title: Cigarette smoke and lipopolysaccharide induce a proliferative airway smooth muscle phenotype.
abstract: BACKGROUND
  A major feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, which includes an increased airway smooth muscle (ASM) mass. The mechanisms underlying ASM remodelling in COPD are currently unknown. We hypothesized that cigarette smoke (CS) and/or lipopolysaccharide (LPS), a major constituent of CS, organic dust and gram-negative bacteria, that may be involved in recurrent airway infections and exacerbations in COPD patients, would induce phenotype changes of ASM.
  
  
  METHODS
  To this aim, using cultured bovine tracheal smooth muscle (BTSM) cells and tissue, we investigated the direct effects of CS extract (CSE) and LPS on ASM proliferation and contractility.
  
  
  RESULTS
  Both CSE and LPS induced a profound and concentration-dependent increase in DNA synthesis in BTSM cells. CSE and LPS also induced a significant increase in BTSM cell number, which was associated with increased cyclin D1 expression and dependent on activation of ERK 1/2 and p38 MAP kinase. Consistent with a shift to a more proliferative phenotype, prolonged treatment of BTSM strips with CSE or LPS significantly decreased maximal methacholine- and KCl-induced contraction.
  
  
  CONCLUSIONS
  Direct exposure of ASM to CSE or LPS causes the induction of a proliferative, hypocontractile ASM phenotype, which may be involved in airway remodelling in COPD.
authors.affiliation: Department of Molecular Pharmacology, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands. t.pera@rug.nl
authors.forename: Tonio
authors.initials: T
authors.lastname: Pera
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
authors.forename: Andries H
authors.initials: AH
authors.lastname: Lesterhuis
authors.forename: Riham
authors.initials: R
authors.lastname: Sami
authors.forename: Marco
authors.initials: M
authors.lastname: van der Toorn
authors.forename: Johan
authors.initials: J
authors.lastname: Zaagsma
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016210:Methacholine Chloride / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D011189:Potassium Chloride / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D046509:Tissue Culture Techniques; D014132:Trachea / Q000187:drug effects* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D005419:Flavonoids; D007093:Imidazoles; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012906:Smoke; C482199:lipopolysaccharide, E coli O55-B5; D016210:Methacholine Chloride; D019938:Cyclin D1; D011189:Potassium Chloride; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one