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Title: Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis.

Authors: Osborn-Heaford, Heather L; Murthy, Shubha; Gu, Linlin; Larson-Casey, Jennifer L; Ryan, Alan J; Shi, Lei; Glogauer, Michael; Neighbors, Jeffrey D; Hohl, Raymond; Carter, A Brent

Published In Free Radic Biol Med, (2015 Sep)

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.

PubMed ID: 25958207 Exiting the NIEHS site

MeSH Terms: Adolescent; Adult; Animals; Case-Control Studies; Diphosphonates/pharmacology*; Disease Progression; Drug Evaluation, Preclinical; Enzyme Activation; Humans; Macrophages, Alveolar/drug effects; Macrophages, Alveolar/metabolism; Mice, Inbred C57BL; Middle Aged; Molecular Targeted Therapy; Neuropeptides/metabolism; Oxidative Stress; Protein Processing, Post-Translational; Pulmonary Fibrosis/drug therapy*; Pulmonary Fibrosis/metabolism; Pulmonary Fibrosis/pathology; Terpenes/metabolism; Terpenes/pharmacology*; Young Adult; rac1 GTP-Binding Protein/metabolism

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