Tipping P G, Davenport P, Gallicchio M, Filonzi E L, Apostolopoulos J, Wojta J
Department of Medicine (Monash Medical Centre), Monash University, Clayton, Victoria, Australia.
Am J Pathol. 1993 Sep;143(3):875-85.
The capacity of macrophages to influence directly and indirectly fibrinolytic processes in atherosclerosis was studied using macrophages isolated from atherosclerotic plaques of patients undergoing surgical repair of distal aortic and femoral arteries. These cells were characterized by their morphology, adherence, esterase positivity, and expression of CD14 antigen. Production of plasminogen activator inhibitor type-1 (PAI-1) by plaque macrophages (6.7 +/- 2.7 ng/10(5) cells/24 hours [mean +/- SEM]) was significantly greater than PAI-1 production by blood monocytes isolated simultaneously from the same patients (1.8 +/- 1.5 ng/10(5) cells/24 hours). Production of tissue type plasminogen activator and urokinase type was not augmented compared to blood monocytes. Conditioned medium from cultured plaque macrophages significantly increased production of PAI-1 by endothelial cells (85 +/- 11% above basal) and vascular smooth muscle cells (25 +/- 10%) in vitro. This response was significantly greater than the response to monocyte-conditioned medium (endothelial cells 38 +/- 11%, vascular smooth muscle cells 2.5 +/- 2.0%). Stimulation of endothelial cell PAI-1 production by macrophage-conditioned medium was partially inhibitable by a monoclonal antibody to transforming growth factor-beta. Tissue type plasminogen activator production by endothelial cells and vascular smooth muscle cells was not affected by plaque macrophage- or monocyte-conditioned medium. Urokinase type plasminogen activator production by endothelial cells and vascular smooth muscle cells was undetectable in control medium and was augmented to similar levels in response to plaque macrophage- and monocyte-conditioned media. These results demonstrate upregulation of PAI-1 production by macrophages in atheromatous plaques and the capacity of soluble products from plaque macrophages to upregulate PAI-1 production by endothelial cells and vascular smooth muscle cells in vitro. These data suggest that macrophages in atherosclerotic plaques may inhibit thrombolysis both directly and indirectly by effects of their soluble products on endothelial cells and vascular smooth muscle cells.
利用从接受远端主动脉和股动脉手术修复患者的动脉粥样硬化斑块中分离出的巨噬细胞，研究了巨噬细胞直接和间接影响动脉粥样硬化中纤维蛋白溶解过程的能力。这些细胞通过其形态、黏附性、酯酶阳性以及CD14抗原的表达来进行表征。斑块巨噬细胞产生纤溶酶原激活物抑制剂1型（PAI-1）的量（6.7±2.7 ng/10⁵细胞/24小时[平均值±标准误]）显著高于同时从同一患者分离出的血液单核细胞产生PAI-1的量（1.8±1.5 ng/10⁵细胞/24小时）。与血液单核细胞相比，组织型纤溶酶原激活物和尿激酶型的产生并未增加。培养的斑块巨噬细胞的条件培养基在体外显著增加了内皮细胞（比基础水平高85±11%）和血管平滑肌细胞（25±10%）PAI-1的产生。这种反应显著大于对单核细胞条件培养基的反应（内皮细胞38±11%，血管平滑肌细胞2.5±2.0%）。巨噬细胞条件培养基对内皮细胞PAI-1产生的刺激可被抗转化生长因子-β单克隆抗体部分抑制。内皮细胞和血管平滑肌细胞组织型纤溶酶原激活物的产生不受斑块巨噬细胞或单核细胞条件培养基的影响。内皮细胞和血管平滑肌细胞尿激酶型纤溶酶原激活物的产生在对照培养基中未检测到，并且在对斑块巨噬细胞和单核细胞条件培养基的反应中增加到相似水平。这些结果表明动脉粥样斑块中巨噬细胞PAI-1产生上调，以及斑块巨噬细胞的可溶性产物在体外上调内皮细胞和血管平滑肌细胞PAI-1产生的能力。这些数据表明动脉粥样硬化斑块中的巨噬细胞可能通过其可溶性产物对内皮细胞和血管平滑肌细胞的作用直接和间接抑制血栓溶解。
