Interleukin 8 and bronchial phagocytes in patients with non-allergic asthma and diverse respiratory responses to cold stimulus

Introduction. The role of phagocytes, regulated by interleukin 8 (IL-8), in the formation of the bronchial response to environmental stimuli in patients with asthma is not well understood.

Aim. To study the functional activity of IL-8 and the pool of phagocytic cells in the inflammatory pattern of the bronchi in patients with non-allergic asthma during inhalation exposure to cold air.

Materials and methods. In 129 patients with mild to moderate asthma, the content of IL-8 and the cellular composition of sputum before and after the bronchoprovocation test with isocapnic hyperventilation with cold air (-20°C) (IHCA) were analyzed.

Results. Based on the results of the IHCA by the assessment of changes in FEV1 (Δ,%), 54 patients (1st group) were verified with cold airway hyperresponsiveness (CAHR), the comparison group consisted of asthma patients (2nd group, n=75) who did not respond to the trigger (ΔFEV1 = -18.9±1.2 and -3.3±0.4%; p<0.0001, respectively). The content of neutrophils in sputum before provocation was 41.1±2.2% and 34.5±2.2% (p><0.05), macrophages – 36.2±2.7% and 43.1±2.5% (p> ˂ 0.0001, respectively). The content of neutrophils in sputum before provocation was 41.1±2.2% and 34.5±2.2% (p ˂ 0.05), macrophages – 36.2±2.7% and 43.1±2.5% (p>0.05), respectively. In response to the IHCA in the 1st group, the number of neutrophils increased to 48.2±2.0% (p ˂ 0.05), macrophages decreased to 28.7±2.1% (p ˂ 0.01), and the level of IL-8 increased from 12838±2328 to 17412±2980 pg/mL (p ˂ 0.05). In the 2nd group, the concentration of IL-8 before the IHCA was 14639±2691 pg/mL, after the test 10545±1746 pg/mL (p>0.05); the number of neutrophils after the test 40.0±2.3% (p>0.05); macrophages – 35.8±2.0% (p ˂ 0.01).

Conclusion. In asthma patients with CAHR, the inflammatory pattern of the bronchi in response to the cold trigger shows enhanced IL-8 activity and more pronounced changes in the content of phagocytes, mobilized with the involvement of this cytokine.

1. Stemmler S., Arinir U., Klein W., Rohde G, Hoffjan S., Wirkus N., Reinitz-Rademacher K., Bufe A., Schultze-Werninghaus G., Epplen J.T. Association of interleukin-8 receptor α polymorphisms with chronic obstructive pulmonary disease and asthma. Genes Immun. 2005; 6(3): 225–230. https://doi.org/10.1038/sj.gene.6364181

2. Menyaуlo M.E., Malashchenko V.V., Shmarov V.A., Gazatova N.D., Melashchenko O.B., Goncharov A.G., Seledtsova G.V., Seledtsov V.I. [Interleukin-8 is able to support the pro-inflammatory activity of human monocytes (macrophages)]. Geny i kletki = Genes & Cells 2018; 13(1): 65–69 (in Russian). https://doi.org/10.23868/201805007

3. Puthothu B., Krueger M., Heinze J., Forster J., Heinzmann A. Impact of IL8 and IL8-receptor alpha polymorphisms on the genetics of bronchial asthma and severe RSV infections. Clin. Mol. Allergy 2006; 4: 2. https://doi.org/10.1186/1476-7961-4-2

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

5. Yamasaki A., Okazaki R., Harada T. Neutrophils and asthma. Diagnostics (Basel) 2022; 12(5): 1175. https://doi.org/10.3390/diagnostics12051175

6. Vasilyeva G.I., Ivanova I.A., Tyukavkina S.Yu. [Cooperative interaction of mono- and polynuclear phagocytes, mediated by mono- and neutrophilokines]. Immunology 2000; (5): 11–17 (in Russian).

7. Williams H., Mack C., Baraz R., Marimuthu R., Naralashetty S., Li S., Medbury H. Monocyte differentiation and heterogeneity: Intersubset and interindividual differences. Int. J. Mol. Sci. 2023; 24(10): 8757. https://doi.org/10.3390/ijms24108757

8. 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 = Russian Pulmonology 2012; 6: 83–89 (in Russian). https://doi.org/10.18093/0869-0189-2012-0-6-83-89

9. Sarbaeva N.N., Ponomareva Yu.V., Milyakova M.N. [Macrophages. Diversity of phenotypes and functions, interaction with foreign materials]. Geny i kletki = Genes & Cells 2016; 11(1): 9–17 (in Russian).

