Synergistic role of HSP90 alpha and HSP90 beta to promote myofibroblast persistence in lung fibrosis

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 HSP90 alpha and HSP90 beta, whose distinct roles in lung fibrogenesis remain elusive. We determined the level of circulating HSP90 alpha in IPF patients (n=31) and age-matched healthy controls (n= 9) by ELISA. The release of HSP90 alpha and HSP90 beta 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-beta 1. We demonstrate that circulating HSP90 alpha is upregulated in IPF patients in correlation with disease severity. The release of HSP90 alpha is enhanced by the increase in mechanical stress of the fibrotic ECM. This increase in extracellular HSP90 alpha 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 HSP90 beta stabilises LRP1, thus amplifying HSP90 alpha extracellular action. We believe that the specific inhibition of extracellular HSP90 alpha is a promising therapeutic strategy to reduce pro-fibrotic signalling in IPF.