Dipartimento Biomedico di Medicina Interna e Specialistica Università degli Studi di Palermo, Italy.
Curr Pharm Des. 2012;18(28):4266-88. doi: 10.2174/138161212802481237.
In many ways, atherosclerosis is a chronic inflammatory disorder and this issue is confirmed by recent investigations of that have focused on inflammation, providing new insight into mechanisms of disease. Several recent studies have addressed the role of chemokines in leukocyte accumulation in atherosclerosis, extending our knowledge and understanding of the complex and cell type-specific functions of chemokines in atherosclerosis. Activated T-lymphocytes within the atherosclerotic vessel wall express the CD40 ligand surface molecule, known to play a major role in several immunological pathways. In addition to activated T-lymphocytes, functional CD40 and CD40L are coexpressed by human vascular endothelial cells, smooth muscle cells and human macrophages in vitro as well as in situ in human atherosclerotic lesions. Recent studies indicate that CD40L activates atheroma-associated cells by promoting the expression of molecules thought to be involved in atherosclerosis, such as adhesion molecules, cytokines, matrix metalloproteinases, and tissue factor. Atherosclerosis starts with an innate immune response involving the recruitment and activation of monocytes macrophages that respond to an excessive accumulation of modified lipids within the arterial wall, followed by an adaptive immune response involving antigen-specific T lymphocytes. Effector T cells recognize modified auto-antigens such as oxidized LDL and heat shock proteins (i.e. HSP-60) that are presented by antigen-presenting cells such as macrophages or dendritic cells. The accumulation of inflammatory cells within the arterial wall leads to local production of chemokines, interleukins and proteases that enhance the influx of monocytes and lymphocytes, thereby promoting the progression of atherosclerotic lesions Recent reports have helped explain some of these questions by pointing to a role of contact dependent interaction between CD40 and CD40 ligand (CD40L, renamed CD154) as a stimulus for atheroma-associated cells. Also Macrophages play important roles in the progression of atherosclerosis by exhibiting unique characteristics under the various stimuli, evolving the plaque instability, thrombus formation and remodeling. Macrophage recruitment by abnormal endothelium over developing atherosclerotic plaques, is aided by endothelial expression of adhesion molecules (ICAM-1, VCAM, ELAM). The knowledge of atherosclerosis as an inflammatory disease offers the opportunity to develop novel therapeutic strategies targeting the inflammatory component of the disease.
在许多方面，动脉粥样硬化是一种慢性炎症性疾病，这一问题已被最近的研究证实，这些研究集中在炎症上，为疾病的机制提供了新的见解。最近的几项研究探讨了趋化因子在白细胞在动脉粥样硬化中的积累中的作用，扩展了我们对趋化因子在动脉粥样硬化中复杂和细胞类型特异性功能的认识。动脉粥样硬化血管壁内的活化 T 淋巴细胞表达 CD40 配体表面分子，已知该分子在几种免疫途径中发挥重要作用。除了活化的 T 淋巴细胞外，体外培养的人血管内皮细胞、平滑肌细胞和人巨噬细胞以及人动脉粥样硬化病变中也共同表达功能性 CD40 和 CD40L。最近的研究表明，CD40L 通过促进参与动脉粥样硬化的分子的表达来激活动脉粥样硬化相关细胞，如粘附分子、细胞因子、基质金属蛋白酶和组织因子。动脉粥样硬化始于涉及单核细胞/巨噬细胞募集和激活的固有免疫反应，这些细胞对动脉壁内异常脂质的过度积累作出反应，随后是涉及抗原特异性 T 淋巴细胞的适应性免疫反应。效应 T 细胞识别修饰后的自身抗原，如氧化型 LDL 和热休克蛋白（即 HSP-60），这些抗原由巨噬细胞或树突状细胞等抗原呈递细胞呈递。炎症细胞在动脉壁内的积累导致趋化因子、白细胞介素和蛋白酶的局部产生，增强单核细胞和淋巴细胞的流入，从而促进动脉粥样硬化病变的进展。最近的报告通过指出 CD40 和 CD40L（更名为 CD154）之间的接触依赖性相互作用作为动脉粥样硬化相关细胞的刺激因素，有助于解释其中的一些问题。此外，巨噬细胞通过在各种刺激下表现出独特的特征，在动脉粥样硬化的进展中发挥重要作用，导致斑块不稳定、血栓形成和重塑。异常内皮细胞对正在发育的动脉粥样硬化斑块的巨噬细胞募集，是通过内皮细胞表达粘附分子（ICAM-1、VCAM、ELAM）来辅助的。将动脉粥样硬化视为炎症性疾病的知识为开发针对疾病炎症成分的新型治疗策略提供了机会。
