Secreted heat shock proteins control airway remodeling: Evidence from bronchial thermoplasty

Abstract

Background: Increased airway smooth muscle mass is a key pathology in asthma. Bronchial thermoplasty is a treatment for severe asthma based on selective heating of the airways that aims to reduce the mass of airway smooth muscle cells (ASMCs), and thereby bronchoconstriction. However, short heat exposure is insufficient to explain the long-lasting effect, and heat shock proteins (HSPs) have been suggested to play a role.

Objective: We sought to determine the role of HSP70 and HSP90 in the control of airway wall remodeling by bronchial thermoplasty.

Methods: Bronchoalveolar lavage fluid and endobronchial biopsies of 20 patients with severe asthma were obtained before and after thermoplasty. Isolated epithelial cells and ASMCs were exposed to 65^oC for 10 seconds, mimicking thermoplasty. Proteins were determined by immunohistochemistry, Western blotting, immunofluorescence, and ELISA; proliferation by cell counts and antigen Ki67 (MKI67) expression.

Results: Thermoplasty significantly increased the expression of HSP70 and HSP90 in the epithelium and bronchoalveolar lavage fluid. In ASMCs, thermoplasty reduced both HSPs. These cell-type-specific effects were detectable even 1 month after thermoplasty in tissue sections. In epithelial cells, ex vivo exposure to heat (65^oC, 10 seconds) increased the expression and secretion of HSP70 and HSP90. In addition, epithelial cell proliferation was upregulated by heat or treatment with human recombinant HSP70 or HSP90. In ASMCs, heat exposure or exogenous HSPs reduced proliferation and differentiation. In both cell types, HSP70 and HSP90 activated the signaling cascade of serine/threonine-protein kinase →mammalian target of rapamycin→ribosomal protein S6 kinase 1 and CCAAT/enhancer binding protein-β→protein arginine methyltransferase 1→ mitochondria activity.

Conclusions: Epithelial cell-derived HSP70 and HSP90 improve the function of epithelial cells, but block ASMC remodeling.

Keywords: Asthma; HSP70; HSP90; airway smooth muscle cells; airway wall remodeling; bronchial thermoplasty; epithelial cells.