Skip to main content
Log in

BMP-7, MMP-9, and TGF-β tissue remodeling proteins and their correlations with interleukins 6 and 10 in chronic rhinosinusitis

  • Rhinology
  • Published:
European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

Introduction

Chronic rhinosinusitis without nasal polyposis (CRSsNP) and Chronic rhinosinusitis with nasal polyposis (CRSwNP) present distinct tissue remodeling processes. The proteins involved in the process of tissue remodeling have their production and activity related to the inflammatory environment they are. This study aimed to evaluate the protein expression of BMP-7, MMP-9, TGF-β in chronic sinusitis with and without nasal polyposis and their relations with IL-6 and IL-10.

Methods

Cross-sectional observational study with 86 participants was divided into three groups: patients with CRSwNP (n = 34), patients with CRSsNP (n = 26), and a control group (CG) without inflammatory disease of the nasal mucosa (n = 26). The primary outcomes were the concentrations of BMP-7, MMP-9, TGF-β, IL-6, and IL-10. Secondary outcomes were the correlations of these markers.

Results

The TGF-β dosage was elevated in the CRSsNP group and reduced in the CSwNP group. The dosage of IL-6 was higher in the CSwNP group, and the IL-10 dosage lower in the groups with sinusitis, and IL-10 was positively correlated with BMP-7 in all groups. There was a negative correlation between IL-6 and IL-10 in all groups observed. The correlation between MMP-9 and interleukins was lost in the CRSsNP group. There was a positive correlation between TGF-β and IL-6 in the CG, and negative in the CRSsNP group.

Conclusion

An inflammation shown in rhinosinusitis with an increase in IL-6 and decrease in IL-10 when compared with the control group; only TGF-β was altered in the tissue remodeling process when compared with BMP-7 and MMP-9 in rhinosinusitis. There is a loss of correlation between tissue remodeling proteins and interleukins studied in CRSsNP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reltsma S et al (2020) European position paper on rhinosinusitis and nasal polyps. Rhinology 58(Suppl. 29):1–464. https://doi.org/10.4193/Rhin20.600

    Article  PubMed  Google Scholar 

  2. Pezato R, Voegels RL, Pinto Bezerra TF, Perez-Novo C, Stamm AC, Gregorio LC (2014) Mechanical dysfunction in the mucosal oedema formation of patients with nasal polyps. Rhinology 52(2):162–166. https://doi.org/10.4193/rhin13.066

    Article  CAS  PubMed  Google Scholar 

  3. Van Bruaene N, Derycke L, Perez-Novo CA, Gevaert P, Holtappels G, De Ruyck N, Culiver C, Cauwenberge PV, Barchet C (2009) TGF-beta signaling and collagen deposition in chronic rhinosinusitis. J Allergy Clin Immunol 124(2):253-259e1-2. https://doi.org/10.1016/j.jaci.2009.04.013

    Article  CAS  PubMed  Google Scholar 

  4. Meng J, Zhou P, Liu Y, Liu F, Yi X, Liu S, Holtappels G, Bachert C, Zhang N (2013) The development of nasal polyp disease involves early nasal mucosal inflammation and remodelling. PLoS One 8:e82373

    Article  Google Scholar 

  5. Van Buraene N, Pérez-Novo CA, Basinski TM, Van Zele T, Holtappels G, RuyckN De, Schmidt-Weber C, Akids C, Cauwenberge PV, Bachert C, Geavaert P (2008) T-cell regulation in chronic paranasal sinus disease. J Allergy Clin Immunol 121:1435-1441.e1–3. https://doi.org/10.1016/j.jaci.2008.02.018

    Article  CAS  Google Scholar 

  6. Gazzerro E, Canalis E (2006) Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord 7:51–65

    Article  CAS  Google Scholar 

  7. Bragdon B, Moseychuk O, Saldanha S, King D, Julian J, Nohe A (2011) Bone morphogenetic proteins: a critical review. Cell Signal 23(4):609–620. https://doi.org/10.1016/j.cellsig.2010.10.003

