Tobacco smoke induces the generation of procoagulant microvesicles from human monocytes/macrophages.
Tobacco smoke induces the generation of procoagulant microvesicles from human monocytes/macrophages.
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DOI：
10.1161/atvbaha.110.209577
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Liu ML
中科院分区：
文献类型：
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作者：
Li M;Yu D;Williams KJ;Liu ML
Exposure to tobacco smoke substantially increases arterial atherothrombotic events and venous thrombosis. Smokers exhibit higher circulating levels of tissue factor (TF) than do non-smokers, but the underlying mechanisms have not been reported. Because TF released from cells into plasma is always carried by membrane microvesicles (MVs, also called microparticles), we now investigated whether exposure of human monocyte/macrophages to tobacco smoke induces their release of MVs and whether these MVs are procoagulant. We found that exposure of human THP-1 monocytes and primary human monocyte-derived macrophages (hMDMs) to tobacco smoke extract (TSE, 3.75%) significantly increased their total and TF-positive MV generation. Importantly, MVs released from TSE-treated human monocyte/macrophages exhibited three-to-four times the procoagulant activity (PCA) of control MVs, as assessed by TF-dependent generation of factor Xa. Exposure to TSE increased TF mRNA and protein expression and cell-surface TF display by both THP-1 monocytes and primary hMDMs. In addition, TSE exposure caused activation of JNK, p38, and ERK MAP kinases, as well as apoptosis, a major mechanism for MV generation. Treatment of THP-1 cells with inhibitors of ERK, MEK, Ras, or caspase 3, but not p38 or JNK, significantly blunted TSE-induced apoptosis and MV generation. Surprisingly, neither ERK nor caspase 3 inhibition altered the induction of cell-surface TF display by TSE, indicating an effect solely on MV release. Of note, inhibition of ERK or caspase 3 essentially abolished TSE-induced generation of procoagulant MVs from THP-1 monocytes. Tobacco smoke exposure of human monocyte/macrophages induces cell-surface TF display, apoptosis, and ERK- and caspase 3-dependent generation of biologically active, procoagulant MVs. These processes may be novel contributors to the pathologic hypercoagulability of active and second-hand smokers.
