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FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis.

EMBO Mol. Med. 10, 276-293 (2017)
Publishers Version Research data DOI PMC
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as soon as is submitted to ZB.
Published under the terms of the CC BY 4.0 license Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal parenchymal lung disease with limited therapeutic options, with fibroblast-to-myofibroblast transdifferentiation and hyperproliferation playing a major role. Investigating ex vivo-cultured (myo)fibroblasts from human IPF lungs as well as fibroblasts isolated from bleomycin-challenged mice, Forkhead box O3 (FoxO3) transcription factor was found to be less expressed, hyperphosphorylated, and nuclear-excluded relative to non-diseased controls. Downregulation and/or hyperphosphorylation of FoxO3 was reproduced by exposure of normal human lung fibroblasts to various pro-fibrotic growth factors and cytokines (FCS, PDGF, IGF1, TGF-β1). Moreover, selective knockdown of FoxO3 in the normal human lung fibroblasts reproduced the transdifferentiation and hyperproliferation phenotype. Importantly, mice with global- (Foxo3 −/− ) or fibroblast-specific (Foxo3 f.b −/− ) FoxO3 knockout displayed enhanced susceptibility to bleomycin challenge, with augmented fibrosis, loss of lung function, and increased mortality. Activation of FoxO3 with UCN-01, a staurosporine derivative currently investigated in clinical cancer trials, reverted the IPF myofibroblast phenotype in vitro and blocked the bleomycin-induced lung fibrosis in vivo. These studies implicate FoxO3 as a critical integrator of pro-fibrotic signaling in lung fibrosis and pharmacological reconstitution of FoxO3 as a novel treatment strategy.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Fibroblast ; Forkhead Box O Transcription Factors ; Idiopathic Pulmonary Fibrosis ; Myofibroblast ; Transdifferentiation
Reviewing status