    Article  CAS  PubMed  Google Scholar 

  8. Yang T, Chen M, Sun T (2013) Simvastatin attenuates TGF-beta1-unduced epithelial-mesenchymal transition in human alveolar epithelial cells. Cell Physiol Biochem 31:863–874. https://doi.org/10.1016/10.1159/000350104

    Article  CAS  PubMed  Google Scholar 

  9. Izumi N, Mizuguchi S, Inagaki Y, Saika S, Kawada N, Nakajima Y, Inoue K, Suehiro C, Friedman SL, Ikeda K (2006) BMP-7 opposes TGF-beta1-mediated collagen induction in mouse pulmonar myofibroblasts through Id2. Am J Physiol Lung Cell Mol Physiol 290(1):L120–L126. https://doi.org/10.1152/ajplung.00171.2005

    Article  CAS  PubMed  Google Scholar 

  10. Zeisberg M, Bottiglio C, Kumar N, Maeshima Y et al (2003) Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol 285(6):F1060–F1067. https://doi.org/10.1152/ajprenal.00191.2002

    Article  CAS  PubMed  Google Scholar 

  11. Parks WC, Wilson CL, Lopez-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4:617–629

    Article  CAS  Google Scholar 

  12. Watelet JB, Bachert C, Claseys C, Van Cauwernberge P (2004) Matrix metalloproteinase MMP-7, MMP-9 and their tissue inhibitor TIMP-1: expression in chronic sinusitis vs nasal polyposis. Allergy 59:54–60. https://doi.org/10.1046/j.1398-9995.2003.00364.x

    Article  CAS  PubMed  Google Scholar 

  13. Li X, Meng J, Qiao X, Liu Y, Liu F, Zhang N, Zhang J, Holtappels G, Luo B, Zhou P, Zheng Y, Lin P, Liu S, Bachert C (2010) Expression of TGF, matrix metalloproteinases, and tissue inhibitors in Chinese chronic rhinosinusitis. J Allergy Clin Immnuol 125:1061–1068. https://doi.org/10.1016/j.jaci.2010.02.023

    Article  CAS  Google Scholar 

  14. Gaffar O, Lavigne F, Kamil A, Renzi P, Hamid Q (1998) Interleukin-6 expression in chronic sinusitis: colocalization of gene transcripts to eosinophils, macrophages, T lymphocytes, and mast cells. Otolaryngol Head Neck Surg 118:504–511. https://doi.org/10.1016/s0194-5998(98)70209-8

    Article  Google Scholar 

  15. Iyer SS, Cheng G (2012) Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol 32(1):23–63. https://doi.org/10.1615/CritRevImmunol.v32.i1.30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Peter AT, Kato A, Zhang N, Conley D, Suh L, Tancowny B, Carter D, Carr T, Radtke M, Hulse KE, Seshadri S, Chandra R, Grammer LC, Harris KE, Kern R, Schleimer RP (2010) Evidence for altered activity of the IL-6 pathway in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 125(2):397-403.e10. https://doi.org/10.1016/j.jaci.2009.10.072

    Article  CAS  Google Scholar 

  17. Ozkara S, Keles E, Ilhan N, Gungor H, Kaygusuz I, Alpay HC (2012) The relationship between Th1/Th2 balance and 1alpha,25-dihydroxyvitamin D(3) in patients with nasal polyposis. European archives of otorhinolaryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies. Severity (Objective) 12:2519–2524. https://doi.org/10.1007/s00405-012-1967-x

    Article  Google Scholar 

  18. Baba S, Kagoya R, Kondo K, Suzukawa M, Ohta K, Yamasoba T (2015) T-cell phenotypes in chronic rhinosinusitis with nasal polyps in Japanese patients. Allergy Asthma Clin Immunol Severity (Objective) 33. https://doi.org/10.1186/s13223-015-0100-2

