Plaque Progression, Apoptosis and Inflammation

斑块进展、细胞凋亡和炎症

• 批准号: 6654906
• 负责人: Renu Virmani
• 金额: $ 27.91万
• 依托单位: AMERICAN REGISTRY OF PATHOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654906
• 关键词: angiogenesis inhibitors; antiinflammatory agents; apoptosis; atherosclerotic plaque; biomarker; cell migration; clinical research; cysteine endopeptidases; extracellular matrix proteins; human tissue; inflammation; interleukin 8; macrophage; monocyte chemoattractant protein 1; myeloperoxidase; pathologic process; protein degradation; sudden cardiac death; thrombosis; vascular smooth muscle

DESCRIPTION (provided by applicant): Although atherosclerosis is considered a chronic inflammatory disease, its precise role in plaque progression, rupture, and thrombosis is unclear. Because no satisfactory animal model of human plaque rupture currently exists, we rely on autopsy material collected from sudden coronary death victims for study. A considerable amount of research has focused on the effects of matrix degradation within the fibrous cap as potential mechanisms of plaque instability and rupture. Alternatively, a growing body of literature suggests that apoptotic cell death of smooth muscle cells and macrophages are critical for plaque progression and instability. Smooth muscle cells genetically programmed to undergo apoptosis in-vivo have been shown to up regulate the proinflammatory cytokines MCP-1 and IL-8 causing an extensive infiltration of macrophages in experimentally induced lesions. Observations in our laboratory have demonstrated activated caspase-1 in macrophages at plaque rupture sites, while little caspase-1 was detected in the fibrous cap of stable plaques. Caspase-3, another pro-death mediator has also been detected in advanced lesions of atherosclerosis. Caspases may be critical to disease progression and plaque instability since they are directly involved in the processing and maturation of inflammatory cytokines. We believe that monocyte recruitment into the fibrous cap is a critical event, leading to plaque instability. Infiltration of the fibrous cap by monocyte/macrophages may be provoked by proinflammatory signals from apoptotic cell within the lesion itself. The specific aims of this project are (1) the role of smooth muscle cell and macrophage death, including the identification of the upstream and down stream pathways of caspase 1 in the formation of early and late apoptotic compartments (cores) in the human atherosclerotic plaque (2) The role of proinflammatory cytokines in luminal and abluminal macrophage migration in apoptotic cores (3) The role of myeloperoxidase expressing macrophages in plaque rupture and thrombosis, and interaction with EMAP II. (4) The role of extracelllar matrix (hyaluronan, versican, biglycan and decorin), suppressors of inflammation (TSG-6, PAI-2), and endothelial cell apoptosis in acute thrombosis: alternate pathway of luminal thrombosis due to plaque erosion and (5) The correlation of novel peripheral markers of inflammation with the pathology of plaque instability. Our detailed studies of human coronary disease should provide insight into the mechanisms involved in the final pathway of plaque rupture and erosion that may help design newer modalities of treatment to reduce the mortality and morbidity of coronary heart disease.

描述（由申请人提供）：尽管动脉粥样硬化被认为​​是一种慢性炎性疾病，但其在牙菌斑进展，破裂和血栓形成中的精确作用尚不清楚。由于目前没有人类斑块破裂的令人满意的动物模型，因此我们依靠从突然的冠状动脉死亡受害者那里收集的尸检材料进行研究。大量的研究集中在纤维帽内基质降解作为斑块不稳定性和破裂的潜在机制上的影响。另外，越来越多的文献表明平滑肌细胞和巨噬细胞的凋亡细胞死亡对于斑块的进展和不稳定性至关重要。平滑肌细胞在遗传编程中以体内凋亡的凋亡已显示出调节促炎性细胞因子MCP-1和IL-8，从而在实验诱导的病变中广泛渗透巨噬细胞。我们实验室中的观察结果证明了斑块破裂部位的巨噬细胞中激活的caspase-1，而在稳定斑块的纤维帽中很少检测到caspase-1。 caspase-3，在动脉粥样硬化的晚期病变中也检测到了另一种亲死亡介质。胱天蛋白酶可能对疾病进展和斑块不稳定性至关重要，因为它们直接参与炎症细胞因子的加工和成熟。我们认为，单核细胞募集到纤维帽中是一个关键事件，导致斑块不稳定。单核细胞/巨噬细胞对纤维帽浸润可能是由于病变本身中凋亡细胞的促炎信号引起的。该项目的具体目的是（1）平滑肌细胞和巨噬细胞死亡的作用，包括在人动脉粥样硬化斑块中鉴定caspase 1的上游和下游河流途径在早期和晚期凋亡隔室（核心）中的形成（2）促进性细胞动力学中的旋转式迁移的作用（2）在斑块破裂和血栓形成中表达巨噬细胞，以及与EMAP II的相互作用。 （4）外胞外矩阵（透明质酸，versican，Biglancan和Decorin），炎症抑制（TSG-6，PAI-2）和内皮细胞凋亡在急性势头比例中的作用：per症的炎症症状性症状的替代途径在急性剧栓塞中：per虫的炎症症状症状症状。我们对人类冠状动脉疾病的详细研究应提供有关斑块破裂和侵蚀涉及的机制的洞察力，这些机制可能有助于设计更新的治疗方式，以降低冠心病的死亡率和发病率。