Involvement Of Aberrant Re-epithelialization With Cellular Senescence In IPF Pathogenesis

Minagawa, Shunsuke; Araya, Jun; Yumino, Yoko; Nojiri, Satoko; Kojima, Jun; Hara, Hiromichi; Numata, Takanori; Kawaishi, Makoto; Odaka, Makoto; Morikawa, Toshiaki; Nishimura, Stephen L.; Nakayama, Katsutoshi; Kuwano, Kazuyoshi

doi:10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a4923

Cited by 3 publications

(4 citation statements)

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“…There are multiple factors that might contribute to the impaired progenitor function of AEC2s during aging including apoptosis (Korfei et al, 2008), ER stress (Lawson et al, 2011), senescence (Minagawa et al, 2011), and mitochondria dysfunction (Bueno et al, 2015). ZIP8 deficiency added another critical player that contributes to the debilitated progenitor function of AEC2s in the aged lung.…”

Section: Discussionmentioning

confidence: 99%

“…Aging has also been linked to lung fibrosis in animal models (Bueno et al, 2018). Phenotypes of cellular aging including epithelial cell apoptosis (Korfei et al, 2008;Lawson et al, 2011), autophagy (Larson-Casey et al, 2016;Sosulski et al, 2015), senescence (Minagawa et al, 2011), telomere shortening (Alder et al, 2008;Naikawadi et al, 2016), mitochondria dysfunction (Bueno et al, 2015;Ryu et al, 2017), and oxidative stress (Anathy et al, 2018) are observed in IPF lungs. Although the concept that IPF is a disease of aging has been well accepted (Martinez et al, 2017;Selman et al, 2016;Thannickal, 2013), there are limited studies focusing on the agerelated mechanisms that contributes to the development and progression of IPF.…”

Section: Intrductionmentioning

confidence: 99%

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Zinc Metabolic Defect of Aging Alveolar Progenitors in Progressive Pulmonary Fibrosis

Liang

Huang

Liu

et al. 2020

Preprint

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Idiopathic pulmonary fibrosis (IPF) is a fatal form of interstitial lung disease and aging has been identified as a risk factor to the disease. Alveolar type II cells (AEC2s) function as progenitor cells in the lung. Growing evidences indicate that IPF results from repeating AEC2 injury and inadequate epithelial repair. We previously reported that there was a significant loss of alveolar progenitors in the lungs of patients with IPF. In our current study, we performed single cell RNA-seq of epithelial cells from lungs of patients with IPF and healthy donors as well as epithelial cells from old and young mouse lungs with bleomycin injury. We identified a defect of zinc metabolism of AEC2s from IPF lungs and bleomycin-injured old mouse lungs. We further discovered that a specific zinc transporter ZIP8 was down regulated in IPF AEC2s and AEC2s from aged mice. Loss of ZIP8 expression is associated with impaired AEC2 renewal through sirtuin signaling in aging and IPF. Targeted deletion of Zip8 in murine AEC2 compartment led to reduced AEC2 renewal capacity, impaired AEC2 recovery, and worsened lung fibrosis after bleomycin injury. In summary, we have identified novel metabolic defects of AEC2s during aging and in IPF which contribute to the pathogenesis of lung fibrosis. Therapeutic strategies to restore critical components of these metabolic programs could improve AEC2 progenitor activity and mitigate ongoing fibrogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Intrductionmentioning

confidence: 99%

Zinc Metabolic Defect of Aging Alveolar Progenitors in Progressive Pulmonary Fibrosis

Liang

Huang

Liu

et al. 2020

Preprint

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“…It has been reported that senescent metaplastic epithelial cells covering fibroblastic foci (FF) originated mainly from bronchioles in IPF lungs (24), and bronchiolization in distorted parenchyma is a characteristic pathologic finding in IPF lungs. In the context of IPF pathogenesis, TGF-b is known to induce lung epithelial cell senescence in a p21 dependent manner (25).…”

Section: Hbec-derived Evs Attenuate Tgf-b-induced Myofibroblast Diffementioning

confidence: 99%

Human bronchial epithelial cell-derived extracellular vesicle therapy for pulmonary fibrosis via inhibition of TGF-β-WNT crosstalk

