title: Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis.
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.
authors.affiliation: Department of Internal Medicine, University of Iowa.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Osborn-Heaford
authors.affiliation: Department of Internal Medicine, University of Iowa.
authors.forename: Shubha
authors.initials: S
authors.lastname: Murthy
authors.affiliation: Deparment of Medicine, University of Alabama at Birmingham, AL.
authors.forename: Linlin
authors.initials: L
authors.lastname: Gu
authors.affiliation: Free Radical and Radiation Biology Program, University of Iowa.|Deparment of Medicine, University of Alabama at Birmingham, AL.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Larson-Casey
authors.affiliation: Department of Internal Medicine, University of Iowa.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Ryan
authors.affiliation: Human Toxicology Program, University of Iowa.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Canadian Institutes of Health Research Group in Matrix Dynamics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Glogauer
authors.affiliation: Department of Chemistry, University of Iowa.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Neighbors
authors.affiliation: Department of Internal Medicine, University of Iowa.|Department of Pharmacology, University of Iowa.
authors.forename: Raymond
authors.initials: R
authors.lastname: Hohl
authors.affiliation: Department of Internal Medicine, University of Iowa.|Free Radical and Radiation Biology Program, University of Iowa.|Human Toxicology Program, University of Iowa.|Deparment of Medicine, University of Alabama at Birmingham, AL.|Iowa City VA Healthcare System, Iowa City, IA.|Birmingham VAMC, Birmingham, AL.
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D004164:Diphosphonates / Q000494:pharmacology*; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D006801:Humans; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009479:Neuropeptides / Q000378:metabolism; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013729:Terpenes / Q000378:metabolism / Q000494:pharmacology*; D055815:Young Adult; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D013729:Terpenes; C518651:digeranyl bisphosphonate; D020830:rac1 GTP-Binding Protein
keywords: Isoprenoid; Macrophage; Mitochondria; Pathway; Pulmonary fibrosis; Rac1; Reactive oxygen species