Senescent Cells in IPF: Locked in Repair?

Meiners, Silke; Lehmann, Mareike

doi:10.3389/fmed.2020.606330

Cited by 12 publications

(7 citation statements)

References 48 publications

(74 reference statements)

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“…Senescence is a well-established feature in IPF 28 . Senescent cells dictate the generation of several age-related phenotypes, and their removal from aged tissues can prevent or delay organ dysfunction and lengthen healthspan 29 .…”

Section: Discussionmentioning

confidence: 99%

Standard of care drugs do not modulate activity of senescent primary human lung fibroblasts

Badaró-Garcia

Hohmann

Coelho

et al. 2023

Sci Rep

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Cellular senescence is crucial in the progression of idiopathic pulmonary fibrosis (IPF), but it is not evident whether the standard-of-care (SOC) drugs, nintedanib and pirfenidone, have senolytic properties. To address this question, we performed colorimetric and fluorimetric assays, qRT-PCR, and western blotting to evaluate the effect of SOC drugs and D + Q on senescent normal and IPF lung fibroblasts. In this study, we found that SOC drugs did not provoke apoptosis in the absence of death ligand in normal or IPF senescent lung fibroblasts. Nintedanib increased caspase-3 activity in the presence of Fas Ligand in normal but not in IPF senescent fibroblasts. Conversely, nintedanib enhanced B cell lymphoma 2 expression in senescent IPF lung fibroblasts. Moreover, in senescent IPF cells, pirfenidone induced mixed lineage kinase domain-like pseudokinase phosphorylation, provoking necroptosis. Furthermore, pirfenidone increased transcript levels of FN1 and COL1A1 in senescent IPF fibroblasts. Lastly, D + Q augmented growth differentiation factor 15 (GDF15) transcript and protein levels in both normal and IPF senescent fibroblasts. Taken together, these results establish that SOC drugs failed to trigger apoptosis in senescent primary human lung fibroblasts, possibly due to enhanced Bcl-2 levels by nintedanib and the activation of the necroptosis pathway by pirfenidone. Together, these data revealed the inefficacy of SOC drugs to target senescent cells in IPF.

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Section: Discussionmentioning

confidence: 99%

Standard of care drugs do not modulate activity of senescent primary human lung fibroblasts

Badaró-Garcia

Hohmann

Coelho

et al. 2023

Sci Rep

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“…Senescence is a well-established feature of IPF (MEINERS; LEHMANN, 2020). Senescent cells implicate in the generation of age-related phenotypes, and their removal can prevent or delay tissue dysfunction and lengthen healthspan (BAKER; WIJSHAKE; TCHKONIA; LEBRASSEUR et al ., 2011).…”

Section: Discussionmentioning

confidence: 99%

Effects of anti-fibrotic standard of care drugs on senescent human lung fibroblasts

Garcia

Hohmann

Coelho

et al. 2022

Preprint

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RationaleCellular senescence is crucial in the progression of idiopathic pulmonary fibrosis (IPF), but it is yet unclear whether the standard-of-care (SOC) drugs nintedanib and pirfenidone have senolytic properties.ObjectivesWe attempted to illuminate the effects of SOC drugs on senescent normal and IPF lung fibroblasts in vitro.MethodsColorimetric/fluorimetric assays, qRT-PCR, and western blotting were used to evaluate the effect of SOC drugs on senescent normal and IPF lung fibroblasts.ResultsSOC drugs did not induce apoptosis in the absence of death ligands in either normal or IPF senescent cells. Nintedanib increased caspase-3 activity in the presence of Fas Ligand (FasL) in normal but not in IPF senescent fibroblasts. Conversely, nintedanib enhanced B cell lymphoma (Bcl)-2 expression in senescent IPF lung fibroblasts. Moreover, in senescent IPF cells, pirfenidone alone induced mixed lineage kinase domain-like pseudokinase (MLKL) phosphorylation, provoking necroptosis. However, fragmented gasdermin D, indicating pyroptosis, was not detected under any condition. In addition, SOC drugs increased transcript levels of fibrotic and senescence markers in senescent IPF fibroblasts, whereas D+Q inhibited all these markers. Finally, D+Q enhanced growth differentiation factor 15 (GDF15) transcript and protein levels in both normal and IPF senescent fibroblasts.ConclusionsIn the presence and absence of the extrinsic pro-apoptotic ligands, SOC drugs failed to trigger apoptosis in senescent fibroblasts, possibly due to enhanced Bcl-2 levels and the activation of the necroptosis pathway. SOC drugs elevated fibrotic and senescence markers in IPF lung fibroblasts. Together, these data demonstrated the inefficacy of SOC in targeting senescent cells. Further investigation is required to fully elucidate the therapeutic implications of SOC drugs on other senescent cell types in IPF.

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“…7,8 Multiple pathological conditions are characterized by increased abundance of SnCs. Examples include idiopathic pulmonary fibrosis, 26 osteoarthritis, 27 posttransplant state, inflammatory bowel disease, hepatocellular carcinoma, obesity, 28 and viral infections. 29 Whether accumulation of SnCs is related to the etiology in each of these conditions or is a compensatory mechanism is yet to be elucidated.…”

Section: Smentioning

confidence: 99%

Cellular Senescence in Aging, Tissue Repair, and Regeneration

Shvedova

Thanapaul

Thompson

et al. 2021

Plastic &Amp; Reconstructive Surgery

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Summary: Society and our healthcare system are facing unprecedented challenges due to the expansion of the older population. As plastic surgeons, we can improve care of our older patients through understanding the mechanisms of aging that inevitably impact their outcomes and well-being. One of the major hallmarks of aging, cellular senescence, has recently become the focus of vigorous research in academia and industry. Senescent cells, which are metabolically active but in a state of stable cell cycle arrest, are implicated in causing aging and numerous age-related diseases. Further characterization of the biology of senescence revealed that it can be both detrimental and beneficial to organisms depending on tissue context and senescence chronicity. Here, we review the role of cellular senescence in aging, wound healing, tissue regeneration, and other domains relevant to plastic surgery. We also review the current state of research on therapeutics that modulate senescence to improve conditions of aging.

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Senescent Cells in IPF: Locked in Repair?

Cited by 12 publications

References 48 publications

Standard of care drugs do not modulate activity of senescent primary human lung fibroblasts

Standard of care drugs do not modulate activity of senescent primary human lung fibroblasts

Effects of anti-fibrotic standard of care drugs on senescent human lung fibroblasts

Cellular Senescence in Aging, Tissue Repair, and Regeneration

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