CLINICAL AND DIAGNOSTIC VALUE OF YKL-40 AND NGAL IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Introduction. Chronic obstructive pulmonary disease (COPD) is one of the most common diseases of the bronchopulmonary system. Determination of new inflammatory markers for early diagnosis, optimization and monitoring of therapy is a promising direction of modern research. Objective. To evaluate the levels of YKL-40 and NGAL in serum and induced sputum and to determine their significance as markers of inflammation in patients with COPD. Materials and Methods. The study included 50 patients with COPD, 60 patients with asthma. The control group consisted of 30 volunteers, comparable in age and sex, without allergic and bronchoobstructive diseases. Clinical and anamnestic data, indices of external respiratory function were evaluated. Induced sputum was collected with subsequent assessment of cellular composition. Immunophenotyping of lymphocytes by flow cytometry was performed. The concentration of YKL-40 and NGAL in serum was determined using an enzyme immunoassay test system (R&D Systems). The obtained data were processed using STATISTICA and SPSS Statistics software systems. Results. A significant increase in the absolute number of T-lymphocytes in patients of the studied groups compared to the control group was found. The highest number of T-cytotoxic lymphocytes and NK-cells was registered in the COPD group. Analysis of the cellular composition of induced sputum in patients with COPD revealed the predominance of neutrophilic pattern of inflammation. The maximum concentration of YKL-40 in serum was registered in COPD patients. The level of NGAL in serum of COPD patients was not significantly different from that of the asthma group. NGAL level in induced sputum was significantly higher in COPD group. Correlation analysis confirmed the correlation of YKL-40 and NGAL levels in serum with neutrophilic inflammation indices, smoking index, number of hospitalizations due to COPD exacerbation during a calendar year. It was found that YKL-40 and NGAL levels were significantly increased in patients with frequent COPD exacerbations compared to the group with infrequent exacerbations. Conclusions. YKL-40 and NGAL are promising markers of neutrophilic airway inflammation in COPD patients. The obtained data allow us to consider YKL-40 and NGAL as markers of non-T2-endotype COPD with neutrophilic inflammation pattern and high risk of exacerbations.

1. Авдеев С.Н., Емельянов А.В., Айсанов З.Р., Синопальников А.И., Фомина Д.С., Ненашева Н.М., Лещенко И.В., Зайкова-Хелимская И.В., Визель А.А., Демко И.В., Шапорова Н.Л., Шульженко Л.В., Шабанов Е.А. Проблемы и возможности для повышения диагностики бронхиальной астмы и хронической обструктивной болезни легких в России: заключение совета экспертов // Терапевтический архив. – 2022. – Т. 94, № 4. – С. 524-529.

2. Быстрицкая Е.В., Биличенко Т.Н. Заболеваемость, инвалидность и смертность от болезней органов дыхания в Российской Федерации (2015–2019) // Пульмонология. – 2021. – Т. 31, № 5. – С. 551-561.

3. Трофимов В.И., Баранов Д.З. Клинические и функциональные особенности больных бронхиальной астмой, хронической обструктивной болезнью лёгких и сочетанием бронхиальной астмы и хронической обструктивной болезни лёгких // Нефрология. – 2020. – Т. 24, № 4. – С. 80-86.

4. Abramson M.J., Schattner R.L., Sulaiman N.D., Del Colle E.A., Aroni R., Thien F. Accuracy of asthma and COPD diagnosis in Australian general practice: a mixed methods study. Prim. Care Respir. J. 2012, Vol. 21, no 2, pp. 167-173.

5. Adeloye D., Chua S., Lee C., Basquill C., Papana A., Theodoratou E., Nair H., Gasevic D., Sridhar D., Campbell H., Chan K.Y., Sheikh A., Rudan I. Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J. Glob. Health. 2015, Vol. 5, no. 2, p. 020415.

6. Babu A., Narayanswamy H., Baburao A. Sputum Neutrophil Gelatinase-Associated Lipocalin as a Biomarker in Asthma-COPD Overlap. J. Assoc. Physicians India. 2023, Vol. 71, no 9, pp. 34-38.

7. Catalán V., Gómez-Ambrosi J., Rodríguez A., Ramírez B., Rotellar F., Valentí V., Silva C., Gil M.J., Salvador J., Frühbeck G. Increased circulating and visceral adipose tissue expression levels of YKL-40 in obesity-associated type 2 diabetes are related to inflammation: impact of conventional weight loss and gastric bypass. J. Clin. Endocrinol. Metab. 2011, Vol. 96, no 1, pp. 200–209.

8. Cockayne D.A., Cheng D.T., Waschki B., Sridhar S., Ravindran P., Hilton H., Kourteva G., Bitter H., Pillai S.G., Visvanathan S., Müller K.C., Holz O., Magnussen H., Watz H., Fine J.S. Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity. PLoS One. 2012, Vol. 7, no 6, p. e38629.

9. Furuhashi K., Suda T., Nakamura Y., Inui N., Hashimoto D., Miwa S., Hayakawa H., Kusagaya H., Nakano Y., Nakamura H., Chida K. Increased expression of YKL-40, a chitinase-like protein, in serum and lung of patients with idiopathic pulmonary fibrosis. Respir. Med. 2010, Vol. 104, no 8, pp. 1204-1210.

