ArticleInternational journal of toxicology2011
Pulmonary fibrosis inducer, bleomycin, causes redox-sensitive activation of phospholipase D and cytotoxicity through formation of bioactive lipid signal mediator, phosphatidic acid, in lung microvascular endothelial cells.
Article in International journal of toxicology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- Macrophage polarization plasticity in pulmonary fibrosis: a review from pathogenesis to therapeutic targeting.Inflammopharmacology · 2026Review
- The Endothelial Cell Perspective in Pulmonary Fibrosis: From Cell Fate Decisions, Intercellular Communication, and EndoMT to Emerging Therapies.Canadian respiratory journal · 2026Review
- Novel insights into the potential applications of stem cells in pulmonary hypertension therapy.Respiratory research · 2024Review
- Classic Phytochemical Antioxidant and Lipoxygenase Inhibitor, Nordihydroguaiaretic Acid, Activates Phospholipase D through Oxidant Signaling and Tyrosine Phosphorylation Leading to Cytotoxicity in Lung Vascular Endothelial Cells.Cell biochemistry and biophysics · 2023Article
- Construction of a potential microRNA and messenger RNA regulatory network of acute lung injury in mice.Scientific reports · 2022Article
- Metabolic reprogramming of pulmonary fibrosis.Frontiers in pharmacology · 2022Review
- Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways.International journal of molecular sciences · 2020Review
- Role of phospholipase D in bleomycin-induced mitochondrial reactive oxygen species generation, mitochondrial DNA damage, and pulmonary fibrosis.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- Long chain lipid hydroperoxides increase the glutathione redox potential through glutathione peroxidase 4.Biochimica et biophysica acta. General subjects · 2019Article
- Long-term Air Pollution Exposure, Genome-wide DNA Methylation and Lung Function in the LifeLines Cohort Study.Environmental health perspectives · 2018Article
- Potential Metabolic Biomarkers to Identify Interstitial Lung Abnormalities.International journal of molecular sciences · 2016Article
- Physiological and pathophysiological roles for phospholipase D.Journal of lipid research · 2015Review
- Activation of Src and release of intracellular calcium by phosphatidic acid during Xenopus laevis fertilization.Developmental biology · 2014Article
- Phospholipase D signaling mediates reactive oxygen species-induced lung endothelial barrier dysfunction.Pulmonary circulation · 2013Article
- Thiol-redox antioxidants protect against lung vascular endothelial cytoskeletal alterations caused by pulmonary fibrosis inducer, bleomycin: comparison between classical thiol-protectant, N-acetyl-L-cysteine, and novel thiol antioxidant, N,N'-bis-2-mercaptoethyl isophthalamide.Toxicology mechanisms and methods · 2012Article
- Novel lipid-soluble thiol-redox antioxidant and heavy metal chelator, N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) and phospholipase D-specific inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) attenuate mercury-induced lipid signaling leading to protection against cytotoxicity in aortic endothelial cells.International journal of toxicology · 2011Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
The mechanisms of lung microvascular complications and pulmonary hypertension known to be associated with idiopathic pulmonary fibrosis (IPF), a debilitating lung disease, are not known. Therefore, we investigated whether bleomycin, the widely used experimental IPF inducer, would be capable of activating phospholipase D (PLD) and generating the bioactive lipid signal-mediator phosphatidic acid (PA) in our established bovine lung microvascular endothelial cell (BLMVEC) model. Our results revealed that bleomycin induced the activation of PLD and generation of PA in a dose-dependent (5, 10, and 100 µg) and time-dependent (2-12 hours) fashion that were significantly attenuated by the PLD-specific inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI). PLD activation and PA generation induced by bleomycin (5 µg) were significantly attenuated by the thiol protectant (N-acetyl-L-cysteine), antioxidants, and iron chelators suggesting the role of reactive oxygen species (ROS), lipid peroxidation, and iron therein. Furthermore, our study demonstrated the formation of ROS and loss of glutathione (GSH) in cells following bleomycin treatment, confirming oxidative stress as a key player in the bleomycin-induced PLD activation and PA generation in ECs. More noticeably, PLD activation and PA generation were observed to happen upstream of bleomycin-induced cytotoxicity in BLMVECs, which was protected by FIPI. This was also supported by our current findings that exposure of cells to exogenous PA led to internalization of PA and cytotoxicity in BLMVECs. For the first time, this study revealed novel mechanism of the bleomycin-induced redox-sensitive activation of PLD that led to the generation of PA, which was capable of inducing lung EC cytotoxicity, thus suggesting possible bioactive lipid-signaling mechanism/mechanisms of microvascular disorders encountered in IPF.
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