Clinical-instrumental, cytological and inflammatory markers of airway remodeling in children with bronchial asthma




bronchial asthma, children, remodeling, bronchial hyperreactivity, matrix metalloproteinase-9


Purpose - to investigate the clinical-instrumental, cytological and inflammatory characteristics of the disease in children with bronchial asthma, taking into account the content of the remodeling marker matrix metalloproteinase-9 (MMP-9) in the sputum to optimize the timely detection of structural remodeling of the bronchi.

Materials and methods. A cohort of 99 children with BA was examined by the method of random sampling in the conditions of the Pulmonary Allergology Department of the RMCE CRCCH.

All children underwent a complex clinical and paraclinical examination with the determination of the cytological composition of sputum, the determination of bronchial hyperreactivity and their hypersensitivity in a sample with serial dilution of histamine, the study of the concentration of metabolites of nitrogen monoxide in peripheral blood and condensate of pulmonary expiratory air.

Two clinical groups were formed. The Group I included 55 patients in whom the content of MMP-9 in the sputum supernatant did not reach the level of 5.4 ng/ml, and the II group was formed by 44 patients with MMP-9 content ≥5.4 ng/ml. The main clinical characteristics of the observation groups were comparable.

Results. It was established that the risk of a clinically more severe exacerbation of the disease is twice as high in children with an increased content of MMP-9 in the sputum (relative risk - 1.4, odds ratio - 2.0) with the preservation of this trend during 5 days of inpatient treatment. The work also shows that in patients with an increased content of MMP-9 in sputum, the concentration of FeNO more than 22.0 μmol/l occurs twice as often as in the first clinical group (pφ<0.05). This finding reflects the association of the processes of allergic inflammation of the respiratory tract and their remodeling. The results of the PC20H bronchoprovocation test indicate statistically significantly lower levels of the provocation dose and provocation concentration of histamine, which corresponds to significant bronchial hypersensitivity, the chances of which increase against the background of the accumulation of MMP-9 in sputum: 27.7 times for PC20H (FEV1) <3.7mg/ml and 48.8 times for PD20H (FEV1) <0.8mg.

Conclusions. An increase in the content of MMP-9 in the supernatant fluid of sputum was associated with a more severe course of exacerbations of bronchial asthma in children, an increase in the content of metabolites of nitrogen monoxide in the blood and lung expiratory air, more pronounced signs of bronchial hypersensitivity.

The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of participating institution. The informed consent of the patient was obtained for conducting the studies.

No conflict of interests was declared by the authors.


Allam VS, Waern I, Taha S, Akula S, Wernersson S, Pejler G. (2023). Nafamostat has anti-asthmatic effects associated with suppressed pro-inflammatory gene expression, eosinophil infiltration and airway hyperreactivity. Front Immunol. 14: 1136780.; PMid:37153590 PMCid:PMC10160450

Barbaro MP, Spanevello A, Palladino GP, Salerno FG, Lacedonia D, Carpagnano GE. (2014). Exhaled matrix metalloproteinase-9 (MMP-9) in different biological phenotypes of asthma. Eur J Intern Med. 25 (1): 92-96.; PMid:24070522

Bezrukov LA, Nechitajlo YuN, Cherevko SA. i dr. (1989). Diagnostika i lechenie ostryh pnevmonij i ORVI, oslozhnennyh BOS u detej rannego vozrasta. Chernovcy: 23.

Bougault V, Turmel J, Boulet LP. (2022). Serum and sputum MMP-9/TIMP-1 in winter sports athletes and swimmers: relationships with airway function. Biomarkers. 27 (2): 127-137.; PMid:34927510

Bourdin A, Kleis S, Chakra M, Vachier I, Paganin F, Godard P, Chanez P. (2012). Limited short-term steroid responsiveness is associated with thickening of bronchial basement membrane in severe asthma. Chest. 141 (6): 1504-1511.; PMid:22135380

Bullone M, Lavoie JP. (2020). The equine asthma model of airway remodeling: from a veterinary to a human perspective. Cell Tissue Res. 380 (2): 223-236.; PMid:31713728

Camoretti-Mercado B, Lockey RF. (2021). Airway smooth muscle pathophysiology in asthma. J Allergy Clin Immunol. 147 (6): 1983-1995.; PMid:34092351

Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, Cockcroft DW, Fish JE, Sterk PJ. (2000). Guidelines for methacholine and exercise challenge testing 1999. Am. J. Respir. Crit. Care Med. 161: 09-329.

Gibson PG, Henry RL, Thomas P. (2000). Noninvasive assessment of airway inflammation in children: induced sputum, exhaled nitric oxide, and breath condensate. Eur Respir J. 16: 1008-1015.

