Abstract
Constriction of airways during asthmatic exacerbation is the result of airway smooth muscle (ASM) contraction. Although it is generally accepted that ASM is hypercontractile in asthma, this has not been unambiguously demonstrated. Whether airway hyperresponsiveness (AHR) is the result of increased ASM mass alone or also increased contractile force generation per unit of muscle directly determines the potential avenues for treatment.
To assess whether ASM is hypercontractile we performed a series of mechanics measurements on isolated ASM from intrapulmonary airways and trachealis from human lungs. We analysed the ASM and whole airway proteomes to verify if proteomic shifts contribute to changes in ASM properties.
We report an increase in isolated ASM contractile stress and stiffness specific to asthmatic human intrapulmonary bronchi, the site of increased airway resistance in asthma. Other contractile parameters were not altered. Principal component analysis (PCA) of unbiased mass spectrometry data showed clear clustering of asthmatic subjects with respect to ASM specific proteins. The whole airway proteome showed upregulation of structural proteins. We did not find any evidence for a difference in the regulation of myosin activity in the asthmatic ASM.
In conclusion, we showed that ASM is indeed hyperreactive at the level of intrapulmonary airways in asthma. We identified several proteins that are upregulated in asthma that could contribute to hyperreactivity. Our data also suggest enhanced force transmission associated with enrichment of structural proteins in the whole airway. These findings may lead to novel directions for treatment development in asthma.
Abstract
Intrapulmonary, but not tracheal, airway smooth muscle is hyperreactive in asthma, together with pro-contractile changes in the airway smooth muscle proteome. Several proteins were identified that could be targeted for treatment of the hyperreactivity. http://bit.ly/33esYSU
Footnotes
All analysed data and materials associated with this study are in the paper, raw data are available upon request.
This article has supplementary material available from erj.ersjournals.com
Author contributions: G. Ijpma: conception and design; acquisition of data; analysis and interpretation of data; drafting and review of manuscript; L. Kachmar: acquisition of data; article review; A. Panariti: acquisition of data; analysis of data; article review; O.S. Matusovsky: acquisition of data; article review; D. Torgerson: proteomics analysis advice; article review; A. Benedetti: statistical advice; article review; A-M. Lauzon: conception and design; analysis and interpretation of data; drafting and review of manuscript.
Conflict of interest: G. Ijpma has nothing to disclose.
Conflict of interest: L. Kachmar has nothing to disclose.
Conflict of interest: A. Panariti has nothing to disclose.
Conflict of interest: O.S. Matusovsky has nothing to disclose.
Conflict of interest: D. Torgerson has nothing to disclose.
Conflict of interest: A. Benedetti has nothing to disclose.
Conflict of interest: A-M. Lauzon has nothing to disclose.
Support statement: This work was supported by a National Heart, Lung and Blood Institute grant (RO1-HL 103405-02), the Canadian Institute for Health Research and the Costello Fund. The Meakins–Christie Laboratories of the Research Institute of McGill University Health Center are supported in part by a centre grant from the Fonds de la Recherche en Santé Respiratoire du Québec. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received November 8, 2019.
- Accepted March 5, 2020.
- Copyright ©ERS 2020