title: Cigarette smoke and α,β-unsaturated aldehydes elicit VEGF release through the p38 MAPK pathway in human airway smooth muscle cells and lung fibroblasts.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF) is an angiogenic factor known to be elevated in the sputum of asymptomatic smokers as well as smokers with bronchitis type of chronic obstructive pulmonary disease. The aim of this study was to investigate whether acute exposure to cigarette smoke extract altered VEGF production in lung parenchymal cells.
  
  
  METHODS
  We exposed human airway smooth muscle cells (ASMC), normal human lung fibroblasts (NHLF) and small airways epithelial cells (SAEC) to aqueous cigarette smoke extract (CSE) in order to investigate the effect of cigarette smoke on VEGF expression and release.
  
  
  RESULTS
  Vascular endothelial growth factor release was elevated by sub-toxic concentrations of CSE in both ASMC and NHLF, but not in SAEC. CSE-evoked VEGF release was mimicked by its component acrolein at concentrations (10-100 µM) found in CSE, and prevented by the antioxidant and α,β-unsaturated aldehyde scavenger, N-acetylcysteine (NAC). Both CSE and acrolein (30 µM) induced VEGF mRNA expression in ASMC cultures, suggesting an effect at transcriptional level. Crotonaldehyde and 4-hydroxy-2-nonenal, an endogenous α,β-unsaturated aldehyde, stimulated VEGF release, as did H(2)O(2). CSE-evoked VEGF release was accompanied by rapid and lasting phosphorylation of p38 MAPK (mitogen-activated protein kinase), which was abolished by NAC and mimicked by acrolein. Both CSE- and acrolein-evoked VEGF release were blocked by selective inhibition of p38 MAPK signalling.
  
  
  CONCLUSIONS
  α,β-Unsaturated aldehydes and possibly reactive oxygen species contained in cigarette smoke stimulate VEGF expression and release from pulmonary cells through p38 MAPK signalling.
authors.affiliation: Department of Pharmacology, Chiesi Farmaceutici S.p.A., Parma, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Volpi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Facchinetti
authors.forename: Nadia
authors.initials: N
authors.lastname: Moretto
authors.forename: Maurizio
authors.initials: M
authors.lastname: Civelli
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000171:Acrolein / Q000494:pharmacology*; D000447:Aldehydes / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015220:Calcium Channels; D002478:Cells, Cultured; D045424:Complex Mixtures / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D000074025:TRPA1 Cation Channel; D014026:Nicotiana; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000447:Aldehydes; D015220:Calcium Channels; D045424:Complex Mixtures; D009419:Nerve Tissue Proteins; D018733:Nicotinic Antagonists; D012333:RNA, Messenger; D012906:Smoke; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; D042461:Vascular Endothelial Growth Factor A; D000171:Acrolein; C012796:2-butenal; D048051:p38 Mitogen-Activated Protein Kinases; D000111:Acetylcysteine