Salivary Protease Activity in Children with Cystic Fibrosis

Objective: Patients with cystic fibrosis (CF) present with impaired protease-antiprotease balance in their lungs. However, salivary protease equilibrium in children with CF with poor oral health has not been reported. The current study investigated salivary matrix metalloproteinase-8 (MMP-8), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), neutrophil elastase (NE), and myeloperoxidase (MPO) levels in children with CF with or without gingivitis. Materials and Methods: Eleven CF and 11 systemically healthy children aged 3-12 years were evaluated. Clinical periodontal examinations including probing pocket depth (PPD), gingival index (GI), plaque index (PI), and bleeding on probing (BOP) were recorded and saliva samples were obtained. Salivary MMP-8, TIMP-1, NE, and MPO levels were analyzed by immunofluorometric assay and enzyme-linked immunosorbent assay. Results: Salivary levels of MMP-8, TIMP-1, NE, MPO, and MMP-8/TIMP-1 molar ratios were similar in CF and systemically healthy children (p>0.05). Levels of MMP-8, NE, and MPO were significantly higher in the saliva of children with gingivitis compared to periodontally healthy children in both CF and systemically healthy groups (p<0.05). MMP-8 and MMP-8/TIMP-1 levels were positively correlated with GI, PI, and BOP (p<0.05), while NE and MPO levels were related to all periodontal parameters (p<0.01). Conclusion: CF may not alter the activity of MMP-8, NE, and MPO. On the other hand, gingival inflammation had a pronounced effect on salivary levels of these enzymes and the MMP-8/TIMP-1 molar ratio in children, irrespective of CF. Further investigations in larger cohorts are needed to better clarify this issue.

Anahtar Kelime:

Kistik Fibrozisli Çocuklarda Tükürük Proteaz Aktivitesi

Öz:

Amaç: Kistik fibrozisli (KF) hastalar, akciğerlerde bozulmuş proteaz-antiproteaz dengesi ile kendini göstermektedir. Bununla birlikte, ağız sağlığı kötü olan KF’li çocuklarda tükürük proteaz dengesini gösteren bir çalışma henüz bulunmamaktadır. Bu çalışmanın amacı, gingivitise sahip olan veya olmayan KF’li çocuklarda tükürük matriks metalloproteinaz-8 (MMP-8), matriks metalloproteinaz-1 doku inhibitörü (TIMP-1), nötrofil elastaz (NE) ve miyeloperoksidaz (MPO) seviyelerinin araştırılmasıdır. Gereç ve Yöntemler: Üç - on iki yaşları arasında 11 KF ve 11 sistemik sağlıklı çocuk değerlendirildi. Klinik periodontal muayenede, sondalanabilir cep derinliği, gingival indeks (Gİ), plak indeksi (Pİ) ve sondalamada kanama (SK) değerleri kaydedildi; ve tükürük örnekleri alındı. Tükürük MMP-8, TIMP-1, NE ve MPO seviyeleri, immünoflorometrik analiz ve enzime bağlı immünosorbent analiz metodlarıyla değerlendirildi. Bulgular: KF ve sistemik sağlıklı çocuklarda tükürük MMP-8, TIMP-1, NE, MPO ve MMP-8/TIMP-1 molar oranı düzeyleri benzerdi (p>0,05). Gingivitise sahip olan çocuklarda tükürük MMP-8, NE ve MPO seviyeleri periodontal olarak sağlıklı çocuklara göre hem KF hem de sistemik olarak sağlıklı gruplarda anlamlı olarak daha yüksekti (p<0,05). MMP-8 ve MMP-8/TIMP-1 seviyeleri Gİ, Pİ ve SK ile pozitif korelasyon gösterirken (p<0,05), NE ve MPO seviyeleri tüm klinik periodontal parametrelerle ilişkili bulundu (p<0,01). Sonuç: KF, MMP-8, NE ve MPO'nun aktivitesini değiştirmeyebilir. Ancak çocuklarda gingival enflamasyon, KF’den bağımsız olarak bu enzimlerin tükürük seviyeleri ve MMP-8/TIMP-1 molar oranı üzerinde belirgin bir etkiye sahipti. Bu konuyu açıklığa kavuşturmak için daha büyük kohort çalışmalarına ve ileri araştırmalara ihtiyaç vardır.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. Rath T, Zwaschka L, Hage L, Kügler M, Menendez K, Naehrlich L, et al. Identification of neutrophil activation markers as novel surrogate markers of CF lung disease. PLoS One 2014; 9: e115847.
2. Aps JK, Delanghe J, Martens LC. Salivary electrolyte concentrations are associated with cystic fibrosis transmembrane regulator genotypes. Clin Chem Lab Med 2002; 40: 345-50.
3. Alkhateeb AA, Mancl LA, Presland RB, Rothen ML, Chi DL. Unstimulated Saliva-Related Caries Risk Factors in Individuals with Cystic Fibrosis: A Cross-Sectional Analysis of Unstimulated Salivary Flow, pH, and Buffering Capacity. Caries Res 2017; 51: 1-6.
4. 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: 1065-75.
5. Devereux G, Steele S, Jagelman T, Fielding S, Muirhead R, Brady J, et al. An observational study of matrix metalloproteinase (MMP)-9 in cystic fibrosis. J Cyst Fibros 2014; 13: 557-63.
6. Voynow JA, Fischer BM, Zheng S. Proteases and cystic fibrosis. Int J Biochem Cell Biol 2008; 40: 1238-45.
7. Jackson PL, Xu X, Wilson L, Weathington NM, Clancy JP, Blalock JE, et al. Human neutrophil elastase-mediated cleavage sites of MMP-9 and TIMP-1: implications to cystic fibrosis proteolytic dysfunction. Mol Med 2010; 16: 159-66.
8. Sorsa T, Tjäderhane L, Konttinen YT, Lauhio A, Salo T, Lee HM, et al. Matrix metalloproteinases: contribution to pathogenesis, diagnosis and treatment of periodontal inflammation. Ann Med 2006;38:306- 21.
9. 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: 384-94.
10. da Silva Modesto KB, de Godói Simões JB, de Souza AF, Damaceno N, Duarte DA, Leite MF, et al. Salivary flow rate and biochemical composition analysis in stimulated whole saliva of children with cystic fibrosis. Arch Oral Biol 2015; 60: 1650-4.
11. Javaid MA, Ahmed AS, Durand R, Tran SD. Saliva as a diagnostic tool for oral and systemic diseases. J Oral Biol Craniofac Res 2016; 6: 66-75.
12. Garg M, Leach ST, Coffey MJ, Katz T, Strachan R, Pang T, et al. Age-dependent variation of fecal calprotectin in cystic fibrosis and healthy children. J Cyst Fibros 2017; 16: 631-6.
13. Silness J, Löe H. Periodontal disease in pregnancy II. Correlation between oral hygiene and periodontal condition. Acta Odontol Scand 1964; 22: 121-35.
14. Löe H, Silness J. Periodontal disease in pregnancy I. Prevalence and severity. Acta Odontol Scand 1963; 21: 533-51.
15. Ainamo J, Bay I. Problems and proposals for recording gingivitis and plaque. Int Dent J 1975; 25: 229-35.
16. Aps JK, Van Maele GO, Martens LC. Caries experience and oral cleanliness in cystic fibrosis homozygotes and heterozygotes. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002; 93: 560-3.
17. Navazesh M. Methods for collecting saliva. Ann N Y Acad Sci 1993; 694: 72-7.
18. Gursoy UK, Könönen E, Pradhan-Palikhe P, Tervahartiala T, Pussinen PJ, Suominen-Taipale L, et al. Salivary MMP-8, TIMP-1, and ICTP as markers of advanced periodontitis. J Clin Periodontol 2010; 37: 487-93.
19. Akcalı A, Bostanci N, Özçaka Ö, Gümüş P, Öztürk-Ceyhan B, Tervahartiala T, et al. Gingival Inflammation and Salivary or Serum Granulocyte-Secreted Enzymes in Patients With Polycystic Ovary Syndrome. J Periodontol 2017; 88: 1145-52.
20. Dabrowska E, Błahuszewska K, Minarowska A, Kaczmarski M, Niedźwiecka-Andrzejewicz I, Stokowska W. Assessment of dental status and oral hygiene in the study population of cystic fibrosis patients in the Podlasie province. Adv Med Sci 2006; 51 Suppl 1: 100-3.
21. Martens LJ, Aps JKM, Van Maele GOG. Is oral health at risk in people with cystic fibrosis. Eur J Paediatr Dent 2001; 4: 21-7.
22. Ferrazzano GF, Orlando S, Sangianantoni G, Cantile T, Ingenito A. Dental and periodontal health status in children affected by cystic fibrosis in a southern Italian region. Eur J Paediatr Dent 2009; 10: 65-8.
23. Narang A, Maguire A, Nunn JH, Bush A. Oral health and related factors in cystic fibrosis and other chronic respiratory disorders. Arch Dis Child 2003; 88: 702-7.
24. Pawlaczyk-Kamieńska T, Borysewicz-Lewicka M, Śniatała R, Batura-Gabryel H, Cofta S. Dental and periodontal manifestations in patients with cystic fibrosis - A systematic review. J Cyst Fibros 2019; 18: 762-71.
25. Duruel O, Berker E, Özşin-Özler C, Gharibzadeh-Hızal M, Gürpınar Ö, Eryılmaz-Polat S, et al. Levels of pro- and anti-inflammatory cytokines in cystic fibrosis patients with or without gingivitis. Cytokine 2020; 127: 154987.
26. Nie S, Zhang H, Mayer KM, Oppenheim FG, Little FF, Greenberg J, et al. Correlations of salivary biomarkers with clinical assessments in patients with cystic fibrosis. PLoS One 2015; 10: e0135237.
27. Herman K, Kowalczyk-Zając M, Pytrus T. Oral cavity health among cystic fibrosis patients: Literature overview. Adv Clin Exp Med 2017; 26: 1147-53.
28. Gonçalves AC, Marson FA, Mendonça RM, Ribeiro JD, Ribeiro AF, Paschoal IA, Levy CE. Saliva as a potential tool for cystic fibrosis diagnosis. Diagn Pathol 2013; 8: 46.
29. Livnat G, Bentur L, Kuzmisnsky E, Nagler RM. Salivary profile and oxidative stress in children and adolescents with cystic fibrosis. J Oral Pathol Med 2010; 39: 16-21.
30. Yucel ZPK, Silbereisen A, Emingil G, Tokgoz Y, Kose T, Sorsa T, et al. Salivary biomarkers in the context of gingival inflammation in children with cystic fibrosis. J Periodontol 2020; 91: 1339-47.
31. Rai B, Kharb S, Jain R, Anand SC. Biomarkers of periodontitis in oral fluids. J Oral Sci 2008; 50: 53-6.
32. Gursoy UK, Könönen E, Huumonen S, Tervahartiala T, Pussinen PJ, Suominen AL, et al. Salivary type I collagen degradation endproducts and related matrix metalloproteinases in periodontitis. J Clin Periodontol 2013; 40: 18-25.
33. Gupta N, Gupta ND, Gupta A, Khan S, Bansal N. Role of salivary matrix metalloproteinase-8 (MMP-8) in chronic periodontitis diagnosis. Front Med 2015; 9: 72-6.
34. Johnson N, Ebersole JL, Kryscio RJ, Danaher RJ, Dawson D 3rd, Al-Sabbagh M, et al. Rapid assessment of salivary MMP-8 and periodontal disease using lateral flow immunoassay. Oral Dis 2016; 22: 681-7.
35. de Morais EF, Pinheiro JC, Leite RB, Santos PPA, Barboza CAG, Freitas RA. Matrix metalloproteinase-8 levels in periodontal disease patients: A systematic review. J Periodontal Res 2018; 53: 156-63.
36. Nascimento GG, Baelum V, Sorsa T, Tervahartiala T, Skottrup PD, López R. Salivary levels of MPO, MMP-8 and TIMP-1 are associated with gingival inflammation response patterns during experimental gingivitis. Cytokine 2019; 115: 135-41.

