Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis.

Autor: Osborn-Heaford HL; Department of Internal Medicine, University of Iowa., Murthy S; Department of Internal Medicine, University of Iowa., Gu L; Deparment of Medicine, University of Alabama at Birmingham, AL., Larson-Casey JL; Free Radical and Radiation Biology Program, University of Iowa.; Deparment of Medicine, University of Alabama at Birmingham, AL., Ryan AJ; Department of Internal Medicine, University of Iowa., Shi L; Human Toxicology Program, University of Iowa., Glogauer M; Canadian Institutes of Health Research Group in Matrix Dynamics, University of Toronto, Toronto, Ontario, Canada., Neighbors JD; Department of Chemistry, University of Iowa., Hohl R; Department of Internal Medicine, University of Iowa.; Department of Pharmacology, University of Iowa., Carter AB; 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.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2015 Sep; Vol. 86, pp. 47-56. Date of Electronic Publication: 2015 May 07.
DOI: 10.1016/j.freeradbiomed.2015.04.031
Abstrakt: 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.
(Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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