Amplified canonical transforming growth factor-β signalling via heat shock protein 90 in pulmonary fibrosis

• Published in: The European respiratory journal Vol. 49; no. 2; p. 1501941
• Main Authors: Sibinska, Zaneta, Tian, Xia, Korfei, Martina, Kojonazarov, Baktybek, Kolb, Janina Susanne, Klepetko, Walter, Kosanovic, Djuro, Wygrecka, Malgorzata, Ghofrani, Hossein Ardeschir, Weissmann, Norbert, Grimminger, Friedrich, Seeger, Werner, Guenther, Andreas, Schermuly, Ralph T
• Format: Journal Article
• Language: English
• Published: England European Respiratory Society Journals Ltd 01.02.2017
• Subjects: A549 Cells; Animal models; Animals; Benzoquinones - pharmacology; Bleomycin; Bleomycin - adverse effects; Cell Transdifferentiation - drug effects; Epithelial-Mesenchymal Transition - drug effects; Extracellular matrix; Extracellular Matrix - drug effects; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fibrosis; Growth factors; Heat shock factors; Heat shock proteins; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humans; Idiopathic Pulmonary Fibrosis - drug therapy; Immunoprecipitation; Lactams, Macrocyclic - pharmacology; Lung - pathology; Lung diseases; Lungs; Male; Matrix metalloproteinase; Mesenchyme; Metalloproteinase; Mice; Mice, Inbred C57BL; Pulmonary fibrosis; Receptor mechanisms; Respiratory function; Signal Transduction - drug effects; Smad protein; Smad2 protein; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Transforming growth factor-b1
• ISSN: 0903-1936; 1399-3003
• DOI: 10.1183/13993003.01941-2015

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 inhibition by applying 17-AAG (17-allylamino-17-demethoxygeldanamycin) to lung fibroblasts and A549 cells and by 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.