TY - JOUR
T1 - FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis
AU - Al-Tamari, Hamza M.
AU - Dabral, Swati
AU - Schmall, Anja
AU - Sarvari, Pouya
AU - Ruppert, Clemens
AU - Paik, Jihye
AU - DePinho, Ronald A.
AU - Grimminger, Friedrich
AU - Eickelberg, Oliver
AU - Guenther, Andreas
AU - Seeger, Werner
AU - Savai, Rajkumar
AU - Pullamsetti, Soni S.
N1 - Publisher Copyright:
© 2017 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2018/2
Y1 - 2018/2
N2 - 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 (Foxo3f.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.
AB - 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 (Foxo3f.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.
KW - fibroblast
KW - forkhead box O transcription factors
KW - idiopathic pulmonary fibrosis
KW - myofibroblast
KW - transdifferentiation
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U2 - 10.15252/emmm.201606261
DO - 10.15252/emmm.201606261
M3 - Article
C2 - 29217661
AN - SCOPUS:85041406064
SN - 1757-4676
VL - 10
SP - 276
EP - 293
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 2
ER -