Mechanisms of microvascular endothelial cell injury caused by extracellular histones

细胞外组蛋白致微血管内皮细胞损伤的机制

基本信息

批准号：
10679043
负责人：
Anna Birukova
金额：
$ 46.56万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679043
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Affect Agonist Animal Genetics Animal Model Area Bacteria Binding Biochemical Blood Vessels Brain Edema Cause of Death Cell Death Cell Death Induction Cell Nucleus Cells Cessation of life Circulation Complex DNA-Binding Proteins Data Development Dose Endothelial Cells Endothelium Failure Fostering Functional disorder Genetic Models Health Histones Immune Infection Inflammation Inflammatory Injury Investigation Knowledge Lipids Lung Mediating Membrane Lipids Membrane Microdomains Microcirculation Modeling Molecular Molecular Target Multiple Organ Failure NF-kappa B Necrosis Nuclear Operative Surgical Procedures Organ Organ failure Particulate Matter Pathologic Pathway interactions Patients Pattern Peptides Permeability Pilot Projects Play Prognostic Factor Publishing Pulmonary Edema Receptor Cell Regulation Sepsis Severities Signal Transduction Staphylococcus aureus Stimulus Surface Syndrome TNFRSF10B gene Testing Tissues Toxin Trauma Traumatic injury Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Vascular Permeabilities cell injury endothelial dysfunction extracellular imaging approach improved injured insight lung injury mortality novel novel therapeutic intervention pathogenic bacteria receptor recruit respiratory response scavenger receptor tissue injury trafficking translational study vascular inflammation

项目摘要

Mechanisms of microvascular endothelial cell injury caused by extracellular histones Abstract Despite the recent progress towards understanding of the basis of increased vascular permeability and inflammation caused by circulating vasoactive peptides, lipids, and exogenous agents (bacteria, toxins, particulate matter), the impact of intracellular compounds released by injured tissues and known as danger- associated molecular patterns (DAMPs) on severity of ongoing acute respiratory syndrome caused by sepsis or traumatic injury remain poorly understood, and molecular mechanisms underlying deleterious effects of DAMPs warrant further investigations. This translational study will investigate effects of nucleus-associated DAMPs, histones, on vascular endothelial function and test a new hypothetical mechanism by which circulating histones target lung microvascular endothelium and worsen lung injury. The central hypothesis tested in this application is that circulating histones elevated during acute lung injury, sepsis, trauma, severe inflammation, or major surgery target vascular endothelium and contribute to overall vascular dysfunction, organ damage and mortality. This may be achieved through: 1) histone-induced engagement of scavenger receptor cluster of differentiation 36 (CD36) leading to propagation of endothelial inflammation and barrier dysfunction; and 2) CD36-induced activation of death signaling by circulating histones contributing to augmentation of ongoing endothelial dysfunction and lung injury. The proposed study may have a broader impact on the other aspects of vascular responses to inflammatory or pro-angiogenic stimuli. Proposed studies will provide mechanistic insights offering better understanding of factors that define severity of sepsis and trauma. These studies may lead to identification of molecular targets and developing new therapeutic approaches to mitigate such deleterious effects of circulating DAMPs.

细胞外组蛋白致微血管内皮细胞损伤的机制抽象的尽管最近在了解血管通透性增加的基础和由循环血管活性肽、脂质和外源性物质（细菌、毒素、颗粒物），受损组织释放的细胞内化合物的影响被称为危险 - 相关分子模式 (DAMP) 与脓毒症引起的持续急性呼吸综合征严重程度的关系或创伤性损伤仍然知之甚少，并且其有害影响的分子机制 DAMP 值得进一步调查。这项转化研究将调查核相关的影响 DAMP、组蛋白对血管内皮功能的影响，并测试一种新的假设机制，通过该机制循环组蛋白靶向肺微血管内皮并加重肺损伤。本实验检验的中心假设应用是循环组蛋白在急性肺损伤、败血症、创伤、严重炎症、或针对血管内皮的大型手术会导致整体血管功能障碍、器官损伤和死亡。这可以通过以下方式实现：1) 组蛋白诱导的清道夫受体簇的参与分化 36 (CD36) 导致内皮炎症扩散和屏障功能障碍；和 2) CD36 通过循环组蛋白诱导死亡信号激活，有助于增强持续的死亡信号内皮功能障碍和肺损伤。拟议的研究可能会对其他方面产生更广泛的影响血管对炎症或促血管生成刺激的反应。拟议的研究将提供机制见解可以更好地理解定义脓毒症和创伤严重程度的因素。这些研究可能导致分子靶点的识别并开发新的治疗方法来减轻这种情况循环 DAMP 的有害影响。