ArticleFree radical biology & medicine2015
Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis.
Article in Free radical biology & medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
- Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target.Clinical and translational medicine · 2023Review
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- Molecular hydrogen is a promising therapeutic agent for pulmonary disease.Journal of Zhejiang University. Science. B · 2022Article
- Role of Molecular Hydrogen in Ageing and Ageing-Related Diseases.Oxidative medicine and cellular longevity · 2022Review
- TRIB3‒GSK-3Acta pharmaceutica Sinica. B · 2021Article
- Nox2 impairs VEGF-A-induced angiogenesis in placenta via mitochondrial ROS-STAT3 pathway.Redox biology · 2021Article
- Analysis of Functional Domains in Rho5, the Yeast Homolog of Human Rac1 GTPase, in Oxidative Stress Response.International journal of molecular sciences · 2019Article
- Preclinical investigation of a potent geranylgeranyl diphosphate synthase inhibitor.Investigational new drugs · 2018Article
- Macrophages: friend or foe in idiopathic pulmonary fibrosis?Respiratory research · 2018Review
- Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors.Molecules (Basel, Switzerland) · 2017Review
- Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase.Molecular pharmacology · 2017Article
- Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis.Immunity · 2016Article
- The Metabolic Prospective and Redox Regulation of Macrophage Polarization.Journal of clinical & cellular immunology · 2015Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Fibrotic remodeling in lung injury is a major cause of morbidity. The mechanism that mediates the ongoing fibrosis is unclear, and there is no available treatment to abate the aberrant repair. Reactive oxygen species (ROS) have a critical role in inducing fibrosis by modulating extracellular matrix deposition. Specifically, mitochondrial hydrogen peroxide (H2O2) production by alveolar macrophages is directly linked to pulmonary fibrosis as inhibition of mitochondrial H2O2 attenuates the fibrotic response in mice. Prior studies indicate that the small GTP-binding protein, Rac1, directly mediates H2O2 generation in the mitochondrial intermembrane space. Geranylgeranylation of the C-terminal cysteine residue (Cys(189)) is required for Rac1 activation and mitochondrial import. We hypothesized that impairment of geranylgeranylation would limit mitochondrial oxidative stress and, thus, abrogate progression of pulmonary fibrosis. By targeting the isoprenoid pathway with a novel agent, digeranyl bisphosphonate (DGBP), which impairs geranylgeranylation, we demonstrate that Rac1 mitochondrial import, mitochondrial oxidative stress, and progression of the fibrotic response to lung injury are significantly attenuated. These observations reveal that targeting the isoprenoid pathway to alter Rac1 geranylgeranylation halts the progression of pulmonary fibrosis after lung injury.
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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.