Cellular Senescence in Idiopathic Pulmonary Fibrosis

Kellogg, Dean L.; Musi, Nicolas; Nambiar, Anoop M.

doi:10.1007/s40610-021-00145-4

Cited by 37 publications

(34 citation statements)

References 115 publications

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“…On the one hand, senescence may act as a mechanism limiting fibrosis in liver, heart, and wound healing (Jun & Lau, 2010 ; Krizhanovsky et al, 2008 ; Meyer et al, 2016 ). On the other hand, it has also been proposed that senescence can promote fibrosis in other settings, including lung, kidney, and pancreas fibrotic diseases (Kellogg et al, 2021 ; Schafer et al, 2017 ). Our results clearly show the downregulation of myofibroblast markers in cellular models of senescence.…”

Section: Discussionmentioning

confidence: 99%

Dynamic regulation of myofibroblast phenotype in cellular senescence

et al. 2022

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Cellular senescence is an antiproliferative response with a critical role in the control of cellular balance in diverse physiological and pathological settings. Here, we set to study the impact of senescence on the regulation of cell plasticity, focusing on the regulation of the myofibroblastic phenotype in primary fibroblasts. Myofibroblasts are contractile, highly fibrogenic cells with key roles in wound healing and fibrosis. Using cellular models of fibroblast senescence, we find a consistent loss of myofibroblastic markers and functional features upon senescence implementation. This phenotype can be transmitted in a paracrine manner, most likely through soluble secreted factors. A dynamic transcriptomic analysis during paracrine senescence confirmed the non‐cell‐autonomous transmission of this phenotype. Moreover, gene expression data combined with pharmacological and genetic manipulations of the major SASP signaling pathways suggest that the changes in myofibroblast phenotype are mainly mediated by the Notch/TGF‐β axis, involving a dynamic switch in the TGF‐β pathway. Our results reveal a novel link between senescence and myofibroblastic differentiation with potential implications in the physiological and pathological functions of myofibroblasts.

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Section: Discussionmentioning

confidence: 99%

Dynamic regulation of myofibroblast phenotype in cellular senescence

et al. 2022

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“…Aging is an important factor in IPF and can give rise to non-functional and pro-inflammatory senescent cells [ 35 ]. Senescence has gained significant interest in the past decade, and strategies to clear senescent cells during IPF are actively tested [ 36 , 37 , 38 , 39 ]. Beyond senescence, hypoxia is a major hallmark of IPF, where scar tissue deposition hampers gas exchange.…”

Section: The Physiopathology Of Pulmonary Fibrosismentioning

confidence: 99%

Extracellular Lipids in the Lung and Their Role in Pulmonary Fibrosis

Burgy

Loriod

Beltramo

et al. 2022

Cells

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Lipids are major actors and regulators of physiological processes within the lung. Initial research has described their critical role in tissue homeostasis and in orchestrating cellular communication to allow respiration. Over the past decades, a growing body of research has also emphasized how lipids and their metabolism may be altered, contributing to the development and progression of chronic lung diseases such as pulmonary fibrosis. In this review, we first describe the current working model of the mechanisms of lung fibrogenesis before introducing lipids and their cellular metabolism. We then summarize the evidence of altered lipid homeostasis during pulmonary fibrosis, focusing on their extracellular forms. Finally, we highlight how lipid targeting may open avenues to develop therapeutic options for patients with lung fibrosis.

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“…Additionally, some studies have highlighted that a variety of aging-related pathways are activated in epithelial cells, fibroblasts, and progenitor cells in the lungs of patients with IPF (Mora et al, 2017;Chen et al, 2019); these activated pathways promote abnormal secretory phenotype in lung epithelial cells, augment the resistance of myofibroblasts to apoptosis, and accelerate IPF progression. In the lung biopsies of patients with IPF, the level of SA-β-gal, a specific cellular senescence marker, was increased compared to that in patients with chronic obstructive pulmonary disease or hypersensitivity pneumonitis (Kellogg et al, 2021). Kim et al (2021) evaluated the genomic profile of fibrotic and normal lung tissues and found that the core molecular network of IPF featured p53 signaling pathway and cellular senescence.…”

Section: Introductionmentioning

confidence: 99%

Identification and Validation of Aging-Related Genes in Idiopathic Pulmonary Fibrosis

2022

Front. Genet.

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Aging plays a significant role in the occurrence and development of idiopathic pulmonary fibrosis (IPF). In this study, we aimed to identify and verify potential aging-associated genes involved in IPF using bioinformatic analysis. The mRNA expression profile dataset GSE150910 available in the Gene Expression Omnibus (GEO) database and R software were used to identify the differentially expressed aging-related genes involved in IPF. Hub gene expression was validated by other GEO datasets. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on differentially expressed aging-related genes. Subsequently, aging-related genes were further screened using three techniques (least absolute shrinkage and selection operator (LASSO) regression, support vector machine, and random forest), and the receiver operating characteristic curves were plotted based on screening results. Finally, real-time quantitative polymerase chain reaction (qRT-PCR) was performed to verify the RNA expression of the six differentially expressed aging-related genes using the blood samples of patients with IPF and healthy individuals. Sixteen differentially expressed aging-related genes were detected, of which the expression of 12 were upregulated and four were downregulated. GO and KEGG enrichment analyses indicated the presence of several enriched terms related to senescence and apoptotic mitochondrial changes. Further screening by LASSO regression, support vector machine, and random forest identified six genes (IGF1, RET, IGFBP2, CDKN2A, JUN, and TFAP2A) that could serve as potential diagnostic biomarkers for IPF. Furthermore, qRT-PCR analysis indicated that among the above-mentioned six aging-related genes, only the expression levels of IGF1, RET, and IGFBP2 in patients with IPF and healthy individuals were consistent with the results of bioinformatic analysis. In conclusion, bioinformatics analysis identified 16 potential aging-related genes associated with IPF, and clinical sample validation suggested that among these, IGF1, RET, and IGFBP2 might play a role in the incidence and prognosis of IPF. Our findings may help understand the pathogenesis of IPF.

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Cellular Senescence in Idiopathic Pulmonary Fibrosis

Cited by 37 publications

References 115 publications

Dynamic regulation of myofibroblast phenotype in cellular senescence

Dynamic regulation of myofibroblast phenotype in cellular senescence

Extracellular Lipids in the Lung and Their Role in Pulmonary Fibrosis

Identification and Validation of Aging-Related Genes in Idiopathic Pulmonary Fibrosis

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