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Lung Fibroblasts from Chronic Obstructive Pulmonary Disease Subjects Have a Deficient Gene Expression Response to Cigarette Smoke Extract Compared to Healthy

Garcia-Ryde, Martin LU ; van der Burg, Nicole M D LU orcid ; Larsson, Carin E LU ; Larsson-Callerfelt, Anna-Karin LU orcid ; Westergren-Thorsson, Gunilla LU ; Bjermer, Leif LU and Tufvesson, Ellen LU (2023) In International journal of chronic obstructive pulmonary disease 18. p.2999-3014
Abstract

BACKGROUND AND AIM: Cigarette smoking is the most common cause of chronic obstructive pulmonary disease (COPD) but more mechanistic studies are needed. Cigarette smoke extract (CSE) can elicit a strong response in many COPD-related cell types, but no studies have been performed in lung fibroblasts. Therefore, we aimed to investigate the effect of CSE on gene expression in lung fibroblasts from healthy and COPD subjects.

PATIENTS AND METHODS: Primary lung fibroblasts, derived from six healthy and six COPD subjects (all current or ex-smokers), were either unstimulated (baseline) or stimulated with 30% CSE for 4 h prior to RNA isolation. The mRNA expression levels were measured using the NanoString nCounter Human Fibrosis V2 panel... (More)

BACKGROUND AND AIM: Cigarette smoking is the most common cause of chronic obstructive pulmonary disease (COPD) but more mechanistic studies are needed. Cigarette smoke extract (CSE) can elicit a strong response in many COPD-related cell types, but no studies have been performed in lung fibroblasts. Therefore, we aimed to investigate the effect of CSE on gene expression in lung fibroblasts from healthy and COPD subjects.

PATIENTS AND METHODS: Primary lung fibroblasts, derived from six healthy and six COPD subjects (all current or ex-smokers), were either unstimulated (baseline) or stimulated with 30% CSE for 4 h prior to RNA isolation. The mRNA expression levels were measured using the NanoString nCounter Human Fibrosis V2 panel (760 genes). Pathway enrichment was assessed for unique gene ontology terms of healthy and COPD.

RESULTS: At baseline, a difference in the expression of 17 genes was found in healthy and COPD subjects. Differential expression of genes after CSE stimulation resulted in significantly less changes in COPD lung fibroblasts (70 genes) than in healthy (207 genes), with 51 genes changed in both. COPD maintained low NOTCH signaling throughout and upregulated JUN >80%, indicating an increase in apoptosis. Healthy downregulated the Mitogen-activated protein kinase (MAPK) signaling cascade, including a ≥50% reduction in FGF2, CRK, TGFBR1 and MEF2A. Healthy also downregulated KAT6A and genes related to cell proliferation, all together indicating possible cell senescence signaling.

CONCLUSION: Overall, COPD lung fibroblasts responded to CSE stimulation with a very different and deficient expression profile compared to healthy. Highlighting that stimulated healthy cells are not an appropriate substitute for COPD cells which is important when investigating the mechanisms of COPD.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Pulmonary Disease, Chronic Obstructive/metabolism, Cigarette Smoking/adverse effects, Lung, Nicotiana, Fibroblasts, Gene Expression, Histone Acetyltransferases/genetics
in
International journal of chronic obstructive pulmonary disease
volume
18
pages
16 pages
publisher
Dove Medical Press Ltd.
external identifiers
  • scopus:85180243304
  • pmid:38143920
ISSN
1178-2005
DOI
10.2147/COPD.S422508
language
English
LU publication?
yes
additional info
© 2023 Garcia-Ryde et al.
id
1c64926a-d5c6-42b0-9bed-23a7654ae67f
date added to LUP
2023-12-31 17:01:49
date last changed
2024-04-16 05:27:04
@article{1c64926a-d5c6-42b0-9bed-23a7654ae67f,
  abstract     = {{<p>BACKGROUND AND AIM: Cigarette smoking is the most common cause of chronic obstructive pulmonary disease (COPD) but more mechanistic studies are needed. Cigarette smoke extract (CSE) can elicit a strong response in many COPD-related cell types, but no studies have been performed in lung fibroblasts. Therefore, we aimed to investigate the effect of CSE on gene expression in lung fibroblasts from healthy and COPD subjects.</p><p>PATIENTS AND METHODS: Primary lung fibroblasts, derived from six healthy and six COPD subjects (all current or ex-smokers), were either unstimulated (baseline) or stimulated with 30% CSE for 4 h prior to RNA isolation. The mRNA expression levels were measured using the NanoString nCounter Human Fibrosis V2 panel (760 genes). Pathway enrichment was assessed for unique gene ontology terms of healthy and COPD.</p><p>RESULTS: At baseline, a difference in the expression of 17 genes was found in healthy and COPD subjects. Differential expression of genes after CSE stimulation resulted in significantly less changes in COPD lung fibroblasts (70 genes) than in healthy (207 genes), with 51 genes changed in both. COPD maintained low NOTCH signaling throughout and upregulated JUN &gt;80%, indicating an increase in apoptosis. Healthy downregulated the Mitogen-activated protein kinase (MAPK) signaling cascade, including a ≥50% reduction in FGF2, CRK, TGFBR1 and MEF2A. Healthy also downregulated KAT6A and genes related to cell proliferation, all together indicating possible cell senescence signaling.</p><p>CONCLUSION: Overall, COPD lung fibroblasts responded to CSE stimulation with a very different and deficient expression profile compared to healthy. Highlighting that stimulated healthy cells are not an appropriate substitute for COPD cells which is important when investigating the mechanisms of COPD.</p>}},
  author       = {{Garcia-Ryde, Martin and van der Burg, Nicole M D and Larsson, Carin E and Larsson-Callerfelt, Anna-Karin and Westergren-Thorsson, Gunilla and Bjermer, Leif and Tufvesson, Ellen}},
  issn         = {{1178-2005}},
  keywords     = {{Humans; Pulmonary Disease, Chronic Obstructive/metabolism; Cigarette Smoking/adverse effects; Lung; Nicotiana; Fibroblasts; Gene Expression; Histone Acetyltransferases/genetics}},
  language     = {{eng}},
  month        = {{12}},
  pages        = {{2999--3014}},
  publisher    = {{Dove Medical Press Ltd.}},
  series       = {{International journal of chronic obstructive pulmonary disease}},
  title        = {{Lung Fibroblasts from Chronic Obstructive Pulmonary Disease Subjects Have a Deficient Gene Expression Response to Cigarette Smoke Extract Compared to Healthy}},
  url          = {{http://dx.doi.org/10.2147/COPD.S422508}},
  doi          = {{10.2147/COPD.S422508}},
  volume       = {{18}},
  year         = {{2023}},
}