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VEGF synthesis is induced by prostacyclin and TGF-β in distal lung fibroblasts from COPD patients and control subjects : Implications for pulmonary vascular remodelling

Westergren-Thorsson, Gunilla LU ; Bagher, Mariam LU ; Andersson-Sjöland, Annika LU ; Thiman, Lena LU ; Löfdahl, Claes Göran LU ; Hallgren, Oskar LU ; Bjermer, Leif LU and Larsson-Callerfelt, Anna Karin LU (2018) In Respirology 23(1). p.68-75
Abstract

Background and objective: Involvement of pulmonary vascular remodelling is a characteristic sign in COPD. Vascular mediators such as vascular endothelial growth factor (VEGF) and prostacyclin may regulate fibroblast activity. The objective was to study the synthesis of VEGF and interactions with prostacyclin and transforming growth factor (TGF)-β1 in lung fibroblasts from patients with COPD and healthy control subjects. To further explore the autocrine role of synthesized VEGF on fibroblast activity, studies were performed in human lung fibroblasts (HFL-1). Methods: Primary distal lung fibroblast cultures were established from healthy individuals and from COPD patients (GOLD stage IV). Lung fibroblasts were stimulated with... (More)

Background and objective: Involvement of pulmonary vascular remodelling is a characteristic sign in COPD. Vascular mediators such as vascular endothelial growth factor (VEGF) and prostacyclin may regulate fibroblast activity. The objective was to study the synthesis of VEGF and interactions with prostacyclin and transforming growth factor (TGF)-β1 in lung fibroblasts from patients with COPD and healthy control subjects. To further explore the autocrine role of synthesized VEGF on fibroblast activity, studies were performed in human lung fibroblasts (HFL-1). Methods: Primary distal lung fibroblast cultures were established from healthy individuals and from COPD patients (GOLD stage IV). Lung fibroblasts were stimulated with the prostacyclin analogue iloprost and the profibrotic stimuli TGF-β1. VEGF synthesis was measured in the cell culture medium. Changes in proliferation rate, migration and synthesis of the extracellular matrix (ECM) proteins proteoglycans were analysed after stimulations with VEGF-A isoform 165 (VEGF165; 1–10 000 pg/mL) in HFL-1. Results: Iloprost and TGF-β1 significantly increased VEGF synthesis in both fibroblasts from COPD patients and control subjects. TGF-β1-induced VEGF synthesis was significantly reduced by the cyclooxygenase inhibitor indomethacin in fibroblasts from COPD patients. VEGF significantly increased proliferation rate and migration capacity in HFL-1. VEGF also significantly increased synthesis of the ECM proteins biglycan and perlecan. The VEGF receptors (VEGFR), VEGFR1, VEGFR2 and VEGFR3, were all expressed in primary lung fibroblasts and HFL-1. Conclusion: VEGF is synthesized in high amounts by distal lung fibroblasts and may have a crucial role in ongoing vascular remodelling processes in the distal lung compartments.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
chronic obstructive pulmonary disease, extracellular matrix, fibroblasts, prostacyclin, vascular endothelial growth factor
in
Respirology
volume
23
issue
1
pages
8 pages
external identifiers
  • scopus:85036589937
ISSN
1323-7799
DOI
10.1111/resp.13142
language
English
LU publication?
yes
id
bc496f2e-c9e2-49b2-af34-76ad80669dd3
date added to LUP
2018-01-02 12:49:26
date last changed
2018-07-08 04:29:12
@article{bc496f2e-c9e2-49b2-af34-76ad80669dd3,
  abstract     = {<p>Background and objective: Involvement of pulmonary vascular remodelling is a characteristic sign in COPD. Vascular mediators such as vascular endothelial growth factor (VEGF) and prostacyclin may regulate fibroblast activity. The objective was to study the synthesis of VEGF and interactions with prostacyclin and transforming growth factor (TGF)-β<sub>1</sub> in lung fibroblasts from patients with COPD and healthy control subjects. To further explore the autocrine role of synthesized VEGF on fibroblast activity, studies were performed in human lung fibroblasts (HFL-1). Methods: Primary distal lung fibroblast cultures were established from healthy individuals and from COPD patients (GOLD stage IV). Lung fibroblasts were stimulated with the prostacyclin analogue iloprost and the profibrotic stimuli TGF-β<sub>1</sub>. VEGF synthesis was measured in the cell culture medium. Changes in proliferation rate, migration and synthesis of the extracellular matrix (ECM) proteins proteoglycans were analysed after stimulations with VEGF-A isoform 165 (VEGF<sub>165</sub>; 1–10 000 pg/mL) in HFL-1. Results: Iloprost and TGF-β<sub>1</sub> significantly increased VEGF synthesis in both fibroblasts from COPD patients and control subjects. TGF-β<sub>1</sub>-induced VEGF synthesis was significantly reduced by the cyclooxygenase inhibitor indomethacin in fibroblasts from COPD patients. VEGF significantly increased proliferation rate and migration capacity in HFL-1. VEGF also significantly increased synthesis of the ECM proteins biglycan and perlecan. The VEGF receptors (VEGFR), VEGFR1, VEGFR2 and VEGFR3, were all expressed in primary lung fibroblasts and HFL-1. Conclusion: VEGF is synthesized in high amounts by distal lung fibroblasts and may have a crucial role in ongoing vascular remodelling processes in the distal lung compartments.</p>},
  author       = {Westergren-Thorsson, Gunilla and Bagher, Mariam and Andersson-Sjöland, Annika and Thiman, Lena and Löfdahl, Claes Göran and Hallgren, Oskar and Bjermer, Leif and Larsson-Callerfelt, Anna Karin},
  issn         = {1323-7799},
  keyword      = {chronic obstructive pulmonary disease,extracellular matrix,fibroblasts,prostacyclin,vascular endothelial growth factor},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {68--75},
  series       = {Respirology},
  title        = {VEGF synthesis is induced by prostacyclin and TGF-β in distal lung fibroblasts from COPD patients and control subjects : Implications for pulmonary vascular remodelling},
  url          = {http://dx.doi.org/10.1111/resp.13142},
  volume       = {23},
  year         = {2018},
}