STAT3 regulates the onset of oxidant-induced senescence in lung fibroblasts

Waters, DW; Blokland, KEC; Pathinayake, PS; Wei, L; Schuliga, M; Jaffar, J; Westall, GP; Hansbro, PM; Prele, CM; Mutsaers, SE; Bartlett, NW; Burgess, JK; Grainge, CL; Knight, DA

STAT3 regulates the onset of oxidant-induced senescence in lung fibroblasts

Waters, DW Blokland, KEC

Pathinayake, PS Wei, L Schuliga, M Jaffar, J Westall, GP

Hansbro, PM

Prele, CM Mutsaers, SE Bartlett, NW

Burgess, JK Grainge, CL Knight, DA

Permalink

Publication Type:: Journal Article
Citation:: American Journal of Respiratory Cell and Molecular Biology, 2019, 61 (1), pp. 61 - 73
Issue Date:: 2019-01-01

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download Accepted Manuscript VersionAdobe PDF (2.98 MB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Waters, DW	en_US
dc.contributor.author	Blokland, KEC https://orcid.org/0000-0002-1807-6359	en_US
dc.contributor.author	Pathinayake, PS	en_US
dc.contributor.author	Wei, L	en_US
dc.contributor.author	Schuliga, M	en_US
dc.contributor.author	Jaffar, J	en_US
dc.contributor.author	Westall, GP https://orcid.org/0000-0002-3711-068X	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.contributor.author	Prele, CM	en_US
dc.contributor.author	Mutsaers, SE	en_US
dc.contributor.author	Bartlett, NW https://orcid.org/0000-0002-2715-5163	en_US
dc.contributor.author	Burgess, JK	en_US
dc.contributor.author	Grainge, CL	en_US
dc.contributor.author	Knight, DA	en_US
dc.date.issued	2019-01-01	en_US
dc.identifier.citation	American Journal of Respiratory Cell and Molecular Biology, 2019, 61 (1), pp. 61 - 73	en_US
dc.identifier.issn	1044-1549	en_US
dc.identifier.uri	http://hdl.handle.net/10453/129975
dc.description.abstract	Copyright © 2019 by the American Thoracic Society. 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 oxidantinduced 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 b-galactosidase accumulation, and restored normalmitochondrial function. The results of this study illustrate that stress-induced senescence in lung fibroblasts involves the activation of STAT3, which can be pharmacologically modulated.	en_US
dc.relation.ispartof	American Journal of Respiratory Cell and Molecular Biology	en_US
dc.relation.isbasedon	10.1165/rcmb.2018-0328OC	en_US
dc.subject.classification	Respiratory System	en_US
dc.subject.mesh	Lung	en_US
dc.subject.mesh	Cell Nucleus	en_US
dc.subject.mesh	Mitochondria	en_US
dc.subject.mesh	Fibroblasts	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Polycyclic Compounds	en_US
dc.subject.mesh	Oxidants	en_US
dc.subject.mesh	Cell Respiration	en_US
dc.subject.mesh	Protein Transport	en_US
dc.subject.mesh	Phosphorylation	en_US
dc.subject.mesh	Phenotype	en_US
dc.subject.mesh	STAT3 Transcription Factor	en_US
dc.subject.mesh	Cellular Senescence	en_US
dc.title	STAT3 regulates the onset of oxidant-induced senescence in lung fibroblasts	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	61	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	61	en_US

Abstract:

Copyright © 2019 by the American Thoracic Society. 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 oxidantinduced 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 b-galactosidase accumulation, and restored normalmitochondrial function. The results of this study illustrate that stress-induced senescence in lung fibroblasts involves the activation of STAT3, which can be pharmacologically modulated.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/129975