Heat Shock Protein 27 modulate mesothelial and epithelial to mesenchymal transition (EMT)

Introduction: Pulmonary fibrosis (PF) has currently no treatment. We have shown that adenoviral gene transfer of TGF-β1 (AdTGF-β1) to the pleura induces a severe pleural fibrosis that invades the parenchyma. In this process, mesothelial cells differentiate into myofibroblastes (α-SMA positive cells) through an EMT-like process suggesting a key role of mesothelial cells in PF. Heat Shock Protein 27 (HSP27), is a chaperon for actin. Its role in fibrogenesis is unknown. Methods: Sprague Dawley rats received intrapleural injection of AdTGF-β1 or AdDL (empty vector). Mesothelial Met-5A and A549 cells were treated with rTGF-β1. Results: in vitro: 1) mesothelial cells are susceptible to rTGF-β1 induced EMT 2) HSP27 is strongly linked to α-SMA during EMT (colocalisation and co-immunoprecipitation). 3) HSP27 overexpression induces an EMT and siRNA mediated HSP27 inhibition blocks TGF-β1 induced EMT and mesothelial cell migration 4) HSP27 modulates the TGF-β1/SMAD pathway. Data were reproduced in A549 epithelial cells. In vivo: 7 days after AdTGF-β1 injection, HSP27 and α-SMA are overexpressed and colocalize in fibrotic sub-pleura areas. AdTGF-β1 rats treated by intrapleural injections of OGX427 (AntiSens Oligonucleotide, ASO, directed against HSP27) have a strong decrease in HPS27, α-SMA expression, mesothelial cells migration into the parenchyma and fibrosis compare to AdTGF-β1 rats treated with control ASO. Conclusion: HSP27 plays a major role in EMT and could be a key target to inhibit EMT in PF and others diseases involving EMT. This work is supported by: – the EU, 7th FP, HEALTH-F2-2007-202224 eurIPFnet – La “Recherche en santé Respiratoire” et la Société de Pneumologie de Langue Française