PT - JOURNAL ARTICLE AU - Pierre-Simon Bellaye AU - Chiko Shimbori AU - Toyoshi Yanagihara AU - David A. Carlson AU - Philip Hughes AU - Chandak Upagupta AU - Seidai Sato AU - Nolan Wheildon AU - Timothy Haystead AU - Kjetil Ask AU - Martin Kolb TI - Synergistic role of HSP90α and HSP90β to promote myofibroblast persistence in lung fibrosis AID - 10.1183/13993003.00386-2017 DP - 2018 Feb 01 TA - European Respiratory Journal PG - 1700386 VI - 51 IP - 2 4099 - http://erj.ersjournals.com/content/51/2/1700386.short 4100 - http://erj.ersjournals.com/content/51/2/1700386.full SO - Eur Respir J2018 Feb 01; 51 AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung parenchyma, causing significant morbidity through worsening dyspnoea and overall functional decline. IPF is characterised by apoptosis-resistant myofibroblasts, which are a major source for the excessive production of extracellular matrix (ECM) overtaking normal lung tissue. We sought to study the role of heat shock protein (HSP) isoforms HSP90α and HSP90β, whose distinct roles in lung fibrogenesis remain elusive.We determined the level of circulating HSP90α in IPF patients (n=31) and age-matched healthy controls (n=9) by ELISA. The release of HSP90α and HSP90β was evaluated in vitro in primary IPF and control lung fibroblasts and ex vivo after mechanical stretch on fibrotic lung slices from rats receiving adenovector-mediated transforming growth factor-β1.We demonstrate that circulating HSP90α is upregulated in IPF patients in correlation with disease severity. The release of HSP90α is enhanced by the increase in mechanical stress of the fibrotic ECM. This increase in extracellular HSP90α signals through low-density lipoprotein receptor-related protein 1 (LRP1) to promote myofibroblast differentiation and persistence. In parallel, we demonstrate that the intracellular form of HSP90β stabilises LRP1, thus amplifying HSP90α extracellular action.We believe that the specific inhibition of extracellular HSP90α is a promising therapeutic strategy to reduce pro-fibrotic signalling in IPF.Extracellular HSP90α and intracellular HSP90β act together to promote lung fibrosis progression http://ow.ly/bAmH30gGQf1