  19. Kim DW, Eun KM, Jin HR, Cho SH, Kim DK (2016) Prolonged allergen exposure is associated with increased thymic stromal lymphopoietin expression and Th2-skewing in mouse models of chronic rhinosinusitis. Laryngoscope Severity (Objective). https://doi.org/10.1002/lary.26004

    Article  PubMed Central  Google Scholar 

  20. Shen Y, Hu GH, Kang HY, Tang XY, Hong SL (2014) Allergen induced Treg response in the peripheral blood mononuclear cells (PBMCs) of patients with nasal polyposis. Asian Pac J Allergy Immunol 4:300–307. https://doi.org/10.12932/AP0469.32.4.2014

  21. Zhang Q, Wang CS, Han DM, Sy C, Huang Q, Sun Y, Fan EZ, Li Y, Zhou B (2013) Differential expression of Toll-like receptor pathway genes in chronic rhinosinusitis with or without nasal polyps. Acta Otolaryngol 2:165–173. https://doi.org/10.3109/00016489.2012.717713 (PMID: 23157229)

    Article  CAS  Google Scholar 

  22. Wu D, Wang J, Zhang M (2016) Altered Th17/Treg ratio in nasal polyps with distinct cytokine profile: association with patterns of inflammation and mucosal remodeling medicine. Severity (objective) (10):e2998. https://doi.org/10.1097/MD.0000000000002998

  23. Pezato R, Świerczyńska-Krępa M, Niżankowska-Mogilnicka E, Holtappels G, De Ruyck N, Sanak M, Derycke L, Crombruggen KV, Bachert C, Pérez-Novo CA (2016) Systemic expression of inflammatory mediators in patients with chronic rhinosinusitis and nasal polyps with and without aspirin exacerbated respiratory disease. Cytokine 77:157–167. https://doi.org/10.1016/j.cyto.2015.10.011

    Article  CAS  PubMed  Google Scholar 

  24. Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1–2):248–254. https://doi.org/10.1006/abio.1976.9999

    Article  CAS  Google Scholar 

  25. Zaravinos A, Soufla G, Bizakis J, Spandidos DA (2008) Expression analysis of VEGFA, FGF2, TGFbeta1, EGF and IGF1 in human nasal polyposis. Oncol Rep 19:385–391. https://doi.org/10.3892/or.19.2.385

    Article  CAS  PubMed  Google Scholar 

  26. Pezato R, Voegels RL, Stamm AC, Gregório LC (2016) Why we should avoid using inferior turbinate tissue as control to nasal polyposis studies. Acta Otolaryngol 136(9):973–975. https://doi.org/10.3109/00016489.2016.1166262

    Article  PubMed  Google Scholar 

  27. Jones SA (2005) Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 173:3463–3468. https://doi.org/10.4049/jimmunol.175.6.3463

    Article  Google Scholar 

  28. Kaplanski G, Marin V, Montero-Julian F, Mantovani A, Farnarier C (2003) IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol 24(1):25–29. https://doi.org/10.1016/s1471-4906(02)00013-3

    Article  CAS  PubMed  Google Scholar 

  29. Romano M, Sironi M, Toniatti C, Polentarutti N, Fruscella P, Ghezzi P, Faggioni R, Luini W, Hinsbergh V, Sozzani S, Bussolino F, Poli V, Ciliberto G, Mantovani A (1997) Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6:315–325. https://doi.org/10.1016/S1074-7613(00)80334-9

    Article  CAS  PubMed  Google Scholar 

  30. Bernstein JM, Ballow M, Rich G, Allen C, Swanson M, Dmochowski J (2004) Lymphocyte subpopulations and cytokines in nasal polyps: is there a local immune system in the nasal polyp? Otolaryngol Head Neck Surg 130:526–535. https://doi.org/10.1016/j.otohns.2003.12.022

