• Mingzhen Li, Demin Yu, Kevin Jon Williams, and Ming-Lin Liu.
• Section of Endocrinology, Diabetes and Metabolism, Temple University School of Medicine, Philadelphia, PA 19140, USA.
• Arterioscler. Thromb. Vasc. Biol. 2010 Sep 1; 30 (9): 1818-24.

ObjectiveTo investigate whether exposure of human monocytes/macrophages to tobacco smoke induces their release of membrane microvesicles (MVs) that carry tissue factor (TF) released from cells, whether smoke-induced MVs are procoagulant, and what cellular processes might be responsible for their production.Methods And ResultsWe found that exposure of human THP-1 monocytes and primary human monocyte-derived macrophages to 3.75% tobacco smoke extract (TSE) significantly increased their total and TF-positive MV generation. More importantly, MVs released from TSE-treated human monocytes/macrophages exhibited 3 to 4 times the procoagulant activity 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 human monocyte-derived macrophages. In addition, TSE exposure caused activation of C-Jun-N-terminal kinase (JNK), p38, extracellular signal regulated kinase (ERK) mitogen-activated protein kinases (MAPK), and apoptosis (a major mechanism for MV generation). Treatment of THP-1 cells with inhibitors of ERK, MAP kinase kinase (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. Inhibition of ERK or caspase 3 essentially abolished TSE-induced generation of procoagulant MVs from THP-1 monocytes.ConclusionsTobacco smoke exposure of human monocytes/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 pathological hypercoagulability of active and secondhand smokers.

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