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. Nikonova A.A., Khaitov M.R., Khaitov R.M. [Characteristics and role of macrophages in pathogenesis of acute and chronic lung diseases]. Meditsinskaya Immunologiya = Medical Immunology (Russia) 2017; 19(6): 657–672 (in Russian). https://doi.org/10.15789/1563-0625-2017-6-657-672

12. Arora S., Deva K., Agarwalb B., Dasc 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

13. Fedorov A.A., Ermak N.A., Gerashchenko T.S., Topolnitsky E.B., Shefer N.A., Rodionov E.O., Stakheeva M.N. [Macrophage polarization: mechanisms, markers and induction factors] Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology 2022; 21(4): 124–136 (in Russian). https://doi.org/10.21294/1814-4861-2022-21-4-124-136

14. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (2023 update). Available at: https://ginasthma.org/wp-content/uploads/2023/07/GINA-2023-Full-report-23_07_06-WMS.pdf

15. Djukanovic R., Sterk P.J., Fahy J.V., Hargreave F.E. Standardised methodology of sputum induction and processing. Eur. Respir. J. Suppl. 2002; 37: 1s–2s. https://doi.org/10.1183/09031936.02.00000102

16. Prikhodko A.G., Perelman J.M., Kolosov V.P. [Airway hyperresponsiveness]. Vladivostok: Dal’nauka; 2011 (in Russian). ISBN: 978-5-8044-1220-4

17. Hastie A.T., Moore W.C., Meyers D.A., Vestal P.L., Li H., Peters S.P., Bleecker E.R. Аnalyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J. Allergy Clin. Immunol. 2010; 125(5): 1028–1036. https://doi.org/10.1016 /j.jaci.2010.02.008

18. Terekhov D.V. [Severe non-allergic bronchial asthma: characteristics of the phenotype and treatment features]. Astma i allergiya 2019; 3: 3–7 (in Russian).

19. Trushina E.Yu., Kostina E.M., Baranova N.I., Tipikin V.A. [The role of cytokines as molecular markers of inflammation in non-allergic bronchial asthma]. Sovremennyye problemy nauki i obrazovaniya 2018; 4: 179 (in Russian). Available at: https://science-education.ru/ru/article/view?id=27799

20. 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

21. Gougerot-Pocidalo M.A., Benna J., Elbim C., Chollet-Martin S., Dang M.C. Regulation of human neutrophil oxidative burst by pro- and anti-inflammatory cytokines. Journal. Soc. Biol. 2002; 196(1): 37–46.

22. Sheppard F.R., Kelher M.R., Moore E.E., McLaughlin N.J.D., Banerjee A., Silliman C.C. Structural organization 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

23. Kolpakova A.F., Sharipov R.N., Latysheva E.N., Kolpakov F.A. [The transcription factor NF-kB plays a key role in the regulation of genes involved in inflammatory and immune reactions] Sibirskoye meditsinskoye obozreniye = Siberian Medical Review 2009; 3(57): 7–12 (in Russian).

24. Singh P., Hasan S., Sharma S., Nagra S., Yamaguchi D.T., Wong D.T.W., Hahn B.H., Hossain A. Th17 cells in inflammation and autoimmunity. Autoimmun. Rev. 2014; 13(12): 1174–1181. https://doi.org/10.1016/j.autrev.2014.08.019

25. Acosta-Rodriguez E.V., Napolitani G., A. Lanzavecchia A., Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat. Immunol. 2007; 8(9): 942–949. https://doi.org/10.1038/ni1496

26. Al-Ramli W., Pre´fontaine D., Chouiali F., Martin J.G., Olivenstein R., Lemie`re C., Hamid Q. T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J. Allergy Clin. Immunol. 2009; 123(5): 1185–1187. https://doi.org/10.1016/j.jaci.2009.02.024

27. Lindén А., Dahlén В. Interleukin-17 cytokine signalling in patients with asthma. Eur. Respir. J. 2014; 44(5): 1339– 1331. https://doi.org/10.1183/09031936.00002314

28. Duvall M.G., Krishnamoorthy N., Levy B.D. Non-type 2 inflammation in severe asthma is propelled by neutrophil cytoplasts and maintained by defective resolution. Allergol. Int. 2019; 68(2): 143–149. https://doi.org/10.1016/j.alit.2018.11.006

29. Еsteban-Gorgojo I., Antolín-Amérigo D., Domínguez-Ortega J., Quirce S. Non-eosinophilic asthma: current perspectives. J. Asthma Allergy 2018; 11: 267–281. https://doi.org/10.2147/JAA.S153097