title: Tobacco smoke induces the generation of procoagulant microvesicles from human monocytes/macrophages.
abstract: OBJECTIVE
  To 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Tobacco 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.
authors.affiliation: Section of Endocrinology, Diabetes and Metabolism, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Li
authors.forename: Demin
authors.initials: D
authors.lastname: Yu
authors.forename: Kevin Jon
authors.initials: KJ
authors.lastname: Williams
authors.forename: Ming-Lin
authors.initials: ML
authors.lastname: Liu
mesh_terms: D017209:Apoptosis; D001777:Blood Coagulation / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D055252:Cell-Derived Microparticles / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D012906:Smoke; D012907:Smoking / Q000009:adverse effects*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D012906:Smoke; D013925:Thromboplastin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015951:Factor Xa; C505407:CASP3 protein, human; D053148:Caspase 3