Cigarette smoke and α,β‐unsaturated aldehydes elicit VEGF release through the p38 MAPK pathway in human airway smooth muscle cells and lung fibroblasts

• Published in: British journal of pharmacology Vol. 163; no. 3; pp. 649 - 661
• Main Authors: Volpi, Giorgia, Facchinetti, Fabrizio, Moretto, Nadia, Civelli, Maurizio, Patacchini, Riccardo
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2011; Nature Publishing Group
• Subjects: 4‐hydroxy‐2‐nonenal; Acetylcysteine - pharmacology; acrolein; Acrolein - pharmacology; airway smooth muscle cells; Aldehydes - pharmacology; Biological and medical sciences; Bronchi - cytology; Bronchi - drug effects; Bronchi - metabolism; Calcium Channels; Cells, Cultured; Chronic obstructive pulmonary disease, asthma; Complex Mixtures - pharmacology; COPD; Fibroblasts - drug effects; Fibroblasts - metabolism; Humans; Lung - cytology; Lung - drug effects; Lung - metabolism; lung fibroblasts; Medical sciences; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Nerve Tissue Proteins - antagonists & inhibitors; Nicotiana; Nicotinic Antagonists - pharmacology; p38 MAPK; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Phosphorylation; Pneumology; Research Papers; RNA, Messenger - metabolism; Smoke - adverse effects; Transient Receptor Potential Channels - antagonists & inhibitors; TRPA1 Cation Channel; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; VEGF; Lung; Smooth muscle; Respiratory system; Respiratory tract; Acrolein; Cobalt alloy; p38 Mitogen activated protein kinase; Bronchus disease; Chronic obstructive pulmonary disease; Obstructive pulmonary disease; 4-hydroxy-2-nonenal; Release; Human; Lung disease; Respiratory disease; VEGF; airway smooth muscle cells; Palladium alloy; Aldehyde; In vitro; p38 MAPK; Vascular endothelium growth factor; lung fibroblasts; Fibroblast; COPD
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01253.x

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 H2O2. 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 AND IMPLICATIONS 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.