell; Endothelium; Event; Extravasation; Gene Expression Profiling; Goals; Hemostatic Agents; Hemostatic function; Histamine; Hypersensitivity; Hypotension; Hypoxia; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Link; Measures; Mediating; Mediator of activation protein; Medical emergency; Microcirculatory Bed; Modeling; Molecular; Morbidity - disease rate; Mortality Determinants; Multiple Organ Failure; Outcome; Oxygen; Pathology; Pathway interactions; Perfusion; Phenotype; Plasma; Platelet Activating Factor; Platelet Activation; Platelet aggregation; Receptor Protein-Tyrosine Kinases; Records; Reporting; Resistance; Role; Sampling Studies; Sepsis; Septic Shock; Shapes; Shock; Side; Signal Pathway; Signal Transduction; Source; Syndrome; TIE-2 Receptor; Technology; Testing; Tissues; Tryptase; Tyrosine Kinase Inhibitor; Vascular Permeabilities; Vasomotor; Viral Hemorrhagic Fevers; Virus; Whole Blood; Wild Type Mouse; Work; base; biobank; clinically relevant; cohort; density; endothelial dysfunction; improved; in vivo; lipid mediator; mast cell; mortality; novel; novel therapeutic intervention; photoacoustic imaging; prevent; response; septic patients; systemic inflammatory response; tool

Abstract: Development of shock in sepsis defines a dramatic deterioration of clinical status and is linked to a significant increase in morbidity and mortality rates. However, the cellular and molecular mechanisms determining the vascular pathology of septic shock remain undefined. Our past work established mast cells (MC) as key effector cells of vascular pathology in different disease contexts. Because MC products are found in the plasma in shock but not during sepsis, this supports that MC activation is a central event leading to septic shock. Employing state-of-the- art technologies such as dynamic photoacoustic imaging of the microvasculature, we provide first evidence that MCs shape key features of shock in sepsis: systemic hypotension, vascular leakage and microvascular perfusion abnormalities. In addition, we elucidate that in sepsis MCs, which are located on the abluminal side of a relatively impermeable endothelium, are stimulated by platelets, which can aggregate in their close proximity following inflammatory triggers. Based on these observations, we hypothesize that specific signaling interactions between platelets, perivascular MCs and the endothelium drive the vascular pathology of septic shock. The objective of our work is first to comprehensively define the mechanisms of MC-mediated vascular pathology in sepsis, second to elucidate the specific mechanism by which platelets trigger MC responses and resultant vascular pathology and lastly, to establish the clinical relevance of our findings in a cohort of septic patients. Together, this project constitutes a key step towards our long-term goal to establish MC responses as a biomarker of sepsis biology and to develop novel therapeutic strategies that may directly target the mechanisms of disease progression in sepsis.

摘要： 脓毒症中休克的发展定义了临床状态的急剧恶化，并与显著的 发病率和死亡率的增加。然而，细胞和分子机制决定了 感染性休克的血管病理仍未明确。 我们过去的工作证实肥大细胞(MC)在不同的血管病变中是关键的效应细胞。 疾病背景。由于MC产物是在休克时在血浆中发现的，而在脓毒症期间没有，这支持了 MC激活是导致感染性休克的中心事件。采用最先进的技术，如 微血管系统的动态光声成像，我们首次提供了MC塑造关键特征的证据 脓毒症休克的原因：全身性低血压、血管渗漏和微血管灌注异常。在……里面 此外，我们还阐明了在脓毒症中，位于创面的MC相对 不通透性内皮细胞是由血小板刺激的，它们可以在紧随其后聚集在一起。 发炎的诱因。 基于这些观察，我们假设血小板之间的特定信号相互作用， 血管周围巨噬细胞和内皮细胞参与了感染性休克的血管病理过程。我们工作的目标是 第一，全面界定MC介导的脓毒症血管病理机制；第二， 阐明血小板触发MC反应和由此产生的血管病理的具体机制 最后，建立我们在败血症患者队列中发现的临床相关性。 总而言之，这个项目是朝着我们的长期目标迈出的关键一步，即建立MC响应，如 脓毒症生物学的生物标志物，并开发可能直接针对 脓毒症的疾病进展机制。