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

• 批准号: 10294004
• 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
• 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/10294004
• 关键词: Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Affect; Agonist; Animal Genetics; Animal Model; Area; Bacteria; Biochemical; Blood Circulation; Blood Vessels; Brain Edema; Cause of Death; Cell Death; Cell Nucleus; Cells; Cessation of life; 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; Lead; Lipids; Lung; Mediating; Membrane Lipids; Membrane Microdomains; Microcirculation; Modeling; Molecular; Molecular Target; Multiple Organ Failure; 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; molecular imaging; mortality; novel; novel therapeutic intervention; pathogenic bacteria; receptor; recruit; respiratory; response; scavenger receptor; tissue injury; trafficking; translational study; vascular inflammation

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 摘要 尽管最近在理解血管通透性增加的基础上取得了进展， 由循环血管活性肽，脂质和外源性物质（细菌，毒素， 颗粒物），损伤组织释放的细胞内化合物的影响，称为危险- 与脓毒症引起的持续性急性呼吸综合征严重程度相关的分子模式（DAMP） 或创伤性损伤仍然知之甚少， DAMP需要进一步调查。这项翻译研究将调查核相关的影响， DAMPs，组蛋白，对血管内皮功能的影响，并测试一种新的假设机制，循环 组蛋白靶向肺微血管内皮并加重肺损伤。本研究中检验的中心假设 本发明的应用是在急性肺损伤、脓毒症、创伤、严重炎症 或大手术靶向血管内皮，并导致整体血管功能障碍、器官损伤和 mortality.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接合， 分化36（CD 36）导致内皮炎症和屏障功能障碍的传播;和2） CD 36通过循环组蛋白诱导的死亡信号传导的激活有助于增强正在进行的 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 提供更好地理解定义败血症和创伤严重程度的因素的见解。这些研究可能 导致分子靶点的鉴定和开发新的治疗方法来减轻这种 循环DAMP的有害影响。