Character of intersystem interactions in patients with asthma

   Introduction. Disruption of the interactions among parameters of oxidative homeostasis, cell signalling and cellular energetic status leads to failure of adaptive mechanisms, which favours progression of pathological changes in asthma.

   Aim. To determine the character of intersystem interactions in mild and moderate controlled and partially controlled asthma.

   Materials and methods. The study enrolled 244 patients with asthma and 60 conditionally healthy subjects. Twenty-five parameters were assessed: expression of interleukin-4 receptors, interleukin-6 receptors (IL-6R), Toll-like receptors (TLR) 2 and 4; the mitochondrial membrane potential coefficient (cMMP) of CD4+ and CD8+ cells; levels of malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), thioredoxin-1 (Trx-1), total antioxidant activity (TAA), glutathione (total, oxidised and reduced), interleukin-4 and interleukin-6; and the fatty-acid composition of leukocyte mitochondrial membranes. Intersystem interactions were analysed with Terentyev’s correlation pleiad method.

   Results. Application of the Terentyev algorithm identified four groups of the most strongly linked indicators for each asthma cohort. In mild controlled asthma, the predictors were Trx-1 level and the MDA/TAA ratio, whereas in mild partially controlled asthma they were Trx-1 and 8-OHdG levels. In moderate controlled asthma, Trx-1 level and the cMMP of CD4+ cells oc-
cupied the central positions within the correlation pleiads. Five predictors were defined for moderate partially controlled asthma: 8-OHdG, cMMP of CD4+ cells, total antioxidant activity, and expression of IL-6R and TLR2 on CD4+ cells. Progression of asthma was accompanied by an increase in the power and robustness of the pleiads.

   Conclusion. Analysis of intersystem interactions in asthma showed that parameters reflecting the intensity of destructive processes, activation of the inflammatory arm of the immune system and destabilisation of signalling interactions take the leading positions within the pleiads. Disease progression and reduced control destabilise intersystem regulatory processes.

1. Asher M.I., Rutter C.E., Bissell K., Chiang C.Y., El Sony A., Ellwood E., Ellwood P., Garcia-Marcos L., Marks G.B., Morales E., Mortimer K., Perez-Fernandez V., Robertson S., Silverwood R.J., Strachan D.P., Pearce N. Global asthma network phase I study group. Worldwide trends in the burden of asthma symptoms in school-aged children: Global Asthma Network Phase I cross-sectional study. Lancet 2021; 398(10311):1569–1580. doi: 10.1016/S0140-6736(21)01450-1

2. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (Update 2024). Available at: https://ginasthma.org/

3. Mortimer K., Lesosky M., Garcia-Marcos L., Asher M.I., Pearce N., Ellwood E., Bissell K., El Sony A., Ellwood P., Marks G.B., Martkinez-Torres A., Morales E., Perez-Fernandez V., Robertson S., Rutter C.E., Silverwood R.J., Strachan D.P., Chiang C.Y. Global asthma network phase I study group. The burden of asthma, hay fever and eczema in adults in 17 countries: GAN phase I study. Eur. Respir. J. 2022; 60(3):2102865. doi: 10.1183/13993003.02865-2021

4. Novgorodtseva T.P., Denisenko Yu.K., Kytikova O.Yu., Antonyuk M.V., Gvozdenko T.A., Vitkina T.I., Knyshova V.V., Bocharova N.V. [Regulatory mechanisms of systemic inflammation in respiratory pathologyedited. Novgorodtseva T.P., editor]. Vladivostok: Dal'nevostochnyy federal'nyy universitet; 2021 (in Russian). ISBN: 978-5-7444-5052-6.

5. Brasier A.R., Jarjour N.N., editors. Precision Approaches to Heterogeneity in Asthma. Advances in Experimental Medicine and Biology. Cham, Switzerland: Springer; 2023. ISBN 978-3-031-32258-7.

6. Zhou W.C., Qu J., Xie S.Y., Sun Y., Yao H.W. Mitochondrial dysfunction in chronic respiratory diseases: implications for the pathogenesis and potential therapeutics. Oxid. Med. Cell Longev. 2021; 2021:5188306. doi: 10.1155/2021/5188306

7. Zhu Z., Camargo C.A.Jr., Hasegawa K. Metabolomics in the prevention and management of asthma. Expert Rev. Respir. Med. 2019; 13(12):1135–1138. doi: 10.1080/17476348.2019.1674650

8. Alves N.D.O., Martins Pereira G., Di Domenico M., Costanzo G., Benevenuto S., de Oliveira Fonoff A.M., de Souza Xavier Costa N., Ribeiro Junior G., Satoru Kajitani G., Cestari Moreno N., Fotoran W., Iannicelli Torres J., de Andrade J.B., Matera Veras M., Artaxo P., Menck C.F.M., de Castro Vasconcellos P., Saldiva P. Inflammation response, oxidative stress and DNA damage caused by urban air pollution exposure increase in the lack of DNA repair XPC protein. Environ. Int. 2020; 145:106150. doi: 10.1016/j.envint.2020.106150

9. El Hadri K., Smith R., Duplus E., El Amri C. Inflammation, oxidative stress, senescence in atherosclerosis: thiore-doxine-1 as an emerging therapeutic target. Int. J. Mol. Sci. 2021; 23(1):77. doi: 10.3390/ijms23010077

