Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis <i>In Vivo</i>

Hohmann, Miriam S. N.; Habiel, David M.; Coelho, Ana Lúcia; Verri, Waldiceu A.; Hogaboam, Cory M.

doi:10.1165/rcmb.2017-0289oc

Cited by 163 publications

(138 citation statements)

References 49 publications

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“…However, these studies differed from our study with respect to the animal model applied and the administration mode of quercetin. In agreement with our results, quercetin demonstrated positive effects in two other animal models of pulmonary fibrosis (50,51). Oral quercetin supplementation (100 mg/kg bodyweight per day) significantly reduced the hydroxyproline content in the lungs of young rats (10-12 weeks) instilled with bleomycin.…”

Section: Discussionsupporting

confidence: 91%

“…In aged mice (>12 months), intraperitoneally quercetin treatment (30 mg/kg every other day) seven days after bleomycin instillation reduced hydroxyproline content in the lungs as well. In this model, the antifibrotic effect of quercetin was combined with decreased pulmonary markers of senescence which in turn reduced the apoptosis resistance of pulmonary fibroblasts (51), indicating that quercetin can also reverse the apoptosis-resistant phenotype of fibroblasts in IPF.…”

Section: Discussionmentioning

confidence: 84%

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The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice

Boots

Veith

Albrecht

et al. 2020

Preprint

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Background Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal disease of which the etiology is still not fully understood. Current treatment comprises two FDA-approved drugs that can slow down yet not stop or reverse the disease. As IPF pathology is associated with an altered redox balance, adding a redox modulating component to current therapy might exert beneficial effects. Quercetin is a dietary antioxidant with strong redox modulating capacities that is suggested to exert part of its antioxidative effects via activation of the redox-sensitive transcription factor Nrf2 that regulates endogenous antioxidant levels. Therefore, the aim of the present study was to investigate if the dietary antioxidant quercetin can exert anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrogenesis through Nrf2-dependent restoration of redox imbalance. Methods Homozygous Nrf2 deficient mice and their wildtype littermates were fed a control diet without or with 800 mg quercetin per kg diet from 7 days prior to a single 1 µg/2µl per g BW bleomycin challenge until they were sacrificed 14 days afterwards. Lung tissue and plasma were collected to determine markers of fibrosis (expression of extracellular matrix genes and histopathology), inflammation (pulmonary gene expression and plasma levels of Tumor Necrosis Factor-α (TNFα) and Keratinocyte Chemoattrachtant (KC)), and redox balance (pulmonary gene expression of antioxidants and malondialdehyde-dG (MDA)- DNA adducts). Results Mice fed the enriched diet for 7 days prior to the bleomycin challenge had significantly enhanced plasma and pulmonary quercetin levels (11.08 ± 0.73 µM versus 7.05 ± 0.2 µM) combined with increased expression of Nrf2 and Nrf2-responsive genes compared to mice fed the control diet in lung tissue. Upon bleomycin treatment, quercetin-fed mice displayed reduced expression of collagen (COL1A2) and fibronectin (FN1) and a tendency of reduced inflammatory lesions (2.8 ± 0.7 versus 1.9 ± 0.8). These beneficial effects were accompanied by reduced pulmonary gene expression of TNFα and KC, but not their plasma levels, and enhanced Nrf2-induced pulmonary antioxidant defences. In Nrf2 deficient mice, no effect of the dietary antioxidant on either histology or inflammatory lesions was observed. Conclusion Quercetin exerts anti-fibrogenic and anti-inflammatory effects on bleomycin-induced pulmonary damage in mice possibly through modulation of the redox balance by inducing Nrf2. However, quercetin could not rescue the bleomycin-induced pulmonary damage indicating that quercetin alone cannot ameliorate the progression of IPF.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 84%

The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice

Boots

Veith

Albrecht

et al. 2020

Preprint

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“…In Drugbank experimental drugs, multiple drugs with great repositioning potential (Related Genes>500 and Diseases>20, Figure 3b, Table S3) were developed for fibrotic diseases and other diseases. Quercetin was discovered to ameliorate liver fibrosis through regulating macrophage infiltration and polarization, and it could alleviate IPF through fibroblasts apoptosis[29, 30]. Based on our results, we confirm that quercetin interacts with numerous genes and is strongly linked to multiple diseases (Repositioning score=0.856, Related Genes=3938, Diseases=150, Table S3).…”

Section: Resultssupporting

confidence: 70%

DrAFC: Drug Repositioning Through Anti-Fibrosis Characteristic

Gao

et al. 2020

Preprint

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16Fibrosis is a key component in the pathogenic mechanism of many diseases. These 17 diseases involving fibrosis may share common mechanisms, therapeutic targets and 18 therefore, common intervention strategies and medicines may be applicable for these 19 diseases. For this reason, deliberately introducing anti-fibrosis characteristics into 20 modelling may lead to more success in drug repositioning. In this study, anti-fibrosis 21 knowledge base was first built by collecting data from multiple resources. Both 22 structural and biological profiles were derived from the knowledge base and used for 23 constructing machine learning models including Structural Profile Prediction Model 24 (SPPM) and Biological Profile Prediction Model (BPPM). Three external public data 25 sets were employed for validation purpose and further exploration of potential 26 repositioning drugs in wider chemical space. The resulting SPPM and BPPM models 27 achieve area under the receiver operating characteristic curve (AUC) of 0.879 and 28 0.972 in the training set, and 0.814 and 0.874 in the testing set. Additionally, our 29 results also demonstrate that substantial amount of multi-targeting natural products 30 possess notable anti-fibrosis characteristics and might serve as encouraging candidates 31 in fibrosis treatment and drug repositioning. To leverage our methodology and 32 findings, we developed repositioning prediction platform, Drug Repositioning based 33 on Anti-Fibrosis Characteristic (Dr AFC) that is freely accessible via 34 https://www.biosino.org/drafc. 35 36

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“…Quercetin, a flavonoid found in apples, also activates AMPK as well as being a senolytic (16) and prevents the development of LPS-induced emphysema in mice (86). Quercetin also promotes apoptosis of IPF fibroblasts and reduces bleomycin-induced lung fibrosis in aged mice (87). There is growing evidence that intracellular oxidative stress from mitochondria is important in agerelated lung diseases, so a mitochondria-targeted antioxidant may be more useful.…”

Section: Targeting Senescence Pathwaysmentioning

confidence: 99%

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Barnes

Baker

Donnelly

2019

Am J Respir Crit Care Med

369

264

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Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16 INK4a respectively, leading to activation of p21 CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence. Loss of key anti-aging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN, thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a, which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6 and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing SASP and reversing cell cycle arrest in epithelial cells from peripheral airways of COPD patients. MiR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 MAP kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

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Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis In Vivo

Cited by 163 publications

References 49 publications

The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice

The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice

DrAFC: Drug Repositioning Through Anti-Fibrosis Characteristic

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

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