p53: A Key Protein That Regulates Pulmonary Fibrosis

Wu, Qi; Zhang, Kejia; Jiang, Shanwen; Fu, Lu; Shi, Yue; Tan, Rubin; Cui, Jie; Zhou, Yao

doi:10.1155/2020/6635794

Cited by 46 publications

(29 citation statements)

References 95 publications

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“…In addition, as described in biopsies from IPF patients [ 25 , 26 ], TUNEL-positive apoptotic cells were seen ( Supplemental Figure S1 ). We also observed the induction of cell cycle regulators p21WAF1 and p16INK4 ( Supplemental Figure S2 ) implicated in cellular senescence and aging and mainly reported in IPF lung biopsies [ 27 , 28 , 29 ]. All together, these results indicate that repetitive instillations of low-dose BLM induce chronic and moderate lung fibrotic disease that recapitulates most of the characteristics of IPF [ 30 ].…”

Section: Discussionsupporting

confidence: 55%

A New Model of Acute Exacerbation of Experimental Pulmonary Fibrosis in Mice

Yegen

Haine

Ferreira

et al. 2022

Cells

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Rationale: idiopathic pulmonary fibrosis (IPF) is the most severe form of fibrosing interstitial lung disease, characterized by progressive respiratory failure leading to death. IPF’s natural history is heterogeneous, and its progression unpredictable. Most patients develop a progressive decline of respiratory function over years; some remain stable, but others present a fast-respiratory deterioration without identifiable cause, classified as acute exacerbation (AE). Objectives: to develop and characterize an experimental mice model of lung fibrosis AE, mimicking IPF-AE at the functional, histopathological, cellular and molecular levels. Methods: we established in C57BL/6 male mice a chronic pulmonary fibrosis using a repetitive low-dose bleomycin (BLM) intratracheal (IT) instillation regimen (four instillations of BLM every 2 weeks), followed by two IT instillations of a simple or double-dose BLM challenge to induce AE. Clinical follow-up and histological and molecular analyses were done for fibrotic and inflammatory lung remodeling analysis. Measurements and main results: as compared with a low-dose BLM regimen, this AE model induced a late burst of animal mortality, worsened lung fibrosis and remodeling, and superadded histopathological features as observed in humans IPF-AE. This was associated with stronger inflammation, increased macrophage infiltration of lung tissue and increased levels of pro-inflammatory cytokines in lung homogenates. Finally, it induced in the remodeled lung a diffuse expression of hypoxia-inducible factor 1α, a hallmark of tissular hypoxia response and a major player in the progression of IPF. Conclusion: this new model is a promising model of AE in chronic pulmonary fibrosis that could be relevant to mimic IPF-AE in preclinical trials.

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Section: Discussionsupporting

confidence: 55%

A New Model of Acute Exacerbation of Experimental Pulmonary Fibrosis in Mice

Yegen

Haine

Ferreira

et al. 2022

Cells

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“…In our study, the mRNA expression levels of PIK3CA and AKT1 in MRC-5 cells increased after TGF- β 1 stimulation and reduced after administration of ZBM, suggesting that ZBM has a regulatory effect on the PI3K/AKT pathway. Mouse double minute 2 (MDM2) mediates the ubiquitination of p53 (one of the key regulators of IPF [ 52 ]) and is responsible for the inhibition of p53 activity, making it important for the regulation of cellular homeostasis [ 53 ]. Interestingly, AKT can promote the activation of MDM2 through phosphorylation, indicating that the regulation of AKT signaling also affects MDM2 [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Systematic Analysis Strategy Based on Network Pharmacology to Investigate the Potential Mechanism of Fritillaria thunbergii Miq. against Idiopathic Pulmonary Fibrosis

Feng

Sun

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Idiopathic pulmonary fibrosis (IPF) is a long-term, distressing, and age-related interstitial lung disease characterized by a complicated etiology and irreversible progression. Fritillaria thunbergii Miq. (Zhe Beimu, ZBM) is frequently used for its heat-clearing and phlegm-resolving properties in herbal compounds for the treatment of IPF. However, the specific mechanisms underlying the effects of ZBM against IPF have not yet been reported. In this study, we applied a systematic analysis strategy based on network pharmacology to explore the probable core targets and major pathways of ZBM against IPF. In addition, molecular docking simulation and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to preliminarily investigate the possible mechanisms underlying the therapeutic effects of ZBM on IPF. We collected a total of 86 components of ZBM and used network pharmacology analysis to screen nine presumptive targets of ZBM against IPF. The molecular-docking results indicated that the components of ZBM exhibited good binding activity with presumptive targets. The qRT-PCR results also suggested that ZBM may partly alleviate IPF by regulating the expression of presumptive targets. This study laid the foundation for further clinical applications of ZBM and the development of IPF-related therapeutic products.

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“…Physiologically, p53 protein is unstable and maintained at low levels under the action of negative regulatory factors in cells ( Brooks and Gu, 2006 ; Blandino and Di Agostino, 2018 ) ( Figure 1 ). However, TP53 is extremely susceptible to mutating all cancer types ( Zhu et al, 2015 ; Sabapathy and Lane, 2019 ), it undergoes a variety of mutations such as point mutation, deletion, frameshift and rearrangement ( Wu et al, 2020 ). When TP53 is mutated, the encoded P53 protein obtains a prolonged half-life and strong stability, which continuously accumulates in the nucleus and loses its monitoring functions ( Itahana and Itahana, 2018 ).…”

Section: P53 Is Required For the Anti-fibrosis Processmentioning

confidence: 99%

“…In response to silica, upregulation of p53 activates the RMRP/miR122 signaling pathway and promotes epithelial-mesenchymal transition (EMT), leading to the progression of pulmonary fibrosis in BALB/c mice ( Li et al, 2021 ). Accordingly, the lung tissue damage and collagen deposition in p53 deficient mice are significantly reduced compared with wild-type mice, suggesting that inhibition of p53 expression could delay the progression of lung fibrosis ( Wu et al, 2020 ).…”

Section: P53 Is Required For the Anti-fibrosis Processmentioning

confidence: 99%

The role of p53 in liver fibrosis

Zhang

2022

Front. Pharmacol.

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The tumor suppressor p53 is the central hub of a molecular network, which controls cell proliferation and death, and also plays an important role in the occurrence and development of liver fibrosis. The abundant post-translational processing and modification endow the functional diversity of p53. Considering the relationship between p53 and liver fibrosis, drug intervention targeting p53 or management of p53 regulation might be effective strategies to treat liver fibrosis. Here, we systematically discuss the regulation of p53 in different liver cells (hepatocytes, immune cells, HSCs, etc) and the role of p53 in the development of liver fibrosis, and propose possible interventions to prevent the pathogenic processes of liver fibrosis.

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p53: A Key Protein That Regulates Pulmonary Fibrosis

Cited by 46 publications

References 95 publications

A New Model of Acute Exacerbation of Experimental Pulmonary Fibrosis in Mice

A New Model of Acute Exacerbation of Experimental Pulmonary Fibrosis in Mice

Systematic Analysis Strategy Based on Network Pharmacology to Investigate the Potential Mechanism of Fritillaria thunbergii Miq. against Idiopathic Pulmonary Fibrosis

The role of p53 in liver fibrosis

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