    Article  PubMed  Google Scholar 

  31. Sanchez-Segura J, Brieva JA, Rodriguez C (1998) T lymphocytes that infiltrate nasal polyps have a specialized phenotype and produce a mixed TH1/TH2 pattern of cytokines. J Allergy Clin Immunol 102:953–960. https://doi.org/10.1016/S0091-6749(98)70333-1

    Article  CAS  PubMed  Google Scholar 

  32. Gevaert P, Holtappels G, Johansson SG, Cuvelier C, Cauwenberge P, Bachert C (2005) Organization of secondary lymphoid tissue and local IgE formation to Staphylococcus aureus enterotoxins in nasal polyp tissue. Allergy 60:71–79. https://doi.org/10.1111/j.1398-9995.2004.00621.x

    Article  CAS  PubMed  Google Scholar 

  33. Ganeshan K, Bryce PJ (2012) Regulatory T cells enhance mast cell production of IL-6 via surface-bound TGF-β. J Immunol 188(2):594–603. https://doi.org/10.4049/jimmunol.1102389

    Article  CAS  PubMed  Google Scholar 

  34. Pezato R, Balsalobre L, Lima M, Bezerra TF, Voegels RL, Gregório LC, Stamm AC, van Zele T (2013) Convergence of two major pathophysiologic mechanisms in nasal polyposis: immune response to Staphylococcus aureus and airway remodeling. J Otolaryngol Head Neck Surg 42:27. https://doi.org/10.1186/1916-0216-42-27

    Article  PubMed  PubMed Central  Google Scholar 

  35. Iyer SS, Cheng G (2012) Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol 32(1):23–63. Epub 21 March 2012

  36. Xu J, Han R, Kim DW, Mo J-H, Jin Y, Rha K-S, Kim YM (2016) Role of interleukin-10 on nasal polypogenesis in patients with chronic rhinosinusitis with nasal polyps. PLoS One 11(9):e0161013. https://doi.org/10.1371/journal.pone.0161013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Okano M, Fujiwara T, Kariya S, Higaki T, Haruna T, Matsushita O, Noda Y, Makihara S, Kanai K, Noyama Y, Taniguchi M, Nishizaki K (2014) Cellular responses to Staphylococcus aureus alpha-toxin in chronic rhinosinusitis with nasal polyps. Allergol Int 63(4):563–573. https://doi.org/10.2332/allergolint.14-OA-0703S1323-8930(15)30069-1[pii]

    Article  CAS  PubMed  Google Scholar 

  38. Oliveira PWB, Pezato R, Agudelo JSH, Perez-Novo CA, Berghe WV, Câmara NO, de Almeida DC, Gregorio LC (2017) Nasal polyp-derived mesenchymal stromal cells exhibit lack of immune-associated molecules and high levels of stem/progenitor cells markers. Front Immunol 8:39. https://doi.org/10.3389/fimmu.2017.00039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zeisberg M, Shah AA, Kalluri R (2005) Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J Biol Chem 280(9):8094–8100. https://doi.org/10.1074/jbc.M413102200

    Article  CAS  PubMed  Google Scholar 

  40. Pezato R, de Almeida DC, Bezerra TF, Silva FA, Gregório LC, Voegels RL et al (2014) Immunoregulatory effects of bone marrow-derived mesenchymal stem cells in the nasal polyp microenvironment. Mediators Inflamm 2014:583409. https://doi.org/10.1155/2014/583409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rogério Pezato.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lucas, B.R., Voegels, R.L., do Amaral, J.B. et al. BMP-7, MMP-9, and TGF-β tissue remodeling proteins and their correlations with interleukins 6 and 10 in chronic rhinosinusitis. Eur Arch Otorhinolaryngol 278, 4335–4343 (2021). https://doi.org/10.1007/s00405-021-06722-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00405-021-06722-8

Keywords

Navigation