The Cyclooxygenase-2–Prostaglandin E<sub>2</sub>Pathway Maintains Senescence of Chronic Obstructive Pulmonary Disease Fibroblasts

Dagouassat, Maylis; Gagliolo, Jean-Marie; Chrusciel, Sandra; Bourin, Marie-Claude; Duprez, Corinne; Caramelle, Philippe; Boyer, Laurent; Hüe, Sophie; Stern, Jean‐Baptiste; Validire, Pierre; Longrois, Dan; Norel, Xavier; Dubois‐Randé, Jean‐Luc; Gouvello, Sabine Le; Adnot, Serge; Boczkowski, Jorge

doi:10.1164/rccm.201208-1361oc

Cited by 94 publications

(88 citation statements)

References 49 publications

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“…Senescent cells contribute to aging and age-related disease by generating a low-grade inflammatory state (42). Our results suggested that cellular senescence may promote inflammation, which is consistent with the findings of other studies demonstrating an increased production of IL-6 and IL-8 by senescent fibroblasts and epithelial cells (43,44). IL-6 and IL-8 may stimulate angiogenesis, enforce macrophage function and induce innate immune responses (45).…”

Section: Discussionsupporting

confidence: 90%

Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration

Liu

Cao

Yang

et al. 2014

International Journal of Molecular Medicine

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Abstract. Drusen are considered a hallmark characteristic of age-related macular degeneration (AMD). In our previous study, we found that amyloid-β (Aβ) peptide, a component of drusen, induced the cells of the retinal pigment epithelium (RPE; RPE cells) to enter senescence; however, its effects in vivo remain unknown. Thus, the present study was carried out to explore the in vivo effects of Aβ peptide on RPE cell senescence and senescence-associated inflammation in C57BL/6 mice. C57BL/6 mice received a subretinal injection of Aβ(1-42) peptide; on day 7 post-injection, the mice were anesthetized and subjected to whole-body perfusion with 4% paraformaldehyde (PFA) in PBS and the whole eyes were then enucleated. Retinal function was assessed by electroretinography (ERG), and the morphological characteristics of the retina were examined by light and electron microscopy. Fundus autofluorescence (FAF) was examined by confocal scanning laser ophthalmoscopy (cSLO). The expression of p16INK4a , a marker of cellular senescence, was examined by immunofluorescence staining and western blot analysis. The RPE-choroid was analyzed for cytokine expression by RT-PCR. In Aβ(1-42)-injected mice, scotopic ERG responses declined. Degenerative alterations, including the disruption of the inner segment (IS)/outer segment (OS) junction and extensive vacuolation and thickness of Bruch's membrane (BrM) were observed under a a light microscope. The accumulation of vacuoles and the loss of basal infoldings in the RPE were identified using an electron microscope. FAF and p16INK4a expression increased in Aβ(1-42)-injected mice. In addition, Aβ(1-42) upregulated interleukin (IL)-6 and IL-8 gene expression in the RPE-choroid. In conclusion, our results confirm the effects of Aβ(1-42) peptide on RPE senescence in vivo. The Aβ-injected mice developed AMD-like ocular pathology. It is thus suggested that RPE cell senescence is a potential mechanistic link between inflammation and retinal degeneration.

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Section: Discussionsupporting

confidence: 90%

Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration

Liu

Cao

Yang

et al. 2014

International Journal of Molecular Medicine

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“…These results suggest that FOXF1 may participate in compensatory mechanisms to fibrogenesis. Since FOXF1 is induced by the p53 family (42) and PGE 2 activates the p53 pathway in fibroblasts (9), it may be hypothesized that this pathway participated in FOXF1 repression by PGE 2 .…”

Section: Discussionmentioning

confidence: 99%

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

Melboucy‐Belkhir

Pradère

Tadbiri

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Aberrant expression of master phenotype regulators or alterations in their downstream pathways in lung fibroblasts may play a central role in idiopathic pulmonary fibrosis (IPF). Interrogating IPF fibroblast transcriptome datasets, we identified Forkhead Box F1 (FOXF1), a DNA-binding protein required for lung development, as a candidate actor in IPF. Thus we determined FOXF1 expression levels in fibroblasts cultured from normal or IPF lungs in vitro, and explored FOXF1 functions in these cells using transient and stable loss-of-function and gain-of-function models. FOXF1 mRNA and protein were expressed at higher levels in IPF fibroblasts compared with normal fibroblasts (mRNA: ϩ44%, protein: ϩ77%). Immunohistochemistry showed FOXF1 expression in nuclei of bronchial smooth muscle cells, endothelial cells, and lung fibroblasts including fibroblastic foci of IPF lungs. In normal lung fibroblasts, FOXF1 repressed cell growth and expression of collagen-1 (COL1) and actin-related protein 2/3 complex, subunit 2 (ARPC2). ARPC2 knockdown inhibited cell growth and COL1 expression, consistent with FOXF1 acting in part through ARPC2 repression. In IPF fibroblasts, COL1 and ARPC2 repression by FOXF1 was blunted, and FOXF1 did not repress growth. FOXF1 expression was induced by the antifibrotic mediator prostaglandin E 2 and repressed by the profibrotic cytokine transforming growth factor-␤1 in both normal and IPF lung fibroblasts. Ex vivo, FOXF1 knockdown conferred CCL-210 lung fibroblasts the ability to implant in uninjured mouse lungs. In conclusion, FOXF1 functions and regulation were consistent with participation in antifibrotic pathways. Alterations of pathways downstream of FOXF1 may participate to fibrogenesis in IPF fibroblasts.

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“…Senescent cells exhibit a complex phenotype characterized by permanent cell cycle arrest mediated by the p53 and/or p16/Rb pathways; increased cell size; altered cell morphology; resistance to apoptosis; altered gene expression, including β-galactosidase (β-Gal) upregulation; and a unique secretory phenotype known as the senescence-associated secretory phenotype (SASP) (8). We previously reported that a characteristic feature of COPD is the accumulation of senescent cells in the lung, which limits the potential for tissue renewal and contributes to chronic inflammation through the SASP (11)(12)(13). Whether cell senescence plays a causal role in the pathogenesis of COPD, however, remains unknown, and the mechanisms underlying cell senescence in COPD need to be clarified.…”

Section: Introductionmentioning

confidence: 99%

mTOR pathway activation drives lung cell senescence and emphysema

et al. 2018

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The Cyclooxygenase-2–Prostaglandin E₂Pathway Maintains Senescence of Chronic Obstructive Pulmonary Disease Fibroblasts

Abstract: 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.

Cited by 94 publications

References 49 publications

Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration

Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

mTOR pathway activation drives lung cell senescence and emphysema

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The Cyclooxygenase-2–Prostaglandin E2Pathway Maintains Senescence of Chronic Obstructive Pulmonary Disease Fibroblasts

Abstract: 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.

Cited by 94 publications

References 49 publications

Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration

Subretinal injection of amyloid-β peptide accelerates RPE cell senescence and retinal degeneration

Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro

mTOR pathway activation drives lung cell senescence and emphysema

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Product

Resources

About

The Cyclooxygenase-2–Prostaglandin E₂Pathway Maintains Senescence of Chronic Obstructive Pulmonary Disease Fibroblasts