Assessment of immunological parameters in induced sputum in children with severe bronchial asthma
https://doi.org/10.15789/1563-0625-AOI-3163
Abstract
Severe bronchial asthma in children is an actual current problem, due to high risk of severe and/ or frequent exacerbations, decreased quality of life in patients and their families, as well as significant costs of socio-economic and medical resources. Personalized medicine suggests the need to search for specific objective indexes of the bronchial asthma severity in children. Biomarkers characterizing the inflammatory process may serve as indexes of the bronchial asthma severity. Aim of the study was to examine the amounts of surfactant protein A (SpA), Clara cell protein (CCP), interleukin-4 (IL-4), interleukin-6 (IL-6) and transforming growth factor β1 (TGF-β1) in induced sputum in children with severe bronchial asthma. 70 children took part in the study. The patients were grouped as follows: group 1, severe bronchial asthma (n = 24); comparison group 2 with mild bronchial asthma (n = 26). The control group 3 consisted of 20 healthy children. IS collection was performed according to standard methods. The concentrations of pneumoproteins and cytokines were determined in the induced sputum using ELISA techniques. In the group of patients with severe bronchial asthma, a statistically significant increase of SpA, CCP, IL-6 and TGF-β1 concentrations in induced sputum and a significant decrease of IL-4 levels was detected, when compared with mild asthma group and healthy persons (Kruskal-Wallis test, p < 0.05). Strongly positive correlations have been found between bronchial asthma severity and sputum proteins: for SpA (Spearman quotient r = 0.893814, p < 0.05); IL-6 (r = 0.827230, p < 0.05), and TGF-β1 (r = 0.886062, p < 0.05). The contents of studied pneumoproteins and cytokines reflect the severity of respiratory inflammatory process in children with bronchial asthma. The data on the IL-4 and IL-6 cytokine production in the group with severe bronchial asthma demonstrate involvement of other immune response types into allergic inflammation. The studied immunological parameters can serve as biomarkers of the asthma severity in children.
About the Authors
A. A. TurovskayaRussian Federation
Alina A. Turovskaya, Assistant Professor, Department of Allergology and Immunology with a Course of Dermatovenerology and Cosmetology
8a Stasov St Penza 440060
Phone: +7 (963) 111-58-22
Competing Interests:
I declare that there is no conflict of interest
E. M. Kostina
Russian Federation
PhD, MD (Medicine), Associate Professor, Professor, Department of Allergology and Immunology with a Course of Dermatovenerology and Cosmetology
Competing Interests:
I declare that there is no conflict of interest
O. A. Levashova
Russian Federation
Сan. of Sci. (Biol.), Associate Professor of the department of Medical Microbiology and Laboratory Medicine, Head of the Laboratory of Molecular and Personalized Medicine
Competing Interests:
I declare that there is no conflict of interest
B. A. Molotilov
Russian Federation
Doc. of Sci. (Med.), Professor of the Department of Allergology and Immunology with a course of Dermatovenerology and Cosmetology
Competing Interests:
I declare that there is no conflict of interest
E. A. Orlova
Russian Federation
Doc. of Sci. (Med.), Associate Professor, Head of the Department of Allergology and Immunology with a course of Dermatovenerology and Cosmetology
Competing Interests:
I declare that there is no conflict of interest
E. Yu. Trushina
Russian Federation
PhD (Medicine), Associate Professor, Department of Pulmonology and Phthisiology
Competing Interests:
I declare that there is no conflict of interest
S. A. Sokolov
Russian Federation
Clinical Research Specialist
Competing Interests:
I declare that there is no conflict of interest
References
1. Baranovskaya T.V., Belevsky A.S., Voskanyan A.G., Gadzhiev K.M., Davletalieva N.E., Emelyanov A.V., Kurbacheva O.M., Knyazheskaya N.P., Mukatova I.Yu., Nenasheva N.M. Severe bronchial asthma-2018. Consensus report of the joint expert group of the Association of Russian-speaking specialists in the field of respiratory medicine, the Russian Respiratory Society, the Russian Association of Allergology and Clinical Immunology. Prakticheskaya pulmonologiya = Practical Pulmonology, 2018, Vol. 28, no. 3, pp. 52-64. (In Russ.)
2. Zhuravleva L.N. Lung surfactant and pathogenic role of surfactant proteins SP-A and SP-D. Okhrana materinstva i detstva = Protection of Motherhood and Childhood, 2016, Vol. 2, no. 28, pp. 82-86. (In Russ.)
3. Zajceva S.V., Zajceva O.V., Lokshina E.E., Zastrozhina A.K., Murtazaeva O.A. Severe bronchial asthma in children. Allergologiya i immunologiya v pediatrii = Allergology and Immunology in Pediatrics, 2019, Vol. 3, no. 58, pp. 4-14. (In Russ.)
