Blood plasma cathepsin S in severe bronchial asthma

The aim. To determine the level of cathepsin S and to identify its possible relationships with clinical, functional and laboratory indicators in patients with severe bronchial asthma.

Methods. 114 patients with severe bronchial asthma were examined. 96 women (84.2%) and 18 (15.8%) men were divided into 2 groups: allergic and non-allergic severe bronchial asthma. The external respiration function was assessed with whole-body plethysmography (“Erich Jaeger”, Germany). The plasma concentration of cytokines IL-4, IL-5, IL-13, periostin, cathepsin S, TGF-β was estimated with ELISA (“eBioscience”, USA).

Results. Fixed obstruction is reported in 48% and 50% of cases of allergic and non-allergic severe asthma, respectively. Peripheral blood eosinophilia occurs in 41.5% of cases with allergic and in 25% of cases with non-allergic asthma. IL-5, IL-13, and cathepsin S levels were increased in both groups. An increase in IL-4 and TGF-β levels was revealed in non-allergic asthma. Periostin levels were increased in patients with allergic asthma as compared with the control and the second group. Positive correlation between cathepsin S and concentration of IL-4, IL-5 was established in both groups. We identified weak positive correlation between cathepsin S levels and clinical symptoms of the disease, such as frequency of SABA use and asphyxiation attacks, only in the allergic asthma group. A positive correlation between cathepsin S and TGF-β was established in both groups.

Conclusion. A positive correlation between serum cathepsin S and TGF-β was established in both allergic and non-allergic severe bronchial asthma. The found moderate relationship may indirectly indicate the involvement of cathepsin S in airway remodeling processes regardless of the disease type.

1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention (2020 update). Available at: www.ginasthma.org

2. Avdeev S.N., Nenasheva N.M., Zhudenkov K.V. et al. [Prevalence, morbidity, phenotypes and other characteristics of severe bronchial asthma in Russian Federation]. Pul’monologiya. 2018; 28 (3): 341– 358. DOI: 10.18093/0869-0189-2018-28-3-341-358 (in Russian).

3. Nenasheva N.M. [Bronchial asthma phenotypes and choice of therapy]. Prakticheskaya pul’monologiya. 2014; 2: 2–11. Available at: https://atmosphere-ph.ru/modules/magazines/articles/pulmo/pp_2_2014_02.pdf (in Russian).

4. Zavasnik-Bergant T., Turk B. Cysteine cathepsins in immune response. Tissue Antigens. 2006; 67 (5): 349–355. DOI: 10.1111/j.1399-0039.2006.00585.x.

5. Brown R., Nath S., Lora A. et al. Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics. Respir. Res. 2020; 21 (1): 111. DOI: 10.1186/S12931-020-01381-5.

6. Yadati T., Houben T., Bitorina A., Shiri-Sverdlov R. The ins and outs of Cathepsins: physiological function and role in disease management. Cells. 2020; 9 (7): 1679. DOI: 10.3390/cells9071679.

7. Patel S., Homaei A., El-Seedi H.R., Akhtar N. Cathepsins: proteases that are vital for survival but can also be fatal. Biomed. Pharmacother. 2018; 105: 526–532. DOI: 10.1016/j.biopha.2018.05.148.

8. Bennett G.H., Carpenter L., Hao W. et al. Risk factors and clinical outcomes associated with fixed airflow obstruction in older adults with asthma. Ann. Allergy Asthma Immunol. 2017; 120 (2): 164–168. e1. DOI: 10.1016/j.anai.2017.10.004.

9. Li C., Chen Q., Jiang Y., Liu Z. Single nucleotide polymorphisms of cathepsin S and the risks of asthma attack induced by acaroid mites. Int. J. Clin. Exp. Med. 2015; 8 (1): 1178–1187. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358566

10. Deschamps K., Cromlish W., Weicker S. et al. Genetic and pharmacological evaluation of cathepsin s in a mouse model of asthma. Am. J. Respir. Cell Mol. Biol. 2011; 45 (1): 81–87. DOI: 10.1165/rcmb.2009-0392OC.

11. Zhang X., Zhou Y., Yu X. et al. Differential roles of cysteinyl cathepsins in TGF-β signaling and tissue fibrosis. iScience. 2019; 19: 607– 622. DOI: 10.1016/j.isci.2019.08.014.

12. Saito A., Horie M., Nagase T. TGF-β signaling in lung health and disease. Int. J. Mol. Sci. 2018; 19 (8): 2460. DOI: 10.3390/ijms19082460.

13. Sobotic B., Vizovisek M., Vidmar R. et al. Proteomic identification of cysteine Cathepsin substrates shed from the surface of cancer cells. Mol. Cell. Proteomics. 2015; 14 (8): 2213–2228. DOI: 10.1074/mcp.M114.044628.

14. Roth M., Zhong J., Zumkeller C. et al. The role of IgE-receptors in IgE-dependent airway smooth muscle cell remodelling. PLoS One. 2013, 8 (2): e56015. DOI: 10.1371/journal.pone.0056015.

15. Tliba O., Panettieri R.A. Paucigranulocytic asthma: Uncoupling of airway obstruction from inflammation. J. Allergy Clin. Immunol. 2019; 143 (4): 1287–1294. DOI: 10.1016/j.jaci.2018.06.008.

16. Elliot J.G., Noble P.B., Mauad T. et al. Inflammation-dependent and independent airway remodelling in asthma. Respirology. 2018; 23 (12): 1138–1145. DOI: 10.1111/resp.13360.

17. Demko I.V., Sobko E.A., Chubarova S.V. et al. [Features of the systemic inflammation, external respiration functions and morphological structure of the bronchial mucous membrane in severe bronchial asthma]. Sibirskoye meditsinskoye obozreniye. 2014; (5): 47–52. Available at: https://smr.krasgmu.ru/journal/1262_47-52.pdf/ (in Russian).