Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 (Cys189) 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.

Original languageEnglish (US)
Pages (from-to)47-56
Number of pages10
JournalFree Radical Biology and Medicine
Volume86
DOIs
StatePublished - Jun 27 2015

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Prenylation
Oxidative stress
Pulmonary Fibrosis
Terpenes
rac1 GTP-Binding Protein
Lung Injury
Hydrogen Peroxide
Cysteine
Reactive Oxygen Species
Oxidative Stress
Fibrosis
Repair
Chemical activation
Alveolar Macrophages
Extracellular Matrix
Morbidity
digeranyl bisphosphonate

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this

Osborn-Heaford, H. L., Murthy, S., Gu, L., Larson-Casey, J. L., Ryan, A. J., Shi, L., ... Carter, A. B. (2015). Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis. Free Radical Biology and Medicine, 86, 47-56. https://doi.org/10.1016/j.freeradbiomed.2015.04.031
Osborn-Heaford, Heather L. ; Murthy, Shubha ; Gu, Linlin ; Larson-Casey, Jennifer L. ; Ryan, Alan J. ; Shi, Lei ; Glogauer, Michael ; Neighbors, Jeffrey ; Hohl, Raymond ; Carter, A. Brent. / Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis. In: Free Radical Biology and Medicine. 2015 ; Vol. 86. pp. 47-56.
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Osborn-Heaford, HL, Murthy, S, Gu, L, Larson-Casey, JL, Ryan, AJ, Shi, L, Glogauer, M, Neighbors, J, Hohl, R & Carter, AB 2015, 'Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis', Free Radical Biology and Medicine, vol. 86, pp. 47-56. https://doi.org/10.1016/j.freeradbiomed.2015.04.031

Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis. / Osborn-Heaford, Heather L.; Murthy, Shubha; Gu, Linlin; Larson-Casey, Jennifer L.; Ryan, Alan J.; Shi, Lei; Glogauer, Michael; Neighbors, Jeffrey; Hohl, Raymond; Carter, A. Brent.

In: Free Radical Biology and Medicine, Vol. 86, 27.06.2015, p. 47-56.

Research output: Contribution to journalArticle

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T1 - Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis

AU - Osborn-Heaford, Heather L.

AU - Murthy, Shubha

AU - Gu, Linlin

AU - Larson-Casey, Jennifer L.

AU - Ryan, Alan J.

AU - Shi, Lei

AU - Glogauer, Michael

AU - Neighbors, Jeffrey

AU - Hohl, Raymond

AU - Carter, A. Brent

PY - 2015/6/27

Y1 - 2015/6/27

N2 - 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 (Cys189) 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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