The role of macrophages, myeloperoxidase, interleukins IL-12, IL-13 in the formation of bronchial response to hyperosmolar stimulus in patients with bronchial asthma

Introduction. The involvement of macrophages in the realization of oxidative / halogenating stress andthe role of macrophage populations in maintaining the balance of Th1/Th2 cytokines in patients with asthma with osmotic types of bronchial hyperresponsiveness has not been sufficiently studied.

Aim. To study the role of macrophages, myeloperoxidase (MPO), IL-12, IL-13 in the formation of the bronchial response to the hyperosmolar trigger in patients with asthma.

Materials and methods. The object of the study was asthma patients (n=35). The level of asthma control (Asthma Control Test, points), cellular composition (%) and MPO (pixel) of induced sputum (IS), bronchial response (ΔFEV_1IHS, %) after 3-minute ultrasonic inhalation of hypertonic (4.5% NaCl) solution (IHS) were assessed. Before and after the IHS test, exhaled air condensate was collected, in which the concentration of IL-12, IL-12 (pg/mL) was determined.

Results. Patients with asthma did not control the disease, ACT was 14 (11; 16.5) points. Group 1 (n=15) included individuals with bronchial hyperresponsiveness to the IHS, group 2 (n=20) included patients with lack of it (ΔFEV_1IHS -19.8±1.9 and 1.43±0.72%, respectively, p<0.001). Baseline FEV1 in groups 1 and 2 was 89.5±2.8 and 93.7±2.3%, respectively (p>0.05). The percentage of sputum macrophages in group 1 was lower (40 [15.95; 50.75]%), and the average cytochemical coefficient in phagocytes was higher (141.4±9.7) than in group 2 (50 [42.5; 63.6]; p=0.039 and 98.8±12.3; p=0.013, respectively). IL-12 expression was to be more significant than IL-13 expression in the initiation of airway inflammation and hyperresponsiveness to hyperosmolar stimulus.

Conclusion. The lower concentration of macrophages in the bronchi of asthma patients with airway hyperresponsiveness to hyperosmolar stimulus is most likely due to an increase in the secretory function of cells. A high level of MPO activity in these patients depended on the peroxidase function of secreting macrophages, was associated with M1 polarization of macrophages, and indicated a Th1 immune response associated with the participation of IL-12 in the regulation of airway hyperresponsiveness to a hypertonic trigger.

1. Lyamina S.V., Shimshelashvili S.L., Kalish S.V., Malysheva Е.V., Larionov N.P., Malyshev I.Yu. [ Changes in phenotype and phenotypic flexibility of alveolar macrophages in inflammatory pulmonary diseases]. Pulmonologiya 2012; (6):83‒89 (in Russian). https://doi.org/10.18093/0869-0189-2012-0-6-83-89

2. Nikonova A.A., Khaitov M.R., Khaitov R.M. [Characteristics and role of macrophages in pathogenesis of acute and chronic lung diseases]. Medical Immunology (Russia) 2017; 19(6):657–672 (in Russian). https://doi.org/10.15789/15630625-2017-6-657-672

3. Arora S., Dev K., Agarwal B., Das P., Ali Syed M. Macrophages: their role, activation and polarization in pulmonary diseases. Immunobiology 2018; 223(4-5):383–396. https://doi.org/10.1016/j.imbio.2017.11.001

4. Abdelaziz M.H., Abdelwahab S.F., Wan J., Cai W., Huixuan W., Jianjun C., Kumar K.D., Vasudevan A., Sadek A., Su Z., Wang S., Xu H. Alternatively activated macrophages; a double-edged sword in allergic asthma. J. Transl. Med. 2020; 18:58. https://doi.org/10.1186/s12967-020-02251-w

5. Wills-Karp M. Interleukin-13 in asthma pathogenesis. Curr. Allergy Asthma Rep. 2004; 4(2):123–131. https://doi.org/10.1007/s11882-004-0057-6

6. Dugarova I.D., Anaev E.Kh., Chuchalin A.G. [On the role of cytokines in bronchial asthma]. Pul'monologiya 2009; 19(4):96–102 (in Russian). https://doi.org/10.18093/0869-0189-2009-4-96-102

7. Mineev V.N., Sorokina L.N., Trofimov V.I., Nyoma M.A., Ivanov V.A. [Interleukin-4 and interleukin-13 receptors: structure, function and genetic polymorphism]. Pulmonologiya 2010; 20(3):113–119 (in Russian). https://doi.org/10.18093/0869-0189-2010-3-113-119

8. Bakhaev D.V., Stenkova A.M., Ivanova Yu.V., Schegoleva O.V., Prosekova E.V., Rasskazov V.A., Isaeva M.P. [Polymorphism of interleukin-13 genes and xenobiotic detoxification system in children with allergic pathology]. Tikhookeanskiy meditsinskiy zhurnal = Pacific Medical Journal 2012; (1):63–65. (in Russian).

