ArticlePloS one2013
FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 85 citations in OpenAlex.
- Caveolin in extracellular vesicles: orchestrating interorgan communication in diabetes-associated cardiovascular diseaseCurrent opinion in physiology · 2025Article
- Reversal of Myofibroblast Apoptosis Resistance and Collagen Deposition by Phaseoloidin-Induced Autophagy Attenuates Pulmonary Fibrosis.Biomedicines · 2025Article
- LTI-03 peptide demonstrates anti-fibrotic activity iniScience · 2025Article
- Mechanisms and Therapeutic Potential of Myofibroblast Transformation in Pulmonary Fibrosis.Journal of respiratory biology and translational medicine · 2025Article
- PI3K/Akt in IPF: untangling fibrosis and charting therapies.Frontiers in immunology · 2025Review
- The aged extracellular matrix and the profibrotic role of senescence-associated secretory phenotype.American journal of physiology. Cell physiology · 2023Review
- FOXO3 regulates Smad3 and Smad7 through SPON1 circular RNA to inhibit idiopathic pulmonary fibrosis.International journal of biological sciences · 2023Article
- Role of Mesenchymal Stem Cells and Extracellular Vesicles in Idiopathic Pulmonary Fibrosis.International journal of molecular sciences · 2022Review
- Syringic and ascorbic acids prevent NDMA-induced pulmonary fibrogenesis, inflammation, apoptosis, and oxidative stress through the regulation of PI3K-Akt/PKB-mTOR-PTEN signaling pathway.Metabolism open · 2022Article
- PTEN: An Emerging Potential Target for Therapeutic Intervention in Respiratory Diseases.Oxidative medicine and cellular longevity · 2022Review
- Regulation of transforming growth factor-β signalling by SUMOylation and its role in fibrosis.Open biology · 2021Article
- M2 macrophages have unique transcriptomes but conditioned media does not promote profibrotic responses in lung fibroblasts or alveolar epithelial cells in vitro.American journal of physiology. Lung cellular and molecular physiology · 2021Article
- CD148 Deficiency in Fibroblasts Promotes the Development of Pulmonary Fibrosis.American journal of respiratory and critical care medicine · 2021Article
- Cellular Senescence: Pathogenic Mechanisms in Lung Fibrosis.International journal of molecular sciences · 2021Review
- A CD44/Brg1 nuclear complex confers mesenchymal progenitor cells with enhanced fibrogenicity in idiopathic pulmonary fibrosis.JCI insight · 2021Article
- Loss of Fas signaling in fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis.JCI insight · 2020Article
- Article
- Analysis of fibroblast migration dynamics in idiopathic pulmonary fibrosis using image-based scaffolds of the lung extracellular matrix.American journal of physiology. Lung cellular and molecular physiology · 2020Article
- Fibroblast Senescence in Idiopathic Pulmonary Fibrosis.Frontiers in cell and developmental biology · 2020Review
- Role of Caveolin-1 in Diabetes and Its Complications.Oxidative medicine and cellular longevity · 2020Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Idiopathic Pulmonary Fibrosis is a lethal fibrotic disease characterized by the unrelenting proliferation and persistence of fibroblasts in a type I collagen-rich matrix that result in an expanding reticular network of fibrotic tissue. However, the underlying mechanism responsible for the persistence of myofibroblasts in IPF remains unclear. During normal tissue repair, unwanted fibroblasts are eliminated during collagen-matrix contraction by a mechanism whereby high PTEN activity suppresses Akt. We have previously found that FoxO3a, a transcriptional activator of apoptosis-inducing proteins, is inactivated in IPF fibroblasts resulting from aberrantly high PI3K/Akt activity due to inappropriately low PTEN activity. Here we demonstrate that this low FoxO3a activity confers IPF fibroblasts with resistance to collagen-mediated apoptosis. We show that the mechanism by which low FoxO3a activity confers IPF fibroblasts with an apoptotic resistant phenotype involves suppression of Fas expression as a result of down regulation of cav-1 expression via a PTEN/Akt-dependent pathway. We demonstrate that PTEN over-expression or Akt inhibition increases FoxO3a expression in IPF fibroblasts, resulting in up-regulation of caveolin-1. We show that FoxO3a binds to the cav-1 promoter region and ectopic expression of FoxO3a transcriptionally increases cav-1 mRNA and protein expression. In turn, we show that overexpression of caveolin-1 increases Fas levels and caspase-3/7 activity and promotes IPF fibroblast apoptosis on polymerized type I collagen. We have found that the expression of caveolin-1, Fas and cleaved caspase-3 proteins in fibroblasts within the fibroblastic foci of IPF patient specimens is low. Our data indicate that the pathologically altered PTEN/Akt axis inactivates FoxO3a down-regulating cav-1 and Fas expression. This confers IPF fibroblasts with an apoptosis-resistant phenotype and may be responsible for IPF progression.
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