Kranzhöfer R, Clinton S K, Ishii K, Coughlin S R, Fenton J W, Libby P
Vascular Medicine and Atherosclerosis Unit, Brigham and Women's Hospital, Boston, Mass 02115, USA.
Circ Res. 1996 Aug;79(2):286-94. doi: 10.1161/01.res.79.2.286.
Thrombosis frequently occurs during atherogenesis and in response to vascular injury. Accumulating evidence supports a role for inflammation in the same situation. The present study therefore sought links between thrombosis and inflammation by determining whether thrombin, which is present in active form at sites of thrombosis, can elicit inflammatory functions of human monocytes and vascular smooth muscle cells (SMCs), two major constituents of advanced atheroma. Human alpha-thrombin (EC50, approximately equal to 500 pmol/L) potently induced interleukin (IL)-6 release from SMCs. The tethered-ligand thrombin receptor appeared to mediate this effect. Furthermore, alpha-thrombin also rapidly increased levels of mRNA encoding IL-6 and monocyte chemotactic protein-1 (MCP-1) in SMCs. In contrast, only alpha-thrombin concentrations of > or = 100 nmol/L could stimulate release of IL-6 or tumor necrosis factor-alpha (TNF alpha) in peripheral blood monocytes or monocyte-derived macrophages. Lipid loading of macrophages did not augment thrombin responsiveness. Likewise, only alpha-thrombin concentrations of > or = 100 nmol/L increased levels of IL-6, IL-1 beta, MCP-1, or TNF alpha mRNA in monocytes. Differential responses of SMCs and monocytes to thrombin extended to early agonist-mediated increases in [Ca2+]i. SMCs and endothelial cells, but not monocytes, contained abundant mRNA encoding the thrombin receptor and displayed cell surface thrombin receptor expression detected with a novel monoclonal antibody. Thus, the level of thrombin receptors appeared to account for the differential thrombin susceptibility of SMCs and monocytes. These data suggest that SMCs may be more sensitive than monocytes/macrophages to thrombin activation in human atheroma. Cytokines produced by thrombin-activated SMCs may contribute to ongoing inflammation in atheroma complicated by thrombosis or subjected to angioplasty.
血栓形成常发生于动脉粥样硬化过程中以及对血管损伤的反应中。越来越多的证据支持炎症在相同情况下发挥作用。因此，本研究通过确定在血栓形成部位以活性形式存在的凝血酶是否能引发人类单核细胞和血管平滑肌细胞（SMC）的炎症功能，来探寻血栓形成与炎症之间的联系，这两种细胞是晚期动脉粥样硬化斑块的主要成分。人α-凝血酶（EC50，约等于500 pmol/L）能有效诱导SMC释放白细胞介素（IL）-6。拴系配体凝血酶受体似乎介导了这一效应。此外，α-凝血酶还能迅速提高SMC中编码IL-6和单核细胞趋化蛋白-1（MCP-1）的mRNA水平。相比之下，只有浓度≥100 nmol/L的α-凝血酶才能刺激外周血单核细胞或单核细胞衍生的巨噬细胞释放IL-6或肿瘤坏死因子-α（TNFα）。巨噬细胞的脂质负载并未增强凝血酶反应性。同样，只有浓度≥100 nmol/L的α-凝血酶才能提高单核细胞中IL-6、IL-1β、MCP-1或TNFα mRNA的水平。SMC和单核细胞对凝血酶的不同反应延伸至早期激动剂介导的细胞内钙离子浓度（[Ca2+]i）升高。SMC和内皮细胞含有丰富的编码凝血酶受体的mRNA，但单核细胞没有，并且用一种新型单克隆抗体检测到它们有细胞表面凝血酶受体表达。因此，凝血酶受体水平似乎解释了SMC和单核细胞对凝血酶敏感性的差异。这些数据表明，在人类动脉粥样硬化中，SMC可能比单核细胞/巨噬细胞对凝血酶激活更敏感。凝血酶激活的SMC产生的细胞因子可能导致伴有血栓形成或接受血管成形术的动脉粥样硬化中持续存在的炎症。