APA	keleş z, Tervahartiala T, Silbereisen A, Tokgöz Y, KÖSE T, Tsilingaridis G, Bostanci N, Sorsa T, Emingil G (2023). Salivary Protease Activity in Children with Cystic Fibrosis. , 19 - 25. 10.4274/meandros.galenos.2021.07078
Chicago	keleş zeynep pınar,Tervahartiala Taina,Silbereisen Angelika,Tokgöz Yavuz,KÖSE Timur,Tsilingaridis Georgios,Bostanci Nagihan,Sorsa Timo,Emingil Gülnur Salivary Protease Activity in Children with Cystic Fibrosis. (2023): 19 - 25. 10.4274/meandros.galenos.2021.07078
MLA	keleş zeynep pınar,Tervahartiala Taina,Silbereisen Angelika,Tokgöz Yavuz,KÖSE Timur,Tsilingaridis Georgios,Bostanci Nagihan,Sorsa Timo,Emingil Gülnur Salivary Protease Activity in Children with Cystic Fibrosis. , 2023, ss.19 - 25. 10.4274/meandros.galenos.2021.07078
AMA	keleş z,Tervahartiala T,Silbereisen A,Tokgöz Y,KÖSE T,Tsilingaridis G,Bostanci N,Sorsa T,Emingil G Salivary Protease Activity in Children with Cystic Fibrosis. . 2023; 19 - 25. 10.4274/meandros.galenos.2021.07078
Vancouver	keleş z,Tervahartiala T,Silbereisen A,Tokgöz Y,KÖSE T,Tsilingaridis G,Bostanci N,Sorsa T,Emingil G Salivary Protease Activity in Children with Cystic Fibrosis. . 2023; 19 - 25. 10.4274/meandros.galenos.2021.07078
IEEE	keleş z,Tervahartiala T,Silbereisen A,Tokgöz Y,KÖSE T,Tsilingaridis G,Bostanci N,Sorsa T,Emingil G "Salivary Protease Activity in Children with Cystic Fibrosis." , ss.19 - 25, 2023. 10.4274/meandros.galenos.2021.07078
ISNAD	keleş, zeynep pınar vd. "Salivary Protease Activity in Children with Cystic Fibrosis". (2023), 19-25. https://doi.org/10.4274/meandros.galenos.2021.07078

