BLOOD MATRIX METALLOPROTEINASES LEVELS IN CYSTIC FIBROSIS CHILDREN (TEN YEARS OBSERVATION)
Introduction. Destructive fibrotic changes in lung tissue play a key role in the pathogenesis of cystic fibrosis (CF) in children. The development of pulmonary fibrosis may be caused by a violation of the pattern of matrix metalloproteinases (MMPs) and elevated production of profibrogenic growth factors (TGF-β1). Aim of the study. To compare the peculiarities of MMP patterns and transforming growth factor TGF-β1 with the data of the visualisation of airways features in cystic fibrosis (CF) children. Patients and Methods. The study included 80 inpatients aged of from 3 months to 18 years suffered from СF with the involvement of the lungs and digestive system observed for ten years. All patients were administered antibiotics (cefoperazone/sulbactam, ceftazidime, tienam, meropenem, amikacin) and inhalation (colisthmethate sodium, tobramycin) intravenously for a long time period. The reference group consisted of 16 children without pulmonary pathology. Blood serum concentrations of transforming growth factor-β1 (TGF-β1), matrix metalloproteinases (MMP-2, MMP-8, MMP-9) and tissue inhibitor of matrix metalloproteinases (TIMP-1) were determined by ELISA method. The morphological features of airways were evaluated by means of computer tomography (CT) with (GE Discovery CT750 HD). Results. In CF children patients blood serum MMP9 levels were significantly higher whereas TIMP-1 and MMP-2 appeared to be less than in children with intact airways. TGF-β1 levels in CF children were 9.8 times more than in cases from the reference group. CT data showed the pronounced changes in the airways structure as multiple bronchoectasias and pneumofibrosis. Conclusion. The revealed morphologic signs of the deterioration in airways’ structure in СF children patients can be related to the elevation of the rate of the fibrosis development due to the violation in the MMP and profibrogenic factors patterns and transforming growth factor TGF-β1.
About the authorsEgorov Maksim S.
Andreev D. A., Bashlakova E. E., Khachanova N. V., Davydovskaya M. V. Registers of patients with cystic fibrosis: domestic and foreign experience. Pediatricheskaya farmakologiya. 2017; 14 (2): 115-26. (in Russian)
The cystic fibrosis / Ed., N.I. Kapranov, N.Yu. Kashirskaya. [Mukovistsidoz]. Moscow; Medpractika. 2014. (in Russian)
Gorinova Yu.V., Simonova OI. Modern opportunities to control Pseudomonas purulent infection with cystic fibrosis. Effectivnaya farmacotherapiya. 2015; (3): 38-45. (in Russian)
Hwang TC, Yeh JT, Zhang J, Yu YC, Yeh HI, Destefano S. Structural mechanisms of CFTR function and dysfunction. J Gen Physiol. 2018;150(4): 539-70.
Van Horck M, Alonso A, Wesseling G, de Winter-de Groot K, van Aalderen W, Hendriks H et al. Biomarkers in Exhaled Breath Condensate Are Not Predictive for Pulmonary Exacerbations in Children with Cystic Fibrosis: Results of a One-Year Observational Study. PLoS One. 2016;11(4):152-6.
Caverly LJ, LiPuma JJ. Cystic fibrosis respiratory microbiota: unraveling complexity to inform clinical practice. Expert Rev Respir Med. 2018;12(10):857-65.
Blagovidov D.A., Simonova O.I., Kostinov M.P., Smirnov I.E. Pseudomonas aeruginosa infection in patients with chronic nonspecific lung diseases and its vaccination. Rossiyskiy pediatricheskiy zhurnal. 2015; 18(6): 54-60. (in Russian)
Shaginyan I.A., Chernukha M.Yu., Avetisyan L.R., Siyanova E.A., Kulyastova D.G., Medvedeva O.S. et al. Epidemiological Features of Chronic Lung Infection in Patients with Cystic Fibrosis. Epidemiologiya i vaktsinoprofilaktika. 2017; 16(6):5-13. (in Russian)
Sagel SD, Gibson RL, Emerson J, McNamara S, Burns JL, Wagener JS. et al. Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis. J Pediatr. 2009;154(2):183-8.
Heltshe SL, Khan U, Beckett V, Baines A, Emerson J, Sanders DB et al. Longitudinal development of initial, chronic and mucoid Pseudomonas aeruginosa infection in young children with cystic fibrosis. J Cyst Fibros. 2017; 26(17): 30919-20.
Sagel SD, Thompson V, Chmiel JF, Montgomery GS, Nasr SZ, Perkett E Effect of treatment of cystic fibrosis pulmonary exacerbations on systemic inflammation. Ann Am Thorac Soc. 2015;12(5):708-17.
Nichols DP, Chmiel JF. Inflammation and its genesis in cystic fibrosis. Pediatr Pulmonol. 2015;50, 40: 39-56.
Taylor SL , Rogers GB, Chen AC, Burr LD, McGuckin MA, Serisier DJ. Matrix metalloproteinases vary with airway microbiota composition and lung function in non-cystic fibrosis bronchiectasis. Ann Am Thorac Soc. 2015;12(5):701-7.
Visse R. Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 2003; 92(6): 827-39.
Gaggar A, Hector A, Bratcher PE, Mall MA, Griese M, Hartl D. The role of matrix metalloproteinases in cystic fibrosis lung disease. Eur Respir J. 2011;38(3):721-7.
Corbel M, Belleguic C, Boichot E, Lagente V. Involvement of gelatinases (MMP-2 and MMP-9) in the development of airway inflammation and pulmonary fibrosis. Cell Biol Toxicol. 2002;18(1):51-61.
Chakrabarti S, Patel KD. Matrix metalloproteinase-2 (MMP-2) and MMP-9 in pulmonary pathology. Exp Lung Res. 2005;31(6):599-621.
Smirnov I.E., Sobolev S.S., Kucherenko A.G., Kustova O.V., Simonova O.I., Urtnasan Tsevegmid. Matrix metalloproteinases in children with chronic bronchopulmonary pathology. Rossiyskiy pediatricheskiy zhurnal. 2010; 6: 11-4. (in Russian)
Smirnov I.E., Kucherenko A.G. Egorov V.S., Smirnova G.I., Urtnasan Tsevegmid, Simonova O.I. Matrix metalloproteinases in cystic fibrosis in children. Rossiyskiy pediatricheskiy zhurnal. 2018; 21(3): 145-51. (in Russian)
Garratt LW, Sutanto EN, Ling KM, Looi K, Iosifidis T, Martinovich KM. et al. Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis. Eur Respir J. 2015;46(2): 384-94.
Ghatak S, Hascall VC, Markwald RR, Feghali-Bostwick C, Artlett CM, Gooz M, et.al Transforming growth factor β1 (TGFβ1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis. J Biol Chem. 2017;292(25):10490-519.
Harris WT, Muhlebach MS, Oster RA, Knowles MR, Noah TL. Transforming growth factor-beta(1) in bronchoalveolar lavage fluid from children with cystic fibrosis. Pediatr Pulmonol. 2009;44(11):1057-64.
Kramer EL, Clancy JP. TGFβ as a therapeutic target in cystic fibrosis. Expert Opin Ther Targets. 2018;22(2):177-89.
Lagente V, Manoury B, Nénan S, Le Quément C, Martin-Chouly C, Boichot E. Role of matrix metalloproteinases in the development of airway inflammation and remodeling. Braz J Med Biol Res. 2005;38(10):1521-30.
Ramsey KA, Schultz A, Stick SM Biomarkers in Paediatric Cystic Fibrosis Lung Disease. Paediatr Respir Rev. 2015;16(4):213-8.
Smirnov I.E., Kustova O.V., Sorokina T.E., Kucherenko A.G. Markers of fibrosis in chronic bronchopulmonary pathology in children. Rossiyskiy pediatricheskiy zhurnal. 2015; 18(1): 14-20. (in Russian)
Cohen-Cymberknoh M, Kerem E, Ferkol T, Elizur A. Airway inflammation in cystic fibrosis: molecular mechanisms and clinical implications. Thorax. 2013;68(12):1157-62.
Gorinova Yu.V., Simonova O.I., Lazareva A.V., Chernevich V.P., Smirnov I.E. The experience of prolonged use of the inhalation solution of tobramycin in chronic Pseudomonas aeruginosa infection in children with cystic fibrosis. Rossiyskiy pediatricheskiy zhurnal. 2015; 18(3): 50-3. (in Russian)
Smirnov I.E., Tarasova O.V., Lukina O.F., Kustova O.V., Sorokina T.E., Simonova O.I. Structural and functional state of the lungs in cystic fibrosis in children. Rossiyskiy pediatricheskiy zhurnal. 2015; 18(2): 11-7. (in Russian)
Bergin DA, Hurley K, Mehta A, Cox S, Ryan D, O’Neill SJ. et al. Airway inflammatory markers in individuals with cystic fibrosis and non-cystic fibrosis bronchiectasis. J Inflamm Res. 2013;6(1):1-11.
Maillé E, Trinh NT, Privé A, Bilodeau C, Bissonnette E, Grandvaux N. et al. Regulation of normal and cystic fibrosis airway epithelial repair processes by TNF-α after injury. Am J Physiol Lung Cell Mol Physiol. 2011; 301(6):945-55.
Roderfeld M, Rath T, Schulz R, Seeger W, Tschuschner A, Graf J. et al. Serum matrix metalloproteinases in adult CF patients: Relation to pulmonary exacerbation. J Cyst Fibros. 2009;8(5):338-47.
Fischer N, Hentschel J, Markert UR, Keller PM, Pletz MW, Mainz JG. Non-invasive assessment of upper and lower airway infection and inflammation in CF patients. Pediatr Pulmonol. 2014;49(11):1065-75.
- Refbacks are not listed
Контент доступен под лицензией Creative Commons Attribution 3.0 License.