10. Farraia M., Cavaleiro Rufo J., Paciencia I., Castro Mendes F., Delgado L., Laerte Boechat J., Moreira A. Metabolic interactions in asthma. Eur. Ann. Allergy Clin. Immunol. 2019; 51(5):196–205. doi: 10.23822/EurAnnACI.1764-1489.101

11. Habib N., Pasha M.A., Tang D.D. Current understanding of asthma pathogenesis and biomarkers. Cells 2022; 11(17):2764. doi: 10.3390/cells11172764

12. Vitkina T.I., Kondrateva E.V., Mineeva E.E., Gvozdenko T.A. Patent 2835342 RU. [Method for predicting exacerbations of mild to moderate bronchial asthma]; published 24. 02. 2025 (in Russian).

13. Denisenko Yu.K., Vitkina T.I., Novgorodtseva T.P., Kondrateva E.V., Zhukova N.V., Borshchev P.V. [Fatty acid spectrum of mitochondrial thrombocytes membranes in patients with chronic non-obstructive bronchitis]. Bûlleten' fiziologii i patologii dyhaniâ = Bulletin Physiology and Pathology of Respiration 2013; 50:34–38 (in Russian).

14. Bligh E.G., Dyer W.J. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 1959; 37(8):911–917. doi: 10.1139/o59-099

15. Carreau J.P., Duback J.P. Adaptation of a macroscale method to the microscale for fatty acid methyl transesterification of biological lipid extract. J. Chromatogr. A. 1978; 151:384–390. doi: 10.1016/S0021-9673(00)88356-9

16. Terentev P.V. [The method of correlation pleiades]. Vestnik Leningradskogo universiteta 1959; 9:137–141 (in Russian).

17. Kondratyeva E.V., Vitkina T.I. [Indicators of oxidative homeostasis and genotoxicity in patients with asthma under exposure to solid suspended atmospheric particulate matter]. Bûlleten' fiziologii i patologii dyhaniâ = Bulletin Physiology and Pathology of Respiration 2024; 94:95–103 (in Russian). doi: 10.36604/1998-5029-2024-94-95-103

18. Erdal H., Gunaydın F., Karaoglanoglu S. Oxidative stress in asthma. Adv. Health Sports Technol. Sci. 2023; 4(1):62–70. doi: 10.54152/asujshr.1290539

19. Karadogan B., Beyaz S., Gelincik A., Buyukozturk S., Arda N. Evaluation of oxidative stress biomarkers and antioxidant parameters in allergic asthma patients with different level of asthma control. J. Asthma 2022; 59(4):663–672. doi: 10.1080/02770903.2020.1870129

20. Lambrecht B.N., Hammad H., Fahy J.V. The cytokines of asthma. Immunity 2019; 50(4):975–991. doi: 10.1016/j.immuni.2019.03.018

21. Boukhenouna S., Wilson M.A., Bahmed K., Kosmider B. Reactive oxygen species in chronic obstructive pulmonary disease. Oxid. Med. Cell Longev. 2018; 2018:5730395. doi: 10.1155/2018/5730395

22. Zhou J., Wang C., Wu J., Fukunaga A., Cheng Z., Wang J., Yamauchi A., Yodoi J., Tian H. Anti-allergic and anti-inflammatory effects and molecular mechanisms of thioredoxin on respiratory system diseases. Antioxid. Redox. Signal. 2020; 32(11):785–801. doi: 10.1089/ars.2019.7807

23. Chen P.Y., Chen C.W., Su Y.J., Chang W.H., Kao W.F., Yang C.C., Wang I.J. Associations between levels of urinary oxidative stress of 8-OHdG and risk of atopic diseases in children. Int. J. Environ Res. Public Health. 2020; 17(21):8207. doi: 10.3390/ijerph17218207

24. Shayoli S. Biomarkers of asthma. IJPPR Human J. 2020; 18(2):531–536.

25. Kondratyeva E.V., Vitkina T.I. [Functional state of mitochondria in chronic respiratory diseases]. Bûlleten' fiziologii i patologii dyhaniâ = Bulletin Physiology and Pathology of Respiration 2022; 84:116–126 (in Russian). doi: 10.36604/1998-5029-2022-84-116-126

26. Novgorodtseva T.P., Karaman Yu.K., Knyshova V.V., Zhukova N.V., Bival'kevich N.V. [The composition of fatty acids of erythrocyte membranes in patients with chronic bronchopulmonary diseases]. Bûlleten' fiziologii i patologii dyhaniâ = Bulletin Physiology and Pathology of Respiration 2013; 48:33–38 (in Russian).

27. Zhou W.C., Qu J., Xie S.Y., Sun Y., Yao H.W. Mitochondrial dysfunction in chronic respiratory diseases: implications for the pathogenesis and potential therapeutics. Oxid. Med. Cell Longev. 2021; 2021:5188306. doi: 10.1155/2021/5188306

28. Lourenco O., Fonseca A.M., Taborda-Barata L. Human CD8+ T cells in asthma: possible pathways and roles for NK-like subtypes. Front. Immunol. 2016; 7:638. doi: 10.3389/fimmu.2016.00638