Hong Z, Lin YM, Qin X, Peng JL. (2012). Serum MMP-9 is elevated in children with asthma. Mol Med Rep. 5 (2): 462-464.

Huo R, Tian X, Chang Q, Liu D, Wang C, Bai J et al. (2021). Targeted inhibition of β-catenin alleviates airway inflammation and remodeling in asthma via modulating the profibrotic and anti-inflammatory actions of transforming growth factor-β1. Ther Adv Respir Dis. 15: 175-198.; PMid:33530899 PMCid:PMC7970683

Janulaityte I, Januskevicius A, Kalinauskaite-Zukauske V, Palacionyte J, Malakauskas K. (2021). Asthmatic Eosinophils Promote Contractility and Migration of Airway Smooth Muscle Cells and Pulmonary Fibroblasts In Vitro. Cells. 10 (6): 1389.; PMid:34199925 PMCid:PMC8229663

Jeffery PK, Laitinen A, Venge P. (2000). Biopsy markers of airway inflammation and remodelling. Respir Med. 94; Suppl F: 9-15.; PMid:11059962

Juniper EF, Cockcroft DW, Hargreave FE. (1994). Histamine and Methacholine inhalation tests Lund, Sweden: 51.

Karakoc GB, Yukselen A, Yilmaz M, Altintas DU, Kendirli SG. (2012). Exhaled breath condensate MMP-9 level and its relationship wıth asthma severity and interleukin-4/10 levels in children. Ann Allergy Asthma Immunol. 108 (5): 300-304.; PMid:22541398

Koloskova OK, Biluk HA, Marusyk UI, Tarnavska SI. (2022). Clinical features of bronchial asthma persistence in children with alternative content of respiratory tract remodeling markers. Modern Pediatrics. Ukraine. 8 (128): 25-31.

Leung TF, Ko FW, Wong GW. (2013). Recent advances in asthma biomarker research. Ther Adv Respir Dis. 7 (5): 297-308.; PMid:23907809

Payne DN, Rogers AV, Adelroth E, Bandi V, Guntupalli KK, Bush A, Jeffery PK. (2003). Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med. 167 (1): 78-82.; PMid:12502479

Rossi RC, Anonni R, Ferreira DS, da Silva LF, Mauad T. (2019). Structural alterations and markers of endothelial activation in pulmonary and bronchial arteries in fatal asthma. Allergy Asthma Clin Immunol. 28: 15-50.; PMid:31485240 PMCid:PMC6714380

Saglani S, Lloyd CM. (2015). Novel concepts in airway inflammation and remodelling in asthma. European Respiratory Journal. 46 (6): 1796-1804.; PMid:26541520

Saravia-Romanholo BM, Barnabe V, Carvalho A. (2003). Comparison of three methods for differential cell count in induced sputum. Chest. 124: 1060-1066.; PMid:12970038

Sterk PJ, Fabbri LM, Quanjer PH, Cockcroft DW. (1993). Standartized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report Working Party Standardization of Lung Function Tests. European Community for Steel and Coal. Official position of the European Respiratory Society. Eur. Respir. J. 6 (16): 53-83.; PMid:24576917

Tenero L, Zaffanello M, Piazza M, Piacentini G. (2018). Measuring Airway Inflammation in Asthmatic Children. Front Pediatr. 6 (6): 196-204.; PMid:30035104 PMCid:PMC6043865

Vignola AM, Paganin F, Capieu L, Scichilone N, Bellia M, Maakel L et al. (2004). Airway remodelling assessed by sputum and high-resolution computed tomography in asthma and COPD. Eur Respir J. 24 (6): 910-917.; PMid:15572531

Wu SM, Li CE, Cai RP, Zhang Q, Xu YJ. (2012). Airway remodeling assessed by high-resolution computed tomography in patients with asthma: relationship to biological markers in induced sputum. Zhonghua Jie He He Hu Xi Za Zhi. 35 (12): 892-896.

Xin XF, Zhao M, Li ZL, Song Y, Shi Y. (2007). Metalloproteinase-9/tissue inhibitor of metalloproteinase-1 in induced sputum in patients with asthma and chronic obstructive pulmonary disease and their relationship to airway inflammation and airflow limitation. Zhonghua Jie He He Hu Xi Za Zhi. 30 (3): 192-196.

Zhang J, Dong L. (2020). Status and prospects: personalized treatment and biomarker for airway remodeling in asthma. J Thorac Dis. 12 (10): 6090-6101.; PMid:33209441 PMCid:PMC7656354





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