The cyclooxygenase-2-prostaglandin E2 pathway maintains senescence of chronic obstructive pulmonary disease fibroblasts
- PMID: 23328527
- DOI: 10.1164/rccm.201208-1361OC
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.
Similar articles
-
Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4.Pharmacol Rev. 2024 May 2;76(3):388-413. doi: 10.1124/pharmrev.123.000901. Pharmacol Rev. 2024. PMID: 38697857 Review.
-
Differential expression of E-type prostanoid receptors 2 and 4 in microglia stimulated with lipopolysaccharide.J Neuroinflammation. 2017 Jan 5;14(1):3. doi: 10.1186/s12974-016-0780-7. J Neuroinflammation. 2017. PMID: 28086956 Free PMC article.
-
Prostaglandin E₂ possesses different potencies in inducing Vascular Endothelial Growth Factor and Interleukin-8 production in COPD human lung fibroblasts.Prostaglandins Leukot Essent Fatty Acids. 2016 Mar;106:11-8. doi: 10.1016/j.plefa.2016.01.005. Epub 2016 Feb 6. Prostaglandins Leukot Essent Fatty Acids. 2016. PMID: 26926362
-
Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors.Biochim Biophys Acta. 2015 Apr;1851(4):414-21. doi: 10.1016/j.bbalip.2014.07.008. Epub 2014 Jul 17. Biochim Biophys Acta. 2015. PMID: 25038274 Review.
-
Phosphodiesterase-4 inhibition augments human lung fibroblast vascular endothelial growth factor production induced by prostaglandin E2.Am J Respir Cell Mol Biol. 2013 Oct;49(4):571-81. doi: 10.1165/rcmb.2013-0004OC. Am J Respir Cell Mol Biol. 2013. PMID: 23656623
Cited by
-
The cyclooxygenase-2 upregulation mediates production of PGE2 autacoid to positively regulate interleukin-6 secretion in chronic rhinosinusitis with nasal polyps and polyp-derived fibroblasts.Sci Rep. 2024 Mar 30;14(1):7559. doi: 10.1038/s41598-024-58143-2. Sci Rep. 2024. PMID: 38555391 Free PMC article.
-
Non-Intrinsic, Systemic Mechanisms of Cellular Senescence.Cells. 2023 Dec 5;12(24):2769. doi: 10.3390/cells12242769. Cells. 2023. PMID: 38132089 Free PMC article. Review.
-
Thrombin-Induced COX-2 Expression and PGE2 Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation.Int J Mol Sci. 2023 Oct 13;24(20):15130. doi: 10.3390/ijms242015130. Int J Mol Sci. 2023. PMID: 37894811 Free PMC article.
-
Comparable Response Following Exposure to Biodiesel and Diesel Exhaust Particles in Advanced Multicellular Human Lung Models.Toxics. 2023 Jun 14;11(6):532. doi: 10.3390/toxics11060532. Toxics. 2023. PMID: 37368632 Free PMC article.
-
EPC-exosomal miR-26a-5p improves airway remodeling in COPD by inhibiting ferroptosis of bronchial epithelial cells via PTGS2/PGE2 signaling pathway.Sci Rep. 2023 Apr 14;13(1):6126. doi: 10.1038/s41598-023-33151-w. Sci Rep. 2023. PMID: 37059741 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous