Journal article
STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts
American Journal of Respiratory Cell and Molecular Biology, Vol.61(1), pp.61-73
2019
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause with a median survival of only 3 years. Other investigators and we have shown that fibroblasts derived from IPF lungs display characteristics of senescent cells, and that dysregulated activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) correlates with IPF progression. The question of whether STAT3 activation is involved in fibroblast senescence remains unanswered. We hypothesized that inhibiting STAT3 activation after oxidant-induced senescence would attenuate characteristics of the senescent phenotype. We aimed to characterize a model of oxidant-induced senescence in human lung fibroblasts and to determine the effect of inhibiting STAT3 activity on the development of senescence. Exposing human lung fibroblasts to 150 μM hydrogen peroxide (H2O2) resulted in increased senescence-associated β-galactosidase content and expression of p21 and IL-6, all of which are features of senescence. The shift into senescence was accompanied by an increase of STAT3 translocation to the nucleus and mitochondria. Additionally, Seahorse analysis provided evidence of increased mitochondrial respiration characterized by increased basal respiration, proton leak, and an associated increase in superoxide (O2−) production in senescent fibroblasts. Targeting STAT3 activity using the small-molecule inhibitor STA-21 attenuated IL-6 production, reduced p21 levels, decreased senescence-associated β-galactosidase accumulation, and restored normal mitochondrial function. The results of this study illustrate that stress-induced senescence in lung fibroblasts involves the activation of STAT3, which can be pharmacologically modulated.
Details
- Title
- STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts
- Authors/Creators
- D.W. Waters (Author/Creator) - University of Newcastle AustraliaK.E.C. Blokland (Author/Creator) - National Health and Medical Research CouncilP.S. Pathinayake (Author/Creator) - University of Newcastle AustraliaL. Wei (Author/Creator) - University of Newcastle AustraliaM. Schuliga (Author/Creator) - University of Newcastle AustraliaJ. Jaffar (Author/Creator) - The Alfred HospitalG.P. Westall (Author/Creator) - The Alfred HospitalP.M. Hansbro (Author/Creator) - University of Newcastle AustraliaC.M. Prêle (Author/Creator) - The University of Western AustraliaS.E. Mutsaers (Author/Creator) - The University of Western AustraliaN.W. Bartlett (Author/Creator) - University of Newcastle AustraliaJ.K. Burgess (Author/Creator) - Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)C.L. Grainge (Author/Creator) - University of Newcastle AustraliaD.A. Knight (Author/Creator) - University of Newcastle Australia
- Publication Details
- American Journal of Respiratory Cell and Molecular Biology, Vol.61(1), pp.61-73
- Publisher
- American Thoracic Society
- Identifiers
- 991005540656607891
- Copyright
- © 2019 American Thoracic Society
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.208 Vasculitis & Autoimmune Disorders
- 1.208.1262 Idiopathic Pulmonary Fibrosis
- Web Of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Respiratory System
- ESI research areas
- Biology & Biochemistry