4. Mikerov A.N. Role of the surfactant protein A in the lung immune defense. Fundamentalnye issledovaniya = Fundamental Research, 2012, no. 2, pp. 204-207. (In Russ.)
5. Mironova I.I., Romanova L.A., Dolgov V.V. General clinical examinations: urine, feces, cerebrospinal fluid, sputum. Moscow: Triada, 2012. 419 p.
6. Namazova-Baranova L.S., Vishneva E.A., Dobrynina E., Alekseeva A.A., Belevskiy A.S., Ilyina N.I., Knyazheskaya N.P., Kurbacheva O.M., Osipova G.L. Pilot Project “All-Russian Registry of Patients with Severe Bronchial Asthma” . The First Results in a Children’s Group of Patients (Moscow’s Observation Program). Pediatricheskaya farmakologiya = Pediatric Pharmacology, 2017, Vol. 14, no. 2, pp. 80-86. (In Russ.)
7. Potapova N.L., Gajmolenko I.N. Analysis of the level of transforming growth factor β1 in children with bronchial asthma. Mat i ditya v Kuzbase = Mother and Baby in Kuzbass, 2019, Vol. 79, no. 4, pp. 21-25. (In Russ.)
8. Potapova N.L., Gaymolenko I.N. The role of small airway remodeling factors in children with bronchial asthma. Pediatriya im. G.N. Speranskogo = Pediatrics. G. Speransky Journal, 2020, Vol. 99, no. 2, pp. 51-56. (In Russ.)
9. Rybakova O.G., Minina E.E., Zhakov Ya.I. Method of induced sputum sampling in children to estimate severity and nature of bronchial mucosa inflammation. Patent no. 2364341 dated 20.08.2009
10. Sukharev A.E., Ermolaeva T.N., Beda N.A., Mamaeva S.A. Immunochemical study of bronchial secretions for estimate of endobronchitis degree. Sovremennye problemy nauki i obrazovaniya = Modern Problems of Science and Education, 2004, no. 2, pp. 27-34. (In Russ.)
11. Trushina E.Yu., Kostina E.M., Molotilov B.A., Tipikin V.A., Baranova N.I. Role of IL-4, IL-6, IL-8, IL-10 cytokines in the immunopathogenesis of chronic obstructive pulmonary disease. Meditsinskaya Immunologiya = Medical Immunology (Russia), 2019, Vol. 21, no. 1, pp. 89-98. (In Russ.) doi: 10.15789/1563-0625-2019-1-89-98.
12. Chuchalin A.G., Avdeev S.N., Ajsanov Z.R., Belevskij A.S., Vasil’eva O.S., Geppe N.A., Ignatova G.L., Knyazheskaya N.P., Malahov A.B., Meshcheryakova N.N., Nenasheva N.M., Fassahov R.S., Haitov R.M., Il’ina N.I., Kurbacheva O.M., Astaf ’eva N.G., Demko I.V., Fomina D.S., Namazova-Baranova L.S., Baranov A.A., Vishneva E.A., Novik G.A. Bronchial asthma: federal clinical guidelines, 2021.
13. Almuntashiri S., Han Y., Zhu Y., Dutta S., Niazi S., Wang X., Siddiqui B., Zhang D. CC16 regulates inflammation, ROS generation and apoptosis in bronchial epithelial cells during Klebsiella pneumoniae infection. Int. J. Mol. Sci., 2021, Vol. 22, no. 21, 11459. doi: 10.3390/ijms222111459.
14. Almuntashiri S., Zhu Y., Han Y., Wang X., Somanath P.R., Zhang D. Club cell secreted protein CC16: potential applications in prognosis and therapy for pulmonary diseases. J. Clin. Med., 2020, Vol. 9, no. 12, 4039. doi: 10.3390/jcm9124039.
15. Bernstein Z.J., Shenoy A., Chen A., Heller N.M., Spangler J.B. Engineering the IL-4/IL-13 axis for targeted immune modulation. Immunol. Rev., 2023, Vol. 320, no. 1, pp. 29-57.
16. Bossley C.J., Fleming L., Gupta A., Regamey N., Frith J., Oates T., Tsartsali L., Lloyd C.M., Bush A., Saglani S. Pediatric severe asthma is characterized by eosinophilia and remodeling without TH2 cytokines. J. Allergy Clin. Immunol., 2012, Vol. 129, no. 4, pp. 974-982.e13.
17. Chen W.J. TGF-β Regulation of T Cells. Annu. Rev. Immunol., 2023, Vol. 41, pp. 483-512.
18. Cheng G., Ueda T., Numao T., Kuroki Y., Nakajima H., Fukushima Y., Motojima S., Fukuda T. Increased levels of surfactant protein A and D in bronchoalveolar lavage fluids in patients with bronchial asthma. Eur. Respir. J. 2000, Vol. 16, no. 5, pp. 831-835.
