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Altered hypoxia-induced cellular responses and inflammatory profile in lung fibroblasts from COPD patients compared to control subjects

Ryde, Martin LU ; Marek, Nora ; Löfdahl, Anna LU ; Pekny, Olivia ; Bjermer, Leif LU ; Westergren-Thorsson, Gunilla LU orcid ; Tufvesson, Ellen LU and Larsson Callerfelt, Anna-Karin LU orcid (2024) In Respiratory Research 25(1).
Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic bronchitis, emphysema and vascular remodelling. The disease is associated with hypoxia, inflammation and oxidative stress. Lung fibroblasts are important cells in remodelling processes in COPD, as main producers of extracellular matrix proteins but also in synthesis of growth factors and inflammatory mediators. Methods: In this study we aimed to investigate if there are differences in how primary distal lung fibroblasts obtained from COPD patients and healthy subjects respond to hypoxia (1% O2) and pro-fibrotic stimuli with TGF-β1 (10 ng/mL). Genes and proteins associated with oxidative stress, endoplasmic... (More)

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic bronchitis, emphysema and vascular remodelling. The disease is associated with hypoxia, inflammation and oxidative stress. Lung fibroblasts are important cells in remodelling processes in COPD, as main producers of extracellular matrix proteins but also in synthesis of growth factors and inflammatory mediators. Methods: In this study we aimed to investigate if there are differences in how primary distal lung fibroblasts obtained from COPD patients and healthy subjects respond to hypoxia (1% O2) and pro-fibrotic stimuli with TGF-β1 (10 ng/mL). Genes and proteins associated with oxidative stress, endoplasmic reticulum stress, remodelling and inflammation were analysed with RT-qPCR and ELISA. Results: Hypoxia induced differences in expression of genes involved in oxidative stress (SOD3 and HIF-1α), ER stress (IRE1, PARK and ATF6), apoptosis (c-Jun and Bcl2) and remodelling (5HTR2B, Collagen7 and VEGFR2) in lung fibroblasts from COPD subjects compared to control subjects, where COPD fibroblasts were in general less responsive. The release of VEGF-C was increased after hypoxia, whereas TGF-β significantly reduced the VEGF response to hypoxia and the release of HGF. COPD fibroblasts had a higher release of IL-6, IL-8, MCP-1 and PGE2 compared to lung fibroblasts from control subjects. The release of inflammatory mediators was less affected by hypoxia, whereas TGFβ1 induced differences in inflammatory profile between fibroblasts from COPD and control subjects. Conclusion: These results suggest that there is an alteration of gene regulation of various stress responses and remodelling associated mediator release that is related to COPD and hypoxia, where fibroblasts from COPD patients have a deficient response.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
COPD, ER stress, Gene expression, Hypoxia, Inflammation, Lung fibroblasts, Oxidative stress, Remodelling
in
Respiratory Research
volume
25
issue
1
article number
282
publisher
BioMed Central (BMC)
external identifiers
  • pmid:39014439
  • scopus:85198631658
ISSN
1465-9921
DOI
10.1186/s12931-024-02907-x
language
English
LU publication?
yes
id
a540550d-2930-451b-acae-902827c962e7
date added to LUP
2024-08-26 14:09:29
date last changed
2024-09-09 15:25:43
@article{a540550d-2930-451b-acae-902827c962e7,
  abstract     = {{<p>Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic bronchitis, emphysema and vascular remodelling. The disease is associated with hypoxia, inflammation and oxidative stress. Lung fibroblasts are important cells in remodelling processes in COPD, as main producers of extracellular matrix proteins but also in synthesis of growth factors and inflammatory mediators. Methods: In this study we aimed to investigate if there are differences in how primary distal lung fibroblasts obtained from COPD patients and healthy subjects respond to hypoxia (1% O<sub>2</sub>) and pro-fibrotic stimuli with TGF-β<sub>1</sub> (10 ng/mL). Genes and proteins associated with oxidative stress, endoplasmic reticulum stress, remodelling and inflammation were analysed with RT-qPCR and ELISA. Results: Hypoxia induced differences in expression of genes involved in oxidative stress (SOD3 and HIF-1α), ER stress (IRE1, PARK and ATF6), apoptosis (c-Jun and Bcl2) and remodelling (5HTR2B, Collagen7 and VEGFR2) in lung fibroblasts from COPD subjects compared to control subjects, where COPD fibroblasts were in general less responsive. The release of VEGF-C was increased after hypoxia, whereas TGF-β significantly reduced the VEGF response to hypoxia and the release of HGF. COPD fibroblasts had a higher release of IL-6, IL-8, MCP-1 and PGE<sub>2</sub> compared to lung fibroblasts from control subjects. The release of inflammatory mediators was less affected by hypoxia, whereas TGFβ1 induced differences in inflammatory profile between fibroblasts from COPD and control subjects. Conclusion: These results suggest that there is an alteration of gene regulation of various stress responses and remodelling associated mediator release that is related to COPD and hypoxia, where fibroblasts from COPD patients have a deficient response.</p>}},
  author       = {{Ryde, Martin and Marek, Nora and Löfdahl, Anna and Pekny, Olivia and Bjermer, Leif and Westergren-Thorsson, Gunilla and Tufvesson, Ellen and Larsson Callerfelt, Anna-Karin}},
  issn         = {{1465-9921}},
  keywords     = {{COPD; ER stress; Gene expression; Hypoxia; Inflammation; Lung fibroblasts; Oxidative stress; Remodelling}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Respiratory Research}},
  title        = {{Altered hypoxia-induced cellular responses and inflammatory profile in lung fibroblasts from COPD patients compared to control subjects}},
  url          = {{http://dx.doi.org/10.1186/s12931-024-02907-x}},
  doi          = {{10.1186/s12931-024-02907-x}},
  volume       = {{25}},
  year         = {{2024}},
}