Kadota

Fujita

Araya

et al. 2020

Preprint

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Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis, resulting in poor patient prognosis. An aberrant recapitulation of developmental lung gene expression, including genes for transforming growth factor (TGF)-β and WNT, has been widely implicated in the pathogenic IPF wound healing process that results from repetitive alveolar epithelial injury. Extracellular vesicles (EVs) have been shown to carry bioactive molecules and to be involved in various physiological and pathological processes. Here, we demonstrate that, by attenuating WNT signaling, human bronchial epithelial cell-derived EVs (HBEC EVs) inhibit TGF-β mediated induction of both myofibroblast differentiation and lung epithelial cellular senescence. This effect of HBEC EVs is more pronounced than that observed with mesenchymal stem cell-derived EVs. Mechanistically, the HBEC EV microRNA (miRNA) cargo is primarily responsible for attenuating both myofibroblast differentiation and cellular senescence. This attenuation occurs via inhibition of canonical and non-canonical WNT signaling pathways. Among enriched miRNA species present in HBEC EVs, miR-16, miR-26a, miR-26b, miR-141, miR-148a, and miR-200a are mechanistically involved in reducing WNT5A and WNT10B expression in LFs, and in reducing WNT3A, WNT5A, and WNT10B expression in HBECs. Mouse models utilizing intratracheal administration of EVs demonstrate efficient attenuation of bleomycin-induced lung fibrosis development accompanied by reduced expression of both β-catenin and markers of cellular senescence. These findings indicate that EVs derived from normal resident lung HBECs may possess anti-fibrotic properties. They further suggest that, via miRNA-mediated inhibition of TGF-β-WNT crosstalk, HBEC EVs administration can be a promising anti-fibrotic modality of treatment for IPF.

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“…Cellular senescence, particularly alveolar epithelial cell senescence, is involved in the pathogenesis of IPF (Minagawa et al, 2011;Martinez et al, 2017). Alveolar epithelial type 2 cell (AEC2) senescence is generally considered to be a driver of IPF (Parimon et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Predictive investigation of idiopathic pulmonary fibrosis subtypes based on cellular senescence-related genes for disease treatment and management

et al. 2023

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Background: Idiopathic pulmonary fibrosis (IPF), a chronic, progressive lung disease characterized by interstitial remodeling and tissue destruction, affects people worldwide and places a great burden on society. Cellular senescence is thought to be involved in the mechanisms and development of IPF. The aim of this study was to predictively investigate subtypes of IPF according to cellular senescence-related genes and their correlation with the outcome of patients with IPF, providing possible treatment and management options for disease control.Methods: Gene expression profiles and follow-up data were obtained from the GEO database. Senescence-related genes were obtained from the CSGene database and analyzed their correlation with the outcome of IPF. A consensus cluster was constructed to classify the samples based on correlated genes. The GSVA and WGCNA packages in R were used to calculate the immune-related enriched fractions and construct gene expression modules, respectively. Metascape and the clusterProfiler package in R were used to enrich gene functions. The ConnectivityMap was used to probe suitable drugs for potential treatment.Results: A total of 99 cellular senescence-related genes were associated with IPF prognosis. Patients with IPF were divided into two subtypes with significant prognostic differences. Subtype S2 was characterized by enhanced fibrotic progression and infection, leading to acute exacerbation of IPF and poor prognosis. Finally, five cellular senescence-related genes, TYMS, HJURP, UBE2C, BIRC5, and KIF2C, were identified as potential biomarkers in poor prognostic patients with IPF.Conclusion: The study findings indicate that cellular senescence-related genes can be used to distinguish the prognosis of patients with IPF. Among them, five genes can be used as candidate biomarkers to predict patients with a poor prognostic subtype for which anti-fibrosis and anti-infection treatments could be suitable.

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Involvement Of Aberrant Re-epithelialization With Cellular Senescence In IPF Pathogenesis

Cited by 3 publications

References 0 publications

Zinc Metabolic Defect of Aging Alveolar Progenitors in Progressive Pulmonary Fibrosis

Zinc Metabolic Defect of Aging Alveolar Progenitors in Progressive Pulmonary Fibrosis

Human bronchial epithelial cell-derived extracellular vesicle therapy for pulmonary fibrosis via inhibition of TGF-β-WNT crosstalk

Predictive investigation of idiopathic pulmonary fibrosis subtypes based on cellular senescence-related genes for disease treatment and management

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