9. Arora P., Ansari S. Role of various mediators in inflammation of asthmatic airways. In: Pereira C., editor. Asthma ‒ Biological Evidences [Internet]. London: IntechOpen; 2019 [cited 2022 Oct 21]. Available from: https://www.intechopen.com/chapters/66708. https://doi.org/10.5772/intechopen.84357

10. Jiang Z., Zhu L. Update on the role of alternatively activated macrophages in asthma. J. Asthma Allergy 2016; 9:101‒107. https://doi.org/10.2147/JAA.S104508

11. Malyshev I.Yu., Lyamina S.V., Shimshelashvili S.L., Vasserman E.N. [Functions of alveolar macrophages and surfactant protein D in lung disease]. Pulmonologiya 2011; (3):101‒107 (in Russian). https://doi.org/10.18093/0869-01892011-0-3-101-107

12. Sarbaeva N.N., Ponomareva J.V., Milyakova M.N. [Macrophages: diversity of phenotypes and functions, interaction with foreign materials]. Genes & Cells 2016; 11(1):9–17 (in Russian). https://doi.org/10.23868/gc120550

13. Schroder K., Hertzog P.J., Ravasi T., Hume D.A. Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 2004; 75(2):163–189. https://doi.org/10.1189/jlb.0603252

14. Gattoni A., Parlato A., Vangieri B., Bresciani M., Derna R. Interferon-gamma: biologic functions and HCV therapy (type I/II) (1 of 2 parts). Clin. Ter. 2006; 157(4):377–386. PMID: 17051976.

15. Lutckii A.A., Zhirkov A.A., Lobzin D.Yu., Rao M., Alekseeva L.A., Maeurer M., Lobzin Yu.V. [Interferon-γ: biological function and application for study of cellular immune response]. Journal Infectology 2015; 7(4):10–22 (in Russian). https://doi.org/10.22625/2072-6732-2015-7-4-10-22

16. Gee K., Guzzo C., Che Mat N.F., Ma W., Kumar A. The IL-12 family of cytokines in infection, inflammation and autoimmune disorders. Inflamm. Allergy Drug Targets 2009; 8(1):40–52. https://doi.org/10.2174/187152809787582507

17. Hamza T., Barnett J.B., Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int. J. Mol. Sci. 2010; 11(3):789–806. https://doi.org/10.3390/ijms11030789

18. Soodaeva S.K. [Free radical mechanisms of injury in respiratory disease]. Pulmonologiya 2012; (1):5‒10 (in Russian). https://doi.org/10.18093/0869-0189-2012-0-1-5-10

19. Panasenko O.M., Gorudko I.V., Sokolov A.V. Hypochlorous acid as a precursor of free radicals in living systems. Biochemistry (Mosk.) 2013; 78(13):1466–1889. https://doi.org/10.1134/S0006297913130075

20. A.V. Sokolov, V.A. Kostevich, N.P. Gorbunov, D.V. Grigorieva, I.V. Gorudko, V.B Vasilyev., O.M Panasenko. [Alink between active myeloperoxidase and chlorinated ceruloplasmin in blood plasma of patients with cardiovascular diseases]. Medical Immunology (Russia) 2018; 20(5):699–710 (in Russian). https://doi.org/10.15789/1563-0625-2018-5-699710

21. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (2018 update). Available at: www.ginasthma.org

22. Sylvester K.P., Clayton N., Cliff I., Hepple M., Kendrick A., Kirkby J., Miller M., Moore A., Rafferty G.F., O'Reilly L., Shakespeare J., Smith L., Watts T., Bucknall M., Butterfield K. ARTP statement on pulmonary function testing 2020. BMJ Open Respir. Res. 2020; 7(1):e000575. https://doi.org/10.1136/bmjresp-2020-000575

23. Perelman J.M., Naumov D.E., Prikhodko A.G., Kolosov V.P. [Mechanisms and manifestations of osmotic airway hyperresponsiveness]. Vladivostok: Dal'nauka; 2016 (in Russian). ISBN: 978-5-8044-1627-1

24. Djukanovic R., Sterk P.J., Fahy J.V., Hargreave F.E. Standardised methodology of sputum induction and processing. Eur. Respir. J. 2002; 20(37):1s–2s. https://doi.org/10.1183/09031936.02.000001022

25. Hayhoe F.G.J., Quaglino D. [Haematological cytochemistry]. Moscow: Meditsina; 1983 (in Russian).

26. Shuai K., Liu B. Regulation of JAK-STAT signalling in the immune system. Nat. Rev. Immunol. 2003; 3(11):942– 954. https://doi.org/10.1038/nri1226

27. Mineev V.N., Sorokina L.N. [STAT6 expression by peripheral blood lymphocytes in bronchial asthma]. Medical Immunology (Russia) 2007; 9(4–5):405–410 (in Russian). https://doi.org/10.15789/1563-0625-2007-4-5-405-410

28. Usui T., Preiss J.C., Kanno Y., Yao Z.J., Bream J.H., O'Shea J. J., Strober W. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J. Exp. Med. 2006; 203(3):755–766. https://doi.org/10.1084/jem.20052165

29. Mineev V.N., Sorokina L.N., Nyoma M.A., Trofimov V.I. [GATA-3 expression in peripheral blood lymphocytes of patients with bronchial asthma]. Medical Immunology (Russia) 2010; 12(1-2):21–28 (in Russian). https://doi.org/10.15789/1563-0625-2010-1-2-21-28

30. Pirogov A.B., Naumov D.E., Prikhodko A.G., Perelman J.M. [Th1, Th2 cytokines in airway response to acute cold exposure in patients with bronchial asthma]. Bûlleten' fiziologii i patologii dyhaniâ = Bulletin Physiology and Pathology of Respiration 2022; (85):47–55 (in Russian). https://doi.org/10.36604/1998-5029-2022-85-47-55

31. Sheppard F.R., Kelher M.R., Moore E.E., McLaughlin N.J.D., Banerjee A., Silliman C.C. Structural or-ganization of the neutrophil NADPH oxidase: phosphorylation and translocation during priming and activation. J. Leukoc. Biol. 2005; 78(5):1025–1042. https://doi.org/10.1189/jlb.0804442

32. Freidlin I.S. [Mononuclear phagocyte system]. Moscow: Meditsina; 1984 (in Russian).