Role of inflammation in intraplaque hemorrhage pathogenesis

炎症在斑块内出血发病机制中的作用

• 批准号: 10615058
• 负责人: Jenny E. Kanter
• 金额: $ 80.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615058
• 关键词: 3-Dimensional; Acceleration; Achievement; Address; Affect; Antibodies; Arterial Fatty Streak; Atherosclerosis; B-Lymphocytes; Blood Vessels; Cardiovascular system; Carotid Artery Plaques; Carotid Endarterectomy; Cause of Death; Cell Separation; Cells; Cholesterol; Clinical; Coculture Techniques; Collaborations; Complement; Data; Development; Elements; Endothelial Cells; Endothelium; Erythrocytes; Event; Excision; Follow-Up Studies; Goals; Growth; Guidelines; Health Care Costs; Hemoglobin; Hemorrhage; Histologic; Histology; Human; Hypoxia; Image; Imaging Techniques; Immunoglobulin M; In Vitro; Inflammation; Inflammatory; Investigation; Ischemia; Knowledge; Lipids; Low-Density Lipoproteins; Macrophage; Magnetic Resonance Imaging; Measures; Myocardial Infarction; Necrosis; Oxygen; Pathogenesis; Pathology; Patients; Permeability; Persons; Plasma; Production; Quality of life; Residual state; Risk; Role; Scanning; Source; Specimen; Stroke; Testing; Tissues; Tunica Adventitia; United States; Vascular Diseases; Vascular Permeabilities; atheroprotective; blood pressure control; cardiovascular disorder risk; contrast enhanced; coronary plaque; density; driving force; follow-up; histological studies; in vivo; inhibitor therapy; neovascularization; neovasculature; novel; novel therapeutic intervention; prevent; response; therapeutic target; treatment response; vasa vasorum

PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the US. Despite guidelines promoting aggressive anti-atherosclerotic therapies, there is »5%/year residual ASCVD risk in patients who achieve profound LDL-C lowering (median 30 mg/dL) with combined statin and PCSK9 inhibitor therapy. New treatment strategies are needed to target the mechanisms beyond LDL to reduce this residual risk. Histologic studies have demonstrated that plaque neovasculature constitutes the main entrance for inflammatory cells into plaques and provides a major source for the formation and progression of intraplaque hemorrhage (IPH). IPH, mainly resulting from plaque neovascularization, is a common feature of advanced atherosclerotic lesions and a critical element leading to accelerated plaque progression, plaque instability and ischemic vascular events in humans. We found that plaque neovessel permeability (measured as Ktrans, using dynamic contrast enhanced magnetic resonance imaging) is strongly correlated with macrophage content and that greater adventitial Ktrans is associated with IPH. Recent studies have identified that CD163+ macrophages are associated with IPH and can further promote neovascularization leading to IPH progression. On the other hand, B1 cell-derived IgM can inhibit inflammation and reduce atherosclerosis, and circulating human B1 cells are inversely associated with coronary plaque volume and instability features. Our preliminary data showed that plasma IgM levels are reduced in patients with carotid IPH and B1 cells are inversely associated with IPH progression. We, therefore, propose to study the role of B1 cell-derived IgM and B1 cells in IPH pathology. To test a novel hypothesis that B1 cell-derived IgM levels are reduced in patients with IPH and that the reduction in protective IgMs results in unobstructed IPH-promoted inflammation and neovessel permeability, thereby exacerbating plaque progression, we propose to conduct comprehensive studies including: (1) histological examination of CEA specimens to determine whether plaques with increased Ktrans and/or IPH have a lower density of IgM and a higher density of CD163+ macrophages; (2) a longitudinal clinical follow-up study in 250 patients to determine whether lower IgM levels and B1 cells predict progression of Ktrans and IPH and whether IgM production and effect on macrophages are different in B1 cells in patients with and without IPH; (3) in vitro mechanistic studies of endothelial sprouting and leakiness using 3D microvessels to determine the effects of IgM and B1 cells on RBC-induced changes in macrophages and vascular permeability. This proposal utilizes state-of-the-art imaging technique for quantification of vascular permeability and IPH and 3D microvessels for study how hemoglobin-stimulated macrophages and B1 cells and/or IgM influence endothelial function related vascular permeability. Our study will gain new knowledge to uncover inflammatory mechanisms in IPH pathogenesis and to discover potential therapeutic targets with a goal of reduced vascular permeability to prevent IPH and its progression, which will ultimately reduce residual ASCVD risk.

项目摘要 动脉粥样硬化性心血管疾病（ASCVD）仍然是美国的主要死亡原因。尽管 在促进积极抗动脉粥样硬化治疗的指南中， 使用他汀类药物和PCSK 9抑制剂联合治疗达到LDL-C显著降低（中位值30 mg/dL）的患者 疗法需要新的治疗策略来靶向LDL以外的机制，以减少这种残留 风险组织学研究表明，斑块新生血管构成了血管的主要入口， 炎症细胞进入斑块，并为斑块内炎症的形成和进展提供了主要来源。 出血（IPH）。IPH主要由斑块新生血管形成引起，是晚期动脉粥样硬化的共同特征。 动脉粥样硬化病变和导致斑块进展加速、斑块不稳定和 缺血性血管事件。我们发现斑块新生血管通透性（用Ktranss测量， 动态对比增强磁共振成像）与巨噬细胞含量密切相关， 大外膜Ktranss与IPH有关最近的研究表明，CD 163+巨噬细胞 与IPH相关，并可进一步促进导致IPH进展的新血管形成。另 另一方面，B1细胞来源的IgM可以抑制炎症和减少动脉粥样硬化， 与冠状动脉斑块体积和不稳定性特征呈负相关。我们的初步数据显示 颈动脉IPH患者血浆IgM水平降低，B1细胞与IPH呈负相关 进展因此，我们建议研究B1细胞来源的IgM和B1细胞在IPH病理中的作用。 为了检验一个新的假设，即IPH患者B1细胞源性IgM水平降低， 保护性IgM减少导致无阻碍的IPH促进的炎症和新生血管 渗透性，从而加剧斑块进展，我们建议进行全面的研究， 包括：（1）组织学检查CEA标本，以确定斑块是否具有增加的Ktrans 和/或IPH具有较低密度的IgM和较高密度的CD 163+巨噬细胞;（2）纵向临床 在250名患者中进行的一项随访研究，以确定较低的IgM水平和B1细胞是否预测Ktranss的进展 和IPH患者的B1细胞是否产生IgM和对巨噬细胞的影响不同， 无IPH;（3）使用3D微血管进行内皮发芽和渗漏的体外机制研究， 确定IgM和B1细胞对RBC诱导的巨噬细胞和血管通透性变化的影响。 该提案利用最先进的成像技术来量化血管渗透性和IPH 和3D微血管，用于研究血红蛋白刺激的巨噬细胞和B1细胞和/或IgM如何影响 内皮功能相关的血管通透性。我们的研究将获得新的知识，以揭示炎症 IPH发病机制，并发现潜在的治疗靶点，以减少血管 渗透性，以防止IPH及其进展，这将最终降低残余ASCVD风险。