The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration

Lv, Xin; Liu, Chang; Liu, Shanshan; Li, Yunxuan; Wang, Wanyu; Li, Ké; Hua, Fang; Cui, Bing; Zhang, Xiaowei; Yu, Jiaojiao; Yu, J. Jessica; Hu, Zhuo‐Wei

doi:10.1016/j.apsb.2021.07.015

Cited by 23 publications

(23 citation statements)

References 34 publications

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“…DKC1 mutant iAT2 cells displayed a senescent phenotype that included upregulation of the p21 cyclin-dependent kinase inhibitor. Recent observations have revealed similar p21 upregulation in the AT2 cells of human PF lungs and have also demonstrated a causal role for p21 in driving experimental PF in mice ( Lee et al, 2021 ; Lv et al, 2022 ). Senescence of the mutant iAT2 cells manifested only after serial passaging and telomere shortening, demonstrating that the senescence is not a direct result of DKC1 mutation per se.…”

Section: Discussionmentioning

confidence: 72%

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

Fernández

Gardner

Slovik

et al. 2022

eLife

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Dyskeratosis congenita (DC) is a rare genetic disorder characterized by deficiencies in telomere maintenance leading to very short telomeres and the premature onset of certain age-related diseases, including pulmonary fibrosis (PF). PF is thought to derive from epithelial failure, particularly that of type II alveolar epithelial (AT2) cells, which are highly dependent on Wnt signaling during development and adult regeneration. We use human iPSC-derived AT2 (iAT2) cells to model how short telomeres affect AT2 cells. Cultured DC mutant iAT2 cells accumulate shortened, uncapped telomeres and manifest defects in the growth of alveolospheres, hallmarks of senescence, and apparent defects in Wnt signaling. The GSK3 inhibitor, CHIR99021, which mimics the output of canonical Wnt signaling, enhances telomerase activity and rescues the defects. These findings support further investigation of Wnt agonists as potential therapies for DC related pathologies.

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Section: Discussionmentioning

confidence: 72%

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

Fernández

Gardner

Slovik

et al. 2022

eLife

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“…Both pathways can activate the downstream cyclin-dependent kinase inhibitor p21 ( Barnes et al, 2019 ). Activating p21 causes cells to exit the cell cycle, resulting in a permanent cell cycle arrest ( Lv et al, 2021 ). In a recent study, researchers found that p53 and p21 were significantly highly expressed in the lung tissue of PF patients.…”

Section: Discussionmentioning

confidence: 99%

Yiqi Huayu decoction alleviates bleomycin-induced pulmonary fibrosis in rats by inhibiting senescence

Zuo

et al. 2022

Front. Pharmacol.

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Overview: In treating pulmonary fibrosis (PF), traditional Chinese medicine (TCM) has received much attention, but its mechanism is unclear. The pharmacological mechanisms of TCM can be explored through network pharmacology. However, due to its virtual screening properties, it still needs to be verified by in vitro or in vivo experiments. Therefore, we investigated the anti-PF mechanism of Yiqi Huayu Decoction (YHD) by combining network pharmacology with in vivo experiments.Methods: Firstly, we used classical bleomycin (BLM)-induced rat model of PF and administrated fibrotic rats with YHD (low-, medium-, and high-dose). We comprehensively assessed the treatment effect of YHD according to body weight, lung coefficient, lung function, and histopathologic examination. Second, we predict the potential targets by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) combined with network pharmacology. In brief, we obtained the chemical ingredients of YHD based on the UHPLC-MS/MS and TCMSP database. We collected drug targets from TCMSP, HERB, and Swiss target prediction databases based on active ingredients. Disease targets were acquired from drug libraries, Genecards, HERB, and TTD databases. The intersecting targets of drugs and disease were screened out. The STRING database can obtain protein-protein interaction (PPI) networks and hub target proteins. Molecular Complex Detection (MCODE) clustering analysis combined with enrichment analysis can explore the possible biological mechanisms of YHD. Enrichment analyses were conducted through the R package and the David database, including the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Reactome. Then, we further validated the target genes and target proteins predicted by network pharmacology. Protein and gene expression detection by immunohistochemistry, Western blot (WB), and real-time quantitative PCR (rt-qPCR).Results: The results showed that high-dose YHD effectively attenuated BLM-induced lung injury and fibrosis in rats, as evidenced by improved lung function, relief of inflammatory response, and reduced collagen deposition. We screened nine core targets and cellular senescence pathways by UHPLC-MS/MS analysis and network pharmacology. We subsequently validated key targets of cellular senescence signaling pathways. WB and rt-qPCR indicated that high-dose YHD decreased protein and gene expression of senescence-related markers, including p53 (TP53), p21 (CDKN1A), and p16 (CDKN2A). Increased reactive oxygen species (ROS) are upstream triggers of the senescence program. The senescence-associated secretory phenotypes (SASPs), containing interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-β1 (TGF-β1), can further exacerbate the progression of senescence. High-dose YHD inhibited ROS production in lung tissue and consistently reduced the SASPs expression in serum.Conclusion: Our study suggests that YHD improves lung pathological injury and lung function in PF rats. This protective effect may be related to the ability of YHD to inhibit cellular senescence.

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“…A large number of senescent AT2 cells were found in COVID-19-induced acute lung injury (ALI), [104] ventilation, [105] influenza, [106] LPS, [107] and chronic lung diseases, such as lung fibrosis and COPD. [108 , 109] Senescent AT2 cells exhibited lower regenerative capacity, as demonstrated by their impaired regeneration-related signaling pathways, [108] decreased AT2 and AT1 cell markers, [110] minimal stemness markers, [111] and lower proliferation markers. [104] The mechanism linking AT2 cells senescence to impaired lung repair has also been partly revealed.…”

Section: Pulmonary Endogenous Stem Cellsmentioning

confidence: 99%

Pulmonary endogenous progenitor stem cell subpopulation: Physiology, pathogenesis, and progress

Liu

Jiang

et al. 2023

Journal of Intensive Medicine

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The cell cycle inhibitor P21 promotes the development of pulmonary fibrosis by suppressing lung alveolar regeneration

Cited by 23 publications

References 34 publications

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

Yiqi Huayu decoction alleviates bleomycin-induced pulmonary fibrosis in rats by inhibiting senescence

Pulmonary endogenous progenitor stem cell subpopulation: Physiology, pathogenesis, and progress

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