ArticleAmerican journal of respiratory cell and molecular biology2012
Therapeutic value of small molecule inhibitor to plasminogen activator inhibitor-1 for lung fibrosis.
Article in American journal of respiratory cell and molecular biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 85 citations in OpenAlex.
- A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1 (TM5614) in mild to moderate COVID-19.Scientific reports · 2024Trial
- Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis.American journal of physiology. Lung cellular and molecular physiology · 2015Trial
- Plasminogen Activation System and Fibroblasts: Impact on Tissue Remodeling, Disease, and Organ Homeostasis.Inflammation · 2026Review
- A potent inhibitor of PAI-1, MDI-2517, mitigates disease severity in a preclinical systemic sclerosis model.JCI insight · 2026Article
- Review
- Senkyunolide I and Danshensu in combination ameliorate post-MI myocardial fibrosis by regulatingFrontiers in pharmacology · 2026Article
- Targeting Plasminogen Activator Inhibitor-1 with a Novel Small Molecule Inhibitor Attenuates Lung Fibrosis.Research square · 2025Article
- PAI-1 Inhibitor TM5441 Attenuates Emphysema and Airway Inflammation in a Murine Model of Chronic Obstructive Pulmonary Disease.International journal of molecular sciences · 2025Article
- Article
- TGF-β as A Master Regulator of Aging-Associated Tissue Fibrosis.Aging and disease · 2023Review
- Article
- Article
- Circadian rhythm of plasminogen activator inhibitor-1 and cardiovascular complications in type 2 diabetes.Frontiers in endocrinology · 2023Review
- TRPM7 restrains plasmin activity and promotes transforming growth factor-β1 signaling in primary human lung fibroblasts.Archives of toxicology · 2022Article
- Fibrinogen mediates cadmium-induced macrophage activation and serves as a predictor of cadmium exposure in chronic obstructive pulmonary disease.American journal of physiology. Lung cellular and molecular physiology · 2022Article
- Contracting scars from fibrin drops.Integrative biology : quantitative biosciences from nano to macro · 2022Article
- RNA Sequencing of Epithelial Cell/Fibroblastic Foci Sandwich in Idiopathic Pulmonary Fibrosis: New Insights on the Signaling Pathway.International journal of molecular sciences · 2022Article
- Pulmonary toxicity and gene expression changes in response to whole-body inhalation exposure to multi-walled carbon nanotubes in rats.Inhalation toxicology · 2022Article
- Alveolar type 2 epithelial cell senescence and radiation-induced pulmonary fibrosis.Frontiers in cell and developmental biology · 2022Review
- Divergent Regulation of Alveolar Type 2 Cell and Fibroblast Apoptosis by Plasminogen Activator Inhibitor 1 in Lung Fibrosis.The American journal of pathology · 2021Article
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 3 countries.
Funding
Abstract
Fibrosis is a final stage of many lung diseases, with no effective treatment. Plasminogen activator inhibitor-1 (PAI-1), a primary inhibitor of tissue-type and urokinase-type plasminogen activators (tPA and uPA, respectively), plays a critical role in the development of fibrosis. In this study, we explored the therapeutic potential of an orally effective small molecule PAI-1 inhibitor, TM5275, in a model of lung fibrosis induced by transforming growth factor-β1 (TGF-β1), the most potent and ubiquitous profibrogenic cytokine, and in human lung fibroblasts (CCL-210 cells). The results show that an intranasal instillation of AdTGF-β1(223/225), an adenovirus expressing constitutively active TGF-β1, increased the expression of PAI-1 and induced fibrosis in murine lung tissue. On the other hand, treating mice with 40 mg/kg of TM5275 for 10 days, starting 4 days after the instillation of AdTGF-β1(223/225), restored the activities of uPA and tPA and almost completely blocked TGF-β1-induced lung fibrosis, as shown by collagen staining, Western blotting, and the measurement of hydroxyproline. No loss of body weight was evident under these treatment conditions with TM5275. Furthermore, we show that TM5275 induced apoptosis in both myofibroblasts (TGF-β1-treated) and naive (TGF-β1-untreated) human lung fibroblasts, and this apoptosis was associated with the activation of caspase-3/7, the induction of p53, and the inhibition of α-smooth muscle actin, fibronectin, and PAI-1 expression. Such an inhibition of fibrotic responses by TM5275 occurred even in cells pretreated with TGF-β1 for 6 hours. Together, the results suggest that TM5275 is a relatively safe and potent antifibrotic agent, with therapeutic potential in fibrotic lung disease.
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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.