APA	keleş z, Tervahartiala T, Silbereisen A, Tokgöz Y, KÖSE T, Tsilingaridis G, Bostanci N, Sorsa T, Emingil G (2023). Salivary Protease Activity in Children with Cystic Fibrosis. Meandros Medical And Dental Journal, 24(1), 19 - 25. 10.4274/meandros.galenos.2021.07078
Chicago	keleş zeynep pınar,Tervahartiala Taina,Silbereisen Angelika,Tokgöz Yavuz,KÖSE Timur,Tsilingaridis Georgios,Bostanci Nagihan,Sorsa Timo,Emingil Gülnur Salivary Protease Activity in Children with Cystic Fibrosis. Meandros Medical And Dental Journal 24, no.1 (2023): 19 - 25. 10.4274/meandros.galenos.2021.07078
MLA	keleş zeynep pınar,Tervahartiala Taina,Silbereisen Angelika,Tokgöz Yavuz,KÖSE Timur,Tsilingaridis Georgios,Bostanci Nagihan,Sorsa Timo,Emingil Gülnur Salivary Protease Activity in Children with Cystic Fibrosis. Meandros Medical And Dental Journal, vol.24, no.1, 2023, ss.19 - 25. 10.4274/meandros.galenos.2021.07078
AMA	keleş z,Tervahartiala T,Silbereisen A,Tokgöz Y,KÖSE T,Tsilingaridis G,Bostanci N,Sorsa T,Emingil G Salivary Protease Activity in Children with Cystic Fibrosis. Meandros Medical And Dental Journal. 2023; 24(1): 19 - 25. 10.4274/meandros.galenos.2021.07078
Vancouver	keleş z,Tervahartiala T,Silbereisen A,Tokgöz Y,KÖSE T,Tsilingaridis G,Bostanci N,Sorsa T,Emingil G Salivary Protease Activity in Children with Cystic Fibrosis. Meandros Medical And Dental Journal. 2023; 24(1): 19 - 25. 10.4274/meandros.galenos.2021.07078
IEEE	keleş z,Tervahartiala T,Silbereisen A,Tokgöz Y,KÖSE T,Tsilingaridis G,Bostanci N,Sorsa T,Emingil G "Salivary Protease Activity in Children with Cystic Fibrosis." Meandros Medical And Dental Journal, 24, ss.19 - 25, 2023. 10.4274/meandros.galenos.2021.07078
ISNAD	keleş, zeynep pınar vd. "Salivary Protease Activity in Children with Cystic Fibrosis". Meandros Medical And Dental Journal 24/1 (2023), 19-25. https://doi.org/10.4274/meandros.galenos.2021.07078