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

作者：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

来源：European Respiratory Journal, 2017, 49(2): 1501941.

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)-beta/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 in vitro by applying 17-AAG (17-allylamino-17-demethoxygeldanamycin) to lung fibroblasts and A549 cells and in vivo by administering 17-DMAG (17dimethylaminoethylamino-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-beta 1-induced extracellular matrix production and transdifferentiation of lung fibroblasts and epithelial-mesenchymal transition of A549 cells. The antifibrotic effects were associated with TGF-beta receptor disruption and inhibition of Smad2/3 activation. Co-immunoprecipitation revealed that HSP90 beta interacted with TGF-beta receptor II and stabilised TGF-beta 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.

• 出版日期2017-2