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Impaired TNFα-induced VEGF Expression in Human Airway Smooth Muscle Cells from Smokers with COPD: Role of MAPkinases and Histone Acetylation—Effect of Dexamethasone

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Abstract

The cytokine and potent angiogenic factor vascular endothelial growth factor (VEGF) plays an important role in airway remodelling in various airway diseases such as idiopathic pulmonary fibrosis, pulmonary hypertension, lung cancer, asthma and chronic obstructive pulmonary disease (COPD). The effect of cigarette-smoking on VEGF expression, the modulatory role of extracellular signal-regulated kinase (ERK)-1,-2, p38mitogen-activated protein kinase (MAPK), histone acetylation and the anti-inflammatory effect of dexamethasone on TNFα-induced VEGF expression were examined in human airway smooth muscle cells (HASMC) of five non-smokers, 17 smokers without airflow limitation and 15 smokers with COPD. TNFα increased VEGF expression 5.4-fold and 4.0-fold in HASMC from non-smokers and smokers without airflow limitation, respectively, but only 2.5-fold in HASMC from smokers with COPD compared with non-stimulated HASMC. VEGF production was dependent on phosphorylation of ERK-1,-2 and p38MAPK, as was shown by examining the effects of PD 098059 (10 μM), an inhibitor of the upstream activator of MAPKkinase (MKK)-1, and SB 203580 (10 μM), an inhibitor of p38MAPK; there were no differences between non-smokers, smokers without airflow limitation and smokers with COPD in this respect. Dexamethasone (DEX; 10−12–10−4 M) reduced TNFα-induced phosphorylation of ERK-1/-2 and prevented TNFα-induced VEGF generation without differences between non-smokers, smokers with and without COPD. There was an additional inhibitory effect of DEX (10−12 M) on VEGF-release when PD 098059 was added. The basal and TNFα-induced acetylation status of the VEGF-promoter (chromatin immunoprecipitation [ChIP] assay) was increased in HASMC from smokers with COPD compared with smokers without airflow limitation and non-smokers. In comparison to non-stimulated HASMC, TNFα decreased the acetylation status of the VEGF-promoter by ∼46% and ∼43% in HASMC from non-smokers and smokers without COPD compared with ∼68% in HASMC from smokers with COPD. The data suggest that HASMC express VEGF in response to TNFα and that this may be reduced in HASMC of smokers with COPD in a smoking-independent manner. VEGF expression is directly modulated by phosphorylation of ERK-1,-2 and p38MAPK and by histone acetylation and the acetylation status of the VEGF gene is increased in HASMC of smokers with COPD in a smoking-independent manner. TNFα reduced the acetylation status of the VEGF promoter in HASMC.

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Abbreviations

VEGF:

Vascular endothelial growth factor

HASMC:

Human airway smooth muscle cells

ERK-1,-2:

Extracellular signal-regulated proteinkinase-1,-2

p38MAPK :

p38 Mitogen-activated proteinkinase

ChIP:

Chromatin immunoprecipitation

DEX:

Dexamethasone

COPD:

Chronic obstructive pulmonary disease

FEV1 :

Forced expiratory volume in 1 s

FVC:

Forced vital capacity

BAL:

Broncho-alveolar lavage

HAT:

Histone-acetyltransferase

HDAC:

Histone-deacetylase

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Authors and Affiliations

  1. Clinic III for Internal Medicine, Department of Pneumology, University of Cologne, Joseph-Stelzmann-Str. 9, 50924, Cologne, Germany

    Maria Raidl, Bernhard Sibbing, Katja Müller, Haitham Hag, Erland Erdmann & Andrea Koch

  2. Heart & Thoracic Surgery Unit, University of Cologne, Cologne, Germany

    Justus Strauch & Andre Nemat

  3. Visceral Surgery Unit, University of Cologne, Cologne, Germany

    Paul M. Schneider

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  1. Maria Raidl
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Raidl, M., Sibbing, B., Strauch, J. et al. Impaired TNFα-induced VEGF Expression in Human Airway Smooth Muscle Cells from Smokers with COPD: Role of MAPkinases and Histone Acetylation—Effect of Dexamethasone. Cell Biochem Biophys 49, 98–110 (2007). https://doi.org/10.1007/s12013-007-0043-4

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