19. Chung K.F., Adcock I.M. Precision medicine for the discovery of treatable mechanisms in severe asthma. Allergy, 2019, Vol. 74, no. 9, pp. 1649–1659.
20. de Burbure C., Pignatti P., Corradi M., Malerba M., Clippe A., Dumont X., Moscato G., Mutti A., Bernard A. Uteroglobin-related protein 1 and Clara cell protein in induced sputum of patients with asthma and rhinitis. Chest, 2007, Vol. 131, no. 1, pp. 172-179.
21. Deng Z., Fan T., Xiao Ch., Tian H., Zheng Yu., Li Ch., He J. TGF-β signaling in health, disease and therapeutics. Signal Transduct. Target. Ther., 2024, Vol. 9, 61. doi: 10.1038/s41392-024-01764-w.
22. di Palmo E., Cantarelli E., Catelli A., Ricci G., Gallucci M., Miniaci A., Pession A. The predictive role of biomarkers and genetics in childhood asthma exacerbations. Int. J. Mol. Sci., 2021, Vol. 22, no. 9, 4651. doi: 10.3390/ ijms22094651.
23. Eller M.C.N., Vergani K.P., Saraiva-Romanholo B.M., Antonangelo L., Leone C., Rodrigues J.C. Can inflammatory markers in induced sputum be used to detect phenotypes and endotypes of pediatric severe therapyresistant asthma? Pediatr. Pulmonol., 2018, Vol. 53, no. 9, pp. 1208-1217.
24. Emmanouil P., Loukides S., Kostikas K., Papatheodorou G., Papaporfyriou A., Hillaset G., Vamvakaris I., Triggidou R., Katafigiotis P., Kokkini A., Papiris S., Koulouris N., Bakakos P. Sputum and BAL Clara cell secretory protein and surfactant protein D levels in asthma. Allergy, 2015, Vol. 70, no. 6, pp. 711-714.
25. Fitzpatrick A.M., Teague W.G., Meyers D.A., Peters S.P., Li X., Li H., Wenzel S.E., Aujla Sh., Castro M., Bacharier L.B., Gaston B.M., Bleecker E.R., Moore W.C. Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. J. Allergy Clin. Immunol., 2011, Vol. 127, no. 2, pp. 382–389.e1-13.
26. Gagliardo R., Chanez P., Gjomarkaj M., la Grutta S., Bonanno A., Montalbano A.M., di Sano C., Albano G.D., Gras D., Anzalone G., Riccobono L., Profita M. The role of transforming growth factor-β1 in airway inflammation of childhood asthma. Int. J. Immunopathol Pharmacol., 2013, Vol. 26, no. 3, pp. 725-738.
27. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2024. Available at: https://ginasthma.org/wp-content/uploads/2024/05/GINA-2024-Strategy-Report-24_05_22_WMS.pdf.
28. Guilbert T.W., Bacharier L.B., Fitzpatrick A.M. Severe Asthma in Children. J. Allergy Clin. Immunol. Pract., 2014, Vol. 2, no. 5, pp. 489-500.
29. Haktanir-Abul M., Phipatanakul W. Severe asthma in children: Evaluation and management. Allergol. Int., 2019, Vol. 68, no. 2, pp. 150-157.
30. Hedlin G., Bush A., Lodrup Carlsen K., Wennergren G., de Benedictis F.M., Melen E., Paton J., Wilson N., Carlsen K.-H. Problematic severe asthma in children, not one problem but many: a GA2LEN initiative. Eur. Respir. J., 2010, Vol. 36, no. 1, pp. 196-201.
31. Hermans C., Bernard A. Lung epithelium–specific proteins: сharacteristics and potential applications as markers. Am. J. Respir. Crit. Care Med., 1999, Vol. 159, no. 2, pp. 646-678. 32. Huang X., Huang Zh., Shao Ch., Zheng B., Zhang J. Expression of LncRNA-BCYRN1 in pediatric asthma and related factors of disease induction. Cell. Mol. Biol., 2022, Vol., 67, no. 5, pp. 248-255.
32. Jackson D.J., Bacharier L.B., Calatroni A., Gill M.A., Hu J., Liu A.H., Wheatley L.M., Gern J.E., Gruchalla R.S., Hershey G.K.K., Kattan M., Kercsmar C.M., Kim H, O’Connor G.T., Patel Sh., Pongracic J.A., Wood R.A., Busse W.W. Serum IL-6: A biomarker in childhood asthma? J. Allergy Clin. Immunol., 2020, Vol. 145, no. 6, pp. 1701-1704.e3.
