Secretion of stress proteins regulate airway wall remodeling in asthma

Published online: March 2, 2021

Airway wall remodeling in severe asthma is a pathology that is difficult to treat with the drugs that are currently available. Bronchial thermoplasty (heat induced by radiofrequency) is the only proven therapy that effectively reduces airway wall thickness in severe asthma by “burning out” airway smooth muscle cells. Understanding the mechanism by which heat reduces airway wall thickness may lead to novel therapies for asthma.

In a recent research article in The Journal of Allergy and Clinical Immunology (JACI), Fang et al examined the cell type-specific effect of therapeutic and experimental thermoplasty on the expression and function of heat shock protein 70 (HSP70) and HSP90. The expression of both of these stress proteins was determined before and after therapeutic bronchial thermoplasty in tissue samples and broncho alveolar lavage fluid from 20 patients with severe, difficult to treat asthma. The molecular biological mechanism induced by heat was assessed in vitro using isolated epithelial and airway smooth muscle cells obtained from asthma patients.

Fang et al found that bronchial thermoplasty in asthma patients, as well as heat exposure of isolated human cells, stimulated the secretion of HSP70 and HSP90 by epithelial, but not by airway smooth muscle cells. Importantly, the effect of bronchial thermoplasty on the expression of HSP70 and HSP90 was detectable one month after the treatment. This suggests that heat induced a lasting, cell type-specific, epigenetic modification in airway structural cells. In human epithelial cells, heat, as well as HSP70 or HSP90, stimulated their multiplication and differentiation. This might explain the fast repair of the epithelium, which has been reported in asthma patients after treatment with bronchial thermoplasty. In airway smooth muscle cells, exposure to either heat, HSP70 or HSP90 reduced not only the multiplication but also the synthesis of collagen type-I and fibronectin. The combination of these cell-type specific responses might explain the effect of bronchial thermoplasty on the airway wall structure.

This study found that heat or exposure to either extracellular HSP70 or HSP90 modifies the mechanisms that regulate cellular energy provision in a cell type-specific manner. This improves the ability of epithelial cells to regenerate, but reduces the activity of airway smooth muscle cells. The wider implications of these findings support the concept that asthma might result from the exposure to environmental factors, which deregulate the balance of different HSPs in a specific cell type. The observation that the level of HSP70 and HSP90 remain elevated over one month after bronchial thermoplasty, suggests the activation of a so-called “epigenetic event”. This describes a lasting effect on gene activity without changing the gene. Future studies will have to investigate whether the environmental factors which trigger asthma, such as bacterial infection, house-dust mite, pollen or stress, influence the production of any specific HSP. Most bacteria that are associated with asthma produce their own HSPs, and these HSPs have been discussed to initiate the pathogenesis of asthma. Understanding this mechanism will provide the basis to develop novel therapies to prevent or reduce airway wall remodeling in asthma.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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