Synergistic role of HSP90α and HSP90β to promote myofibroblast persistence in lung fibrosis

Pierre Simon Bellaye, Chiko Shimbori, Toyoshi Yanagihara, David A. Carlson, Philip Hughes, Chandak Upagupta, Seidai Sato, Nolan Wheildon, Timothy Haystead, Kjetil Ask, Martin Kolb

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number1700386
JournalEuropean Respiratory Journal
Volume51
Issue number2
DOIs
Publication statusPublished - Feb 1 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine

Fingerprint

Dive into the research topics of 'Synergistic role of HSP90α and HSP90β to promote myofibroblast persistence in lung fibrosis'. Together they form a unique fingerprint.

Cite this