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

David W. Waters, Kaj E. C. Blokland, Prabuddha S. Pathinayake, Lan Wei, Michael Schuliga, Jade Jaffar, Glen P. Westall, Philip M. Hansbro, Cecilia M. Prele, Steven E. Mutsaers, Nathan W. Bartlett, Janette K. Burgess, Christopher L. Grainge, Darryl A. Knight

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    Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause with a median survival of only 3 years. We and others 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 150µM hydrogen peroxide (H2O2) resulted in increased senescence-associated-β-galactosidase (SA-β-Gal) content, expression of p21 and interleukin (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 SA-β-Gal 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.

    Original languageEnglish
    Pages (from-to)61-73
    Number of pages13
    JournalAmerican Journal of Respiratory Cell and Molecular Biology
    Issue number1
    Publication statusPublished - Jul 2019


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