Amplified canonical transforming growth factor-β signallingviaheat shock protein 90 in pulmonary fibrosis.
Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of idiopathic pulmonary fibrosis (IPF), and is governed by transforming growth factor (TGF)-β/Smad signalling. We sought to define the role of heat shock protein (HSP)90 in profibrotic responses in IPF and to determine the therapeutic effects of HSP90 inhibition in a murine model of pulmonary fibrosis.We investigated the effects of HSP90 inhibitionin vitroby applying 17-AAG (17-allylamino-17-demethoxygeldanamycin) to lung fibroblasts and A549 cells andin vivoby administering 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) to mice with bleomycin-induced pulmonary fibrosis.HSP90 expression was increased in (myo)fibroblasts from fibrotic human and mouse lungs compared with controls. 17-AAG inhibited TGF-β1-induced extracellular matrix production and transdifferentiation of lung fibroblasts and epithelial-mesenchymal transition of A549 cells. The antifibrotic effects were associated with TGF-β receptor disruption and inhibition of Smad2/3 activation. Co-immunoprecipitation revealed that HSP90β interacted with TGF-β receptor II and stabilised TGF-β receptors. Furthermore, 17-DMAG improved lung function and decreased fibrosis and matrix metalloproteinase activity in the lungs of bleomycin-challenged mice.In conclusion, this is the first study to demonstrate that HSP90 inhibition blocks pulmonary fibroblast activation and ameliorates bleomycin-induced pulmonary fibrosis in mice.
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.|Both authors contributed equally.
Zaneta
Z
Sibinska
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.|Both authors contributed equally.
Xia
X
Tian
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
Martina
M
Korfei
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
Baktybek
B
Kojonazarov
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
Janina Susanne
JS
Kolb
Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, Germany.|Vienna Medical University, Vienna, Austria.
Walter
W
Klepetko
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
Djuro
D
Kosanovic
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.|Dept of Biochemistry, Faculty of Medicine, University of Giessen, Giessen, Germany.
Malgorzata
M
Wygrecka
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
Hossein Ardeschir
HA
Ghofrani
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
Norbert
N
Weissmann
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
Friedrich
F
Grimminger
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.|Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Werner
W
Seeger
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.|Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, Germany.|European IPF Network and European IPF Registry, Giessen, Germany.
Andreas
A
Guenther
Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany ralph.schermuly@innere.med.uni-giessen.de.
Ralph T
RT
Schermuly
D000072283:A549 Cells; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects; D054338:Cell Transdifferentiation / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy*; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016212:Transforming Growth Factor beta; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D001761:Bleomycin; C112765:tanespimycin