Publication

STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts

Waters, D. W., Blokland, K. E. C., Pathinayake, P. S., Wei, L., Schuliga, M., Jaffar, J., Westall, G. P., Hansbro, P. M., Prele, C. M., Mutsaers, S. E., Bartlett, N. W., Burgess, J. K., Grainge, C. L. & Knight, D. A., Jul-2019, In : American Journal of Respiratory Cell and Molecular Biology. 61, 1, p. 61-73 13 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Waters, D. W., Blokland, K. E. C., Pathinayake, P. S., Wei, L., Schuliga, M., Jaffar, J., ... Knight, D. A. (2019). STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts. American Journal of Respiratory Cell and Molecular Biology, 61(1), 61-73. https://doi.org/10.1165/rcmb.2018-0328OC

Author

Waters, David W ; Blokland, Kaj E C ; Pathinayake, Prabuddha S ; Wei, Lan ; Schuliga, Michael ; Jaffar, Jade ; Westall, Glen P ; Hansbro, Philip M ; Prele, Cecilia M ; Mutsaers, Steven E ; Bartlett, Nathan W ; Burgess, Janette K ; Grainge, Christopher L ; Knight, Darryl A. / STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts. In: American Journal of Respiratory Cell and Molecular Biology. 2019 ; Vol. 61, No. 1. pp. 61-73.

Harvard

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 2019, 'STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts', American Journal of Respiratory Cell and Molecular Biology, vol. 61, no. 1, pp. 61-73. https://doi.org/10.1165/rcmb.2018-0328OC

Standard

STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts. / Waters, David W; Blokland, Kaj E C; Pathinayake, Prabuddha S; Wei, Lan; Schuliga, Michael; Jaffar, Jade; Westall, Glen P; Hansbro, Philip M; Prele, Cecilia M; Mutsaers, Steven E; Bartlett, Nathan W; Burgess, Janette K; Grainge, Christopher L; Knight, Darryl A.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 61, No. 1, 07.2019, p. 61-73.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Waters DW, Blokland KEC, Pathinayake PS, Wei L, Schuliga M, Jaffar J et al. STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts. American Journal of Respiratory Cell and Molecular Biology. 2019 Jul;61(1):61-73. https://doi.org/10.1165/rcmb.2018-0328OC


BibTeX

@article{e147dfeadb1642649ee499109337ae60,
title = "STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts",
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 mu M hydrogen peroxide (H2O2) resulted in increased senescence-associated 3-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 (O-2) production in senescent fibroblasts. Targeting STAT3 activity using the small-molecule inhibitor STA-21 attenuated IL-6 production, reduced p21 levels, decreased senescence-associated beta-galactosidase accumulation, and restored normal mitochondria! function. The results of this study illustrate that stress-induced senescence in lung fibroblasts involves the activation of STAT3, which can be pharmacologically modulated.",
keywords = "senescence, fibroblast, signal transducer and activator of transcription 3, mitochondrial dysfunction, fibrosis, CELLULAR SENESCENCE, MITOCHONDRIAL STAT3, SECRETORY PHENOTYPE, DNA-DAMAGE, CANCER, CELLS, PHOSPHORYLATION, ACTIVATION, PROTEINS, GENE",
author = "Waters, {David W} and Blokland, {Kaj E C} and Pathinayake, {Prabuddha S} and Lan Wei and Michael Schuliga and Jade Jaffar and Westall, {Glen P} and Hansbro, {Philip M} and Prele, {Cecilia M} and Mutsaers, {Steven E} and Bartlett, {Nathan W} and Burgess, {Janette K} and Grainge, {Christopher L} and Knight, {Darryl A}",
year = "2019",
month = "7",
doi = "10.1165/rcmb.2018-0328OC",
language = "English",
volume = "61",
pages = "61--73",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "AMER THORACIC SOC",
number = "1",

}

RIS

TY - JOUR

T1 - STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts

AU - Waters, David W

AU - Blokland, Kaj E C

AU - Pathinayake, Prabuddha S

AU - Wei, Lan

AU - Schuliga, Michael

AU - Jaffar, Jade

AU - Westall, Glen P

AU - Hansbro, Philip M

AU - Prele, Cecilia M

AU - Mutsaers, Steven E

AU - Bartlett, Nathan W

AU - Burgess, Janette K

AU - Grainge, Christopher L

AU - Knight, Darryl A

PY - 2019/7

Y1 - 2019/7

N2 - 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 mu M hydrogen peroxide (H2O2) resulted in increased senescence-associated 3-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 (O-2) production in senescent fibroblasts. Targeting STAT3 activity using the small-molecule inhibitor STA-21 attenuated IL-6 production, reduced p21 levels, decreased senescence-associated beta-galactosidase accumulation, and restored normal mitochondria! function. The results of this study illustrate that stress-induced senescence in lung fibroblasts involves the activation of STAT3, which can be pharmacologically modulated.

AB - 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 mu M hydrogen peroxide (H2O2) resulted in increased senescence-associated 3-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 (O-2) production in senescent fibroblasts. Targeting STAT3 activity using the small-molecule inhibitor STA-21 attenuated IL-6 production, reduced p21 levels, decreased senescence-associated beta-galactosidase accumulation, and restored normal mitochondria! function. The results of this study illustrate that stress-induced senescence in lung fibroblasts involves the activation of STAT3, which can be pharmacologically modulated.

KW - senescence

KW - fibroblast

KW - signal transducer and activator of transcription 3

KW - mitochondrial dysfunction

KW - fibrosis

KW - CELLULAR SENESCENCE

KW - MITOCHONDRIAL STAT3

KW - SECRETORY PHENOTYPE

KW - DNA-DAMAGE

KW - CANCER

KW - CELLS

KW - PHOSPHORYLATION

KW - ACTIVATION

KW - PROTEINS

KW - GENE

U2 - 10.1165/rcmb.2018-0328OC

DO - 10.1165/rcmb.2018-0328OC

M3 - Article

VL - 61

SP - 61

EP - 73

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 1

ER -

ID: 73550132