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）：虽然动脉粥样硬化被认为​​是一种慢性炎症性疾病，但其在斑块进展、破裂和血栓形成中的确切作用尚不清楚。由于目前尚无令人满意的人类斑块破裂动物模型，因此我们依靠从冠心病猝死患者身上收集的尸检材料进行研究。大量研究集中在纤维帽内基质降解的影响作为斑块不稳定和破裂的潜在机制。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至关重要。经基因编程可在体内发生细胞凋亡的平滑肌细胞已被证明可上调促炎细胞因子 MCP-1 和 IL-8，导致实验诱导的病变中巨噬细胞广泛浸润。我们实验室的观察表明，斑块破裂部位的巨噬细胞中 caspase-1 被激活，而稳定斑块的纤维帽中检测到很少的 caspase-1。 Caspase-3，另一种促死亡介质，也在动脉粥样硬化的晚期病变中检测到。半胱天冬酶可能对疾病进展和斑块不稳定至关重要，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，会导致斑块不稳定。单核细胞/巨噬细胞对纤维帽的浸润可能是由病变本身内凋亡细胞的促炎信号引起的。该项目的具体目标是（1）平滑肌细胞和巨噬细胞死亡的作用，包括鉴定caspase 1在人动脉粥样硬化斑块中早期和晚期凋亡区室（核心）形成中的上游和下游途径（2）促炎细胞因子在凋亡核心中的管腔和管腔外巨噬细胞迁移中的作用（3） 斑块破裂和血栓形成中表达髓过氧化物酶的巨噬细胞，以及与 EMAP II 的相互作用。 (4) 细胞外基质（透明质酸、多功能蛋白聚糖、双糖链蛋白聚糖和核心蛋白聚糖）、炎症抑制因子（TSG-6、PAI-2）和内皮细胞凋亡在急性血栓形成中的作用：斑块侵蚀引起的管腔血栓形成的替代途径；（5）新型外周炎症标志物与斑块不稳定病理学的相关性。我们对人类冠心病的详细研究应该可以深入了解斑块破裂和侵蚀的最终途径所涉及的机制，这可能有助于设计新的治疗方式，以降低冠心病的死亡率和发病率。