33. Jevnikar Z., Östling J., Ax E., Calvén J., Thörn K., Israelsson E., Öberg L., Singhania A., Lau L.C.K., Wilson S.J., Ward J.A., Chauhan A., Sousa A.R., De Meulder B., Loza M.J., Baribaud F., Sterk P.J., Chung K.F., Sun K., Guo Y., Adcock I.M., Payne D., Dahlen B., Chanez P., Shaw D.E., Krug N., Hohlfeld J.M., Sandström T., Djukanovic R., James A., Hinks T.S.C. 22, Howarth P.H., Vaarala O., van Geest M., Olsson H. Epithelial IL-6 transsignaling defines a new asthma phenotype with increased airway inflammation. J. Allergy Clin. Immunol., 2019, Vol. 143, no. 2, pp. 577-590.
34. Kraik K., Tota M., Laska J., Lacwik J., Pazdzierz L., Sedek L., Gomulka K. The Role of Transforming Growth Factor-β (TGF-β) in Asthma and Chronic Obstructive Pulmonary Disease (COPD). Cells, 2024, Vol. 13, no. 15, 1271. doi: 10.3390/cells13151271.
35. Lai C.K., Beasley R., Crane J., Foliaki S., Shah J., Weiland S. Global variation in the prevalence and severity of asthma symptoms: phase three of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax, 2009, Vol. 64, no. 6, pp. 476-483.
36. Ledford J.G., Addison K.J., Foster M.W., Que L.G. Eosinophil-associated lung diseases. A cry for surfactant proteins A and D help? Am. J. Respir. Cell Mol. Biol., 2014, Vol. 51, no. 5, pp. 604-614.
37. Nordlund B., Melen E., Schultz E.S., Grönlund H., Hedlin G., Kull I. Prevalence of severe childhood asthma according to the WHO. Respir. Med., 2014, Vol. 108, no. 8, pp. 1234-1237.
38. Peters M.C., Mauger D., Ross K.R., Phillips B., Gaston B., Cardet J.C., Israel E., Levy B.D., Phipatanakul W., Jarjour N.N., Castro M., Wenzel S.E., Hastie A., Moore W., Bleecker E., Fahy J.V., Denlinger L.C. Evidence for exacerbation-prone asthma and predictive biomarkers of exacerbation frequency. Am. J. Respir. Crit. Care. Med., 2020, Vol. 202, no. 7, pp. 973-982.
39. Pijnenburg M.W., Fleming L. Advances in understanding and reducing the burden of severe asthma in children. Lancet Respir. Med., 2020, Vol. 8, no. 10, pp. 1032-1044.
40. Ramratnam S.K., Bacharier L.B., Guilbert T.W. Severe asthma in children. J. Allergy Clin. Immunol. Pract., 2017, Vol. 5, no. 4, pp. 889-898.
41. Reddel H.K., Bacharier L.B., Bateman E.D., Brightling C.E., Brusselle G.G., Buhl R., Cruz A.A., Duijts L., Drazen J.M., FitzGerald J.M., Fleming L.J., Inoue H., Ko F.W., Krishnan J.A., Levy M.L., Lin J., Mortimer K., Pitrez P.M., Sheikh A., Yorgancioglu A.A., Boulet L.-Ph. Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes. Eur. Respir. J., 2022, Vol. 59, no. 1, 2102730. doi: 10.1183/13993003.02730-2021.
42. Rincon M., Irvin C.G. Role of IL-6 in asthma and other inflammatory pulmonary diseases. Int. J. Biol. Sci., 2012, Vol. 8, no. 9, pp. 1281-1290.
43. Scheller J., Chalaris A., Schmidt-Arras D., Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim. Biophys. Acta, 2011, Vol. 1813, no. 5, pp. 878-888.
44. van de Graaf E.A., Jansen H.M., Lutter R., Alberts C., Kobesen J., de Vries I.J., Out T.A. Surfactant protein A in bronchoalveolar lavage fluid. J. Lab. Clin. Med., 1992, Vol. 120, no. 2, pp. 252-263.
45. Wang J.-Y., Reid K.B.M. The immunoregulatory roles of lung surfactant collectins SP-A, and SP-D, in allergen-induced airway inflammation. Immunobiology, 2007, Vol. 212, no. 4-5, pp. 417-425.
46. Wang Yi., Voelker D.R., Lugogo N.L., Wang G., Floros J., Ingram J.L., Chu H.W., Church T.D., Kandasamy P., Fertel D., Wright J.R., Kraft M. Surfactant protein A is defective in abrogating inflammation in asthma. Am. J. Physiol. Lung Cell. Mol. Physiol., 2011, Vol. 301, no. 4, pp. 598-606.
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Turovskaya A.A., Kostina E.M., Levashova O.A., Molotilov B.A., Orlova E.A., Trushina E.Yu., Sokolov S.A. Assessment of immunological parameters in induced sputum in children with severe bronchial asthma. Medical Immunology (Russia). 2025;27(3):589-602. (In Russ.) https://doi.org/10.15789/1563-0625-AOI-3163