Neutrophil dysregulation as a driving mechanism of cardiovascular disease in HIV-1-infection

中性粒细胞失调是 HIV-1 感染者心血管疾病的驱动机制

• 批准号: 9341375
• 负责人: Zdenek Hel
• 金额: $ 57.3万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341375
• 关键词: Acquired Immunodeficiency Syndrome; Address; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Bacterial Translocation; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cell Death; Cells; Cerebrovascular Disorders; Chronic; Chronic Disease; Clinical Trials; Consensus; Coronary artery; DNA; Data; Development; Disease; Disease Progression; Emergency Situation; Epithelial; Event; Exposure to; Genetic Transcription; Granulopoiesis; HIV Infections; HIV-1; Immune; Immunologics; Individual; Infection; Inflammation; Inflammatory; Intervention; Intestinal Mucosa; Intestines; Leukocytes; Link; Longitudinal prospective study; Mediator of activation protein; Methods; Morbidity - disease rate; Mucous Membrane; Myocardial Infarction; Myocardial Ischemia; Neutrophil Activation; Patients; Pharmacology; Phenotype; Population; Process; Production; Prognostic Marker; Proteins; Publishing; Recruitment Activity; Reporting; Research; Research Personnel; Retrospective Studies; Risk; Risk Factors; Role; Stimulus; Stroke; Testing; Thrombus; Vascular Diseases; antiretroviral therapy; arterial stiffness; base; cardiovascular disorder risk; cell type; cohort; cytokine; endothelial dysfunction; extracellular; intimal medial thickening; macrophage; microbial; mortality; neutrophil; novel; novel diagnostics; novel therapeutic intervention; progression marker; randomized trial; release factor; scaffold; translational impact; virology

7. PROJECT SUMMARY / ABSTRACT. HIV infection conveys a 1.5 – 2 fold increased risk for atherosclerotic cardiovascular diseases (CVD). HIV-1-infected individuals are disproportionately impacted by CVD with increased carotid artery intima- medial thickening, subclinical coronary artery atherosclerosis, endothelial dysfunction, arterial stiffness, and silent ischemic heart disease compared to uninfected controls. CVD and other chronic diseases are increasingly replacing AIDS-related complications as the most common causes of morbidity and mortality in ART-treated patients. There is a widespread consensus that chronic inflammation resulting from microbial translocation, persisting despite successful virological control, is responsible for this excess risk. However, the specific mechanisms and mediators of this process are not well understood. Neutrophils, the most abundant leukocyte population, have recently emerged as critical contributors to atherosclerosis and thrombotic disorders. Following activation, a subset of neutrophils undergoes a specific type of cell death referred to as NETosis characterized by a release of large extracellular neutrophil extracellular traps (NETs) composed of chromosomal DNA and neutrophil granular proteins. These NETs provide the stimulus and the scaffold for thrombus formation and prime macrophages for production of cytokines that amplify immune cell recruitment in atherosclerotic plaques. We have demonstrated that neutrophils from HIV-1-infected individuals display an activated phenotype, specific transcriptional profile, increased rate of degranulation, and a high capacity to undergo NETosis. The accumulated evidence strongly suggests that neutrophils undergoing NETosis accelerate CVD progression in HIV-1 infection. The overall objectives of this proposal are to: 1) define the role of activated neutrophils and NETosis as driving mechanisms of CVD in HIV-1-infected individuals, and 2) identify the mechanisms responsible for chronic neutrophilic activation in HIV-1-infected individuals in order to reveal specific checkpoints for intervention. Our central hypothesis is that chronic inflammation in intestinal mucosal tissue of HIV-1-infected individuals results in a release of factors inducing neutrophil activation and accelerated recruitment from bone marrow. The emerging neutrophil population has higher capacity to undergo NETosis following activation by bacterial products leaking across the damaged intestinal barrier. NETs released from activated neutrophils promote the progression of vascular dysfunction in HIV-1 infection. The overall objectives will be accomplished in three specific aims: 1) Determine the extent to which neutrophil activation and NETosis predict the progression of vascular dysfunction in HIV-1-infected individuals; 2) Define the mechanisms of chronic systemic neutrophil activation in HIV-1 infection; and 3) Define the neutrophil-based prognostic markers that are associated with vascular disease-related morbid events in HIV-1-infection. We expect that the proposed project will fundamentally advance our understanding of primary mechanisms of inflammation-driven vascular disease in HIV-1 infection. The definition of mechanisms driving the progression of vascular diseases in HIV-1-infected individuals will have significant translational impact and serve as a basis for novel diagnostic and therapeutic approaches.

7. 项目摘要/摘要。 HIV 感染会使动脉粥样硬化性心血管疾病的风险增加 1.5 至 2 倍 （化学气相沉积）。 HIV-1 感染者因颈动脉内膜增加而受到 CVD 的影响尤为严重。 内侧增厚、亚临床冠状动脉粥样硬化、内皮功能障碍、动脉僵硬和 与未感染的对照相比，无症状的缺血性心脏病。 CVD 和其他慢性疾病 越来越多地取代艾滋病相关并发症成为发病和死亡的最常见原因 接受 ART 治疗的患者。人们普遍认为，微生物引起的慢性炎症 尽管病毒学控制成功，但易位仍然存在，这是造成这种过度风险的原因。然而， 这一过程的具体机制和中介因素尚不清楚。 中性粒细胞是最丰富的白细胞群，最近已成为关键贡献者 动脉粥样硬化和血栓性疾病。激活后，中性粒细胞的子集经历特定的 称为 NETosis 的细胞死亡类型，其特征是释放大量细胞外中性粒细胞 细胞外陷阱 (NET) 由染色体 DNA 和中性粒细胞颗粒蛋白组成。这些网络 为血栓形成提供刺激和支架，并为巨噬细胞产生 细胞因子可增强动脉粥样硬化斑块中免疫细胞的募集。我们已经证明了 来自 HIV-1 感染者的中性粒细胞表现出激活的表型、特定的转录谱、 脱颗粒率增加，并具有较高的 NETosis 能力。积累的证据有力 表明中性粒细胞经历 NETosis 会加速 HIV-1 感染中的 CVD 进展。整体 该提案的目标是： 1) 定义激活的中性粒细胞和 NETosis 作为驱动因素的作用 HIV-1 感染者的 CVD 机制，以及 2) 确定导致慢性疾病的机制 HIV-1 感染者的中性粒细胞激活，以揭示干预的具体检查点。我们的 中心假设是 HIV-1 感染者肠粘膜组织的慢性炎症导致 诱导中性粒细胞活化并加速从骨髓募集的因子的释放。这 新兴的中性粒细胞群在被细菌激活后具有更高的发生NETosis的能力 产品渗漏穿过受损的肠道屏障。活化的中性粒细胞释放的 NETs 促进 HIV-1 感染中血管功能障碍的进展。总体目标分三期完成 具体目标： 1) 确定中性粒细胞激活和 NETosis 预测疾病进展的程度 HIV-1感染者的血管功能障碍； 2）定义慢性全身性中性粒细胞的机制 HIV-1 感染中的激活； 3) 定义与以下相关的基于中性粒细胞的预后标志物 HIV-1 感染中与血管疾病相关的病态事件。 我们期望拟议的项目将从根本上增进我们对初级 HIV-1感染中炎症驱动的血管疾病的机制。驱动机制的定义 HIV-1感染者血管疾病的进展将产生重大的转化影响 作为新的诊断和治疗方法的基础。