10. Gao J., Iwamoto H., Koskela J., Alenius H., Hattori N., Kohno N., Laitinen T., Mazur W., Pulkkinen V. Characterization of sputum biomarkers for asthma-COPD overlap syndrome. Int. J. Chron. Obstruct. Pulm. Dis. 2016, Vol. 11, pp. 2457-2465.

11. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015, Vol. 385, no. 9963, pp. 117-171.

12. Gumus A., Kayhan S., Cinarka H., Kirbas A., Bulmus N., Yavuz A., Sahin U., Ozkaya S. High serum YKL-40 level in patients with COPD is related to hypoxemia and disease severity. Tohoku J. Exp. Med. 2013, Vol. 229, no 2, pp. 163-170.

13. Hodge G., Jersmann H., Tran H.B., Asare P.F., Jayapal M., Reynolds P.N., Holmes M., Hodge S. COPD is associated with increased pro-inflammatory CD28null CD8 T and NKT-like cells in the small airways. Clin. Exp. Immunol. 2022, Vol. 207, no 3, pp. 351-159.

14. James A.J., Reinius L.E., Verhoek M., Gomes A., Kupczyk M., Hammar U., Ono J., Ohta S., Izuhara K., Bel E., Kere J., Soderhall C., Dahlen B., Boot R.G., Dahlen S.-E. Increased YKL-40 and Chitotriosidase in Asthma and Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2016, Vol. 193, no 2, pp. 131-142.

15. Lai T., Wu D., Chen M., Cao C., Jing Z., Huang L., Lv Y., Zhao X., Lv Q., Wang Y., Li D., Wu B., Shen H. YKL-40 expression in chronic obstructive pulmonary disease: relation to acute exacerbations and airway remodeling. Respir. Res. 2016, Vol. 17, no 31, pp. 17-31.

16. Lopez A., Shibuya K., Rao C., Mathers C.D., Hansell A.L., Held L.S., Schmid V., Buist S. Obstructive pulmonary disease: current burden and future projections. Eur. Respir. J. 2006, Vol. 27, no. 2, pp. 397-412.

17. Pan R., Li Q., Zhu X., Zhou Y., Ding L., Cui Y. Diagnostic value of YKL-40 for patients with asthma: A meta-analysis. Allergy Asthma Proc. 2021, Vol. 42, no 6, pp. e167-e173.

18. Przysucha N., Górska K., Krenke R. Chitinases and Chitinase-Like Proteins in Obstructive Lung Diseases - Current Concepts and Potential Applications. Int. J. Chron. Obstruct. Pulmon. Dis. 2020, Vol. 15, pp. 885-899.

19. Schoneveld L., Ladang A., Henket M., Frix A.N., Cavalier E., Guiot J. YKL-40 as a new promising prognostic marker of severity in COVID infection. Crit. care. 2021, Vol. 25, no 1, p. 66.

20. Tong X., Wang D., Liu S., Ma Y., Li Z., Tian P., Fan H. The YKL-40 protein is a potential biomarker for COPD: a meta-analysis and systematic review. Int. J. Chron. Obstruct. Pulmon. Dis. 2018, Vol. 13, pp. 409-418.

21. Villaseñor-Altamirano A.B., Jain D., Jeong Y., Menon J.A., Kamiya M., Haider H., Manandhar R., Amir Sheikh M.D., Athar H., Merriam L.T., Ryu M.H., Sasaki T., Castaldi P.J., Rao D., Sholl L.M., Vivero M., Hersh C.P., Zhou X., Veerkamp J., Yun J.H., Kim E.Y. Activation of CD8+ T Cells in Chronic Obstructive Pulmonary Disease Lung. Am. J. Respir. Crit. Care Med. 2023, Vol. 208, no 11, pp. 1177-1195.

22. Wang J., Lv H., Luo Z., Mou S., Liu J., Liu C., Deng S., Jiang Y., Lin J., Wu C., Liu X., He J., Jiang D. Plasma YKL-40 and NGAL are useful in distinguishing ACO from asthma and COPD. Respir. Res. 2018, Vol. 19, no. 1, p. 47.

23. Wang Y., Jia M., Yan X., Cao L., Barnes P.J., Adcock I.M., Huang M., Yao X. Increased neutrophil gelatinase-associated lipocalin (NGAL) promotes airway remodelling in chronic obstructive pulmonary disease. Clin. Sci. 2017, Vol. 131, no 11, pp. 1147-1159.

24. World Health Organization. Projections of mortality and causes of death, 2015 and 2030.

25. Xiao R., Chen R. Neutrophil gelatinase-associated lipocalin as a potential novel biomarker for ventilator-associated lung injury. Mol. Med. Rep. 2017, Vol. 15, no 6, pp. 3535-3540.

26. Zheng J.L., Lu L., Hu J., Zhang R.Y., Zhang Q., Chen Q.J., Shen W.F. Increased serum YKL-40 and C-reactive protein levels are associated with angiographic lesion progression in patients with coronary artery disease. Atherosclerosis. 2010, Vol. 210, no 2, pp. 590-595.