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The Cyclooxygenase-2–Prostaglandin E2 Pathway Maintains Senescence of Chronic Obstructive Pulmonary Disease Fibroblasts
Abstract
Rationale: Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by the irreversible loss of replicative capacity associated with the secretion of inflammatory mediators. However, the mechanisms of this phenomenon remain poorly defined. Objectives: The aim of this study was to analyze the role of prostaglandin E2 (PGE2), a prostaglandin known to be increased in COPD lung fibroblasts, in inducing senescence and related inflammation in vitro in lung fibroblasts and in vivo in mice. Methods: Fibroblasts were isolated from patients with COPD and from smoker and nonsmoker control subjects. Senescence markers and inflammatory mediators were investigated in fibroblasts and in mice. Measurements and Main Results: Lung fibroblasts from patients with COPD exhibited higher expression of PGE2 receptors EP2 and EP4 as compared with nonsmoker and smoker control subjects. Compared with both nonsmoker and smoker control subjects, during long-term culture, COPD fibroblasts displayed increased senescent markers (increased senescence associated-β galactosidase activity, p16, and p53 expression and lower proliferative capacity), and an increased PGE2, IL-6, IL-8, growth-regulated oncogene (GRO), CX3CL1, and matrix metalloproteinase-2 protein and cyclooxygenase-2 and mPGES-1 mRNA expression. Using in vitro pharmacologic approaches and in vivo experiments in wild-type and p53−/− mice we demonstrated that PGE2 produced by senescent COPD fibroblasts is responsible for the increased senescence and related inflammation. PGE2 acts either in a paracrine or autocrine fashion by a pathway involving EP2 and EP4 prostaglandin receptors, cyclooxygenase-2–dependent reactive oxygen species production and signaling, and consecutive p53 activation. Conclusions: PGE2 is a critical component of an amplifying and self-perpetuating circle inducing senescence and inflammation in COPD fibroblasts. Modulating the described PGE2 signaling pathway could provide a new basis to dampen senescence and senescence-associated inflammation in COPD.
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“Senescent cells are known to produce prostaglandin E2 (PGE2) (Cormenier et al., 2018; Dagouassat et al., 2013; Kabir et al., 2016; Martien et al., 2013; Yang et al., 2011; Zdanov et al., 2007)”
From Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis (2021) · cites this paper as Dagouassat et al., 2013
In the citing paper
“Senescence of these cells plays direct (impaired re-epithelialization) and indirect (increased release of inflammatory mediators) contributing roles in the pathogenesis of COPD/emphysema (1–3, 46).”
From Impaired mitophagy leads to cigarette smoke stress‐induced cellular senescence: implications for chronic obstructive pulmonary disease (2015) · cites this paper as [46]
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Metadata
- Authors
- Dagouassat, M., Gagliolo, J.-M., Chrusciel, S., Bourin, M.-C., Duprez, C., Caramelle, P., Boyer, L., Hue, S., Stern, J.-B., Validire, P., Longrois, D., Norel, X., Dubois-Randé, J.-L., Le Gouvello, S., Adnot, S., & Boczkowski, J.
- Affiliations
- Inserm (FR)
- Service d’Immunologie Biologique
- Faculté de Médecine, Université Paris-Est, UMR U955, Créteil, France
- Département Thoracique and
- Institute Mutualiste Montsouris (FR)
- Corresponding author
- Boczkowski, Jorge
- ORCID
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-04-01
- Volume
- 187
- Issue
- 7
- Pages
- 703-714
- ISSN
- 1073-449X (ISSN-L)
- 1535-4970
- OpenAlex
- W2034209637
- Cited by
- 120
- References
- 52
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 7 · 2023: 11 · 2022: 9 · 2021: 11 · 2020: 8 · 2019: 5 · 2018: 10 · 2017: 3 · 2016: 8 · 2015: 14 · 2014: 13 · 2013: 2
- FWCI
- 10.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
- Keywords
- chronic obstructive pulmonary disease, fibroblast senescence, cyclooxygenase-2, prostaglandin E2, EP2 receptor, EP4 receptor, senescence-associated inflammation, p53 activation, reactive oxygen species, MMP-2, interleukin-6, interleukin-8, smoking, senescence-associated β-galactosidase, p16
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Animals, Cells, Cultured, Female, Fibroblasts, Humans, Lung, Male, Mice, Inbred C57BL, Middle Aged, Dinoprostone, Case-Control Studies, Genes, p53, Reactive Oxygen Species, Statistics, Nonparametric, Autocrine Communication, Paracrine Communication, Pulmonary Disease, Chronic Obstructive, Mice, Cyclooxygenase 2, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Prostaglandin E, EP4 Subtype
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