ArticleAmerican journal of respiratory cell and molecular biology2009
Electrophilic peroxisome proliferator-activated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts.
Article in American journal of respiratory cell and molecular biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
50 citing papers in PubMed, 74 citations in OpenAlex.
- It takes two peroxisome proliferator-activated receptors (PPAR-β/δ and PPAR-γ) to tango idiopathic pulmonary fibrosis.Respiratory research · 2024Article
- Lipid Deficiency Contributes to Impaired Alveolar Progenitor Cell Function in Aging and Idiopathic Pulmonary Fibrosis.American journal of respiratory cell and molecular biology · 2024Article
- miR-338-3p blocks TGFβ-induced myofibroblast differentiation through the induction of PTEN.American journal of physiology. Lung cellular and molecular physiology · 2022Article
- Lobeglitazone attenuates fibrosis in corneal fibroblasts by interrupting TGF-beta-mediated Smad signaling.Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie · 2022Article
- Chinese Herbs and Repurposing Old Drugs as Therapeutic Agents in the Regulation of Oxidative Stress and Inflammation in Pulmonary Diseases.Journal of inflammation research · 2021Review
- Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo.Molecules (Basel, Switzerland) · 2020Article
- Electrophile Modulation of Inflammation: A Two-Hit Approach.Metabolites · 2020Review
- The role of natural products in revealing NRF2 function.Natural product reports · 2020Review
- Analyses of alveolar epithelial injury via lipid-related stress in mammalian target of rapamycin inhibitor-induced lung disease.Laboratory investigation; a journal of technical methods and pathology · 2019Article
- Nitrated fatty acids: from diet to disease.Current opinion in physiology · 2019Article
- Proton pump inhibitors attenuate myofibroblast formation associated with thyroid eye disease through the aryl hydrocarbon receptor.PloS one · 2019Article
- Bronchopulmonary Dysplasia: Crosstalk Between PPARγ, WNT/β-Catenin and TGF-β Pathways; The Potential Therapeutic Role of PPARγ Agonists.Frontiers in pediatrics · 2019Review
- Activated human T lymphocytes inhibit TGFβ-induced fibroblast to myofibroblast differentiation via prostaglandins DAmerican journal of physiology. Lung cellular and molecular physiology · 2018Article
- Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise.Frontiers in pharmacology · 2018Review
- Human lung fibroblasts produce proresolving peroxisome proliferator-activated receptor-γ ligands in a cyclooxygenase-2-dependent manner.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Pharmacologic inhibition of lactate production prevents myofibroblast differentiation.American journal of physiology. Lung cellular and molecular physiology · 2015Article
- Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase.American journal of physiology. Lung cellular and molecular physiology · 2015Article
- Inhibitory effects of PPARγ ligands on TGF-β1-induced CTGF expression in cat corneal fibroblasts.Experimental eye research · 2015Article
- The pulmonary mesenchyme directs lung development.Current opinion in genetics & development · 2015Review
- The Role of PPAR Gamma in Systemic Sclerosis.PPAR research · 2015Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Pulmonary fibrosis is a progressive scarring disease with no effective treatment. Transforming growth factor (TGF)-beta is up-regulated in fibrotic diseases, where it stimulates differentiation of fibroblasts to myofibroblasts and production of excess extracellular matrix. Peroxisome proliferator-activated receptor (PPAR) gamma is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that a novel PPARgamma ligand, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), is a potent inhibitor of TGF-beta-stimulated differentiation of human lung fibroblasts to myofibroblasts, and suppresses up-regulation of alpha-smooth muscle actin, fibronectin, collagen, and the novel myofibroblast marker, calponin. The inhibitory concentration causing a 50% decrease in aSMA for CDDO was 20-fold lower than the endogenous PPARgamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15 d-PGJ(2)), and 400-fold lower than the synthetic ligand, rosiglitazone. Pharmacologic and genetic approaches were used to demonstrate that CDDO mediates its activity via a PPARgamma-independent pathway. CDDO and 15 d-PGJ(2) contain an alpha/beta unsaturated ketone, which acts as an electrophilic center that can form covalent bonds with cellular proteins. Prostaglandin A(1) and diphenyl diselenide, both strong electrophiles, also inhibit myofibroblast differentiation, but a structural analog of 15 d-PGJ(2) lacking the electrophilic center is much less potent. CDDO does not alter TGF-beta-induced Smad or AP-1 signaling, but does inhibit acetylation of CREB binding protein/p300, a critical coactivator in the transcriptional regulation of TGF-beta-responsive genes. Overall, these data indicate that certain PPARgamma ligands, and other small molecules with electrophilic centers, are potent inhibitors of critical TGF-beta-mediated profibrogenic activities through pathways independent of PPARgamma. As the inhibitory concentration causing a 50% decrease in aSMA for CDDO is 400-fold lower than that in rosiglitazone, the translational potential of CDDO for treatment of fibrotic diseases is high.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.