Fiche publication
Date publication
février 2018
Journal
The European respiratory journal
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BELLAYE Pierre-Simon
Tous les auteurs :
Bellaye PS, Shimbori C, Yanagihara T, Carlson DA, Hughes P, Upagupta C, Sato S, Wheildon N, Haystead T, Ask K, Kolb M
Lien Pubmed
Résumé
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 primary IPF and control lung fibroblasts and 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.
Mots clés
Animals, Case-Control Studies, Cells, Cultured, Extracellular Matrix, metabolism, HSP90 Heat-Shock Proteins, metabolism, Humans, Idiopathic Pulmonary Fibrosis, metabolism, Low Density Lipoprotein Receptor-Related Protein-1, metabolism, Lung, pathology, Membrane Glycoproteins, Myofibroblasts, metabolism, Rats, Rats, Sprague-Dawley, Signal Transduction, Up-Regulation
Référence
Eur. Respir. J.. 2018 02;51(2):
