The role of metalloproteinases in remodeling of the sinus mucosa in chronic rhinosinusitis

• Elena L. Savlevich
• Elizaveta S. Mitrofanova
• Oksana M. Kurbacheva
• Miramgul E. Dyneva
• Igor P. Shilovskiy
• Victor I. Egorov
• Dmitry S. Pshennikov
• Musa R. Khaitov

Abstract

Chronic rhinosinusitis (CRS) is a group of diseases with different etiology and pathogenesis characterized by persistent inflammation of the mucous membrane of the nose and paranasal sinuses (PNS) and is subdivided into CRS without polyps, which is more prevalent (more than 2/3 of cases), and rhinosinusitis with nasal polyps (CRSwNP). Histologically, CRSwNP is characterized by mucosal infiltration of PNS with inflammatory cells (eosinophils, lymphocytes, plasmacytes, neutrophils, etc.), modifications in epithelial cell differentiation, tissue remodeling, including basement membrane thickening, epithelial degradation, oedema, and fibrosis of the submucosal layer with accumulation of extracellular matrix (ECM), basal cell dysplasia. Polarized epithelial cells transform into mesenchymal forms with loss of typical morphology, which are characterized by resistance to apoptosis, increased invasiveness and migratory ability, loss of polarity, adhesiveness, intercellular connections and hyperproduction of EMS proteins, the accumulation of which is critical for pathological reconstruction of the PNS mucosa. Metalloproteinases (MMPs), whose activation and biological activity is regulated by tissue inhibitors of metalloproteinases (TIMPs), are the main proteolytic enzymes responsible for extracellular matrix remodeling. The balance between MMPs and TIMPs determines the processes of production and degradation of individual components of the ECM, thereby influencing the pathogenesis of inflammation.

The current review summarizes the data of investigation of the role of ММPs in the upper respiratory tract remodeling during chronic rhinosinusitis. Experimental data on the molecular and cellular action mechanisms of ММPs were reviewed. The systematization of these data could help to reveal promising targets for the development of new approached for CRS treatment.

Keywords:chronic rhinosinusitis; chronic rhinosinusitis with nasal polyps; remodeling of the sinus mucosa; extracellular matrix; matrix metalloproteinase; tissue inhibitors of metalloproteinases; targeted therapy

References

1. Fokkens W.J., Lund V.J., Hopkins C., Hellings P.W., Kern R., Reitsma S., Toppila-Salmi S., Bernal-Sprekelsen M., Mullol J., Alobid I., Terezinha Anselmo-Lima W., Bachert C., Baroody F., von Buchwald C., Cervin A., Cohen N., Constantinidis J., De Gabory L., Desrosiers M., Diamant Z., Douglas R.G., Gevaert P.H., Hafner A., Harvey R.J., Joos G.F., Kalogjera L., Knill A., Kocks J.H., Landis B.N., Limpens J., Lebeer S., Lourenco O., Meco C., Matricardi P.M., O’Mahony L., Philpott C.M., Ryan D., Schlosser R., Senior B., Smith T.L., Teeling T., Tomazic P.V., Wang D.Y., Wang D., Zhang L., Agius A.M., Ahlstrom-Emanuelsson C., Alabri R., Albu S., Alhabash S., Aleksic A., Aloulah M., Al-Qudah M., Alsaleh S., Baban M.A, Baudoin T., Balvers T., Battaglia P., Bedoya J.D., Beule A., Bofares K.M., Braverman I., Brozek-Madry E., Richard B., Callejas C., Carrie S., Caulley L., Chussi D., de Corso E., Coste A., El Hadi U., Elfarouk A., Eloy P.H., Farrokhi S., Felisati G., Ferrari M.D., Fishchuk R., Grayson W., Goncalves P.M., Grdinic B., Grgic V., Hamizan A.W., Heinichen J.V., Husain S., Ping T.I., Ivaska J., Jakimovska F., Jovancevic L., Kakande E., Kamel R., Karpischenko S., Kariyawasam H.H., Kawauchi H., Kjeldsen A., Klimek L., Krzeski A., Kopacheva Barsova G., Kim S.W., Lal D., Letort J.J., Lopatin A., Mahdjoubi A., Mesbahi A., Netkovski J., Nyenbue Tshipukane D., Obando-Valverde A., Okano M., Onerci M., Ong Y.K., Orlandi R., Otori N., Ouennoughy K., Ozkan M., Peric A., Plzak J., Prokopakis E., Prepageran N., Psaltis A., Pugin B., Raftopulos M., Rombaux P., Riechelmann H., Sahtout S., Sarafoleanu C.C., Searyoh K., Rhee C.S., Shi J., Shkoukani M., Shukuryan A.K., Sicak M., Smyth D., Sindvongs K., Soklic Kosak T., Stjarne P., Sutikno B., Steinsvag S., Tantilipikorn P., Thanaviratananich S., Tran T., Urbancic J., Valiulius A., Vasquez de Aparicio C., Vicheva D., Virkkula P.M., Vicente G., Voegels R., Wagenmann M.M., Wardani R.S., Welge-Lussen A., Witterick I., Wright E., Zabolotniy D., Zsolt B., Zwetsloot C.P. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology. 2020; 58 (Suppl S29): 1–464. DOI: https://doi.org/10.4193/Rhin20.600

2. Kozlov V.S., Savlevich E.L. Chronic rhinosinusitis with nasal polyps. The recent trend in the studies of the pathogenesis, diagnosis and treatment of this disease. Bulletin of Otorhinolaryngology. 2015; 80 (4): 95–9. DOI: https://doi.org/10.17116/otorino201580495-99 (in Russian)

3. Wang X., Zhang N., Bo M., Holtappels G., Zheng M., Lou H., Wang H., Zhang L., Bachert C. Diversity of T_H cytokine profiles in patients with chronic rhinosinusitis: A multicenter study in Europe, Asia, and Oceania. J Allergy Clin Immunol. 2016; 138 (5): 1344–53. DOI: https://doi.org/10.1016/j.jaci.2016.05.041

4. Kurbacheva O.M., Dyneva M.E., Shilovskii I.P., Savlevich E.L., Kovchina V.I., Nikolsky A.A., Savushkina E.Yu., Khaitov M.R. Polypous rhinosinusitis in combination with bronchial asthma: clinical features and cellular characteristics of local and systemic inflammation. Russian Journal of Allergy. 2020; 17 (1): 32–49. DOI: https://doi.org/10.17116/10.36691/RAJ.2020.17.1.003 (in Russian)

5. Kurbacheva O.M., Savlevich E.L., Egorov V.I., Dyneva M.E., Shilovskiy I.P., Kovchina V.I., Nikolskii A.A., Barvinskaia E.D., Kaganova M.M., Mitrofanova Е.S., Savushkina E.Y., Gaganov L.E., Khaitov M.R. Expression of the TNFSF13B, APRIL, VEGF, FGF1и EGF genes in different phenotypes of chronic rhinosinusitis with nasal polyps. Immunologiya. 2022; 43 (5): 571–82. DOI: https://doi.org/10.33029/0206-4952-2022-43-5-571-582 (in Russian)

6. Kurbacheva O.M., Dyneva M.E., Shilovskiy I.P., Savlevich E.L., Kovchina V.I., Nikol’skiy A.A., Savushkina E.Yu., Khaitov M.R. Pathogenetic molecular mechanisms of chronic rhinosinusitis with nasal polyps associated with asthma. PULMONOLOGIYA. 2021; 31 (1): 7–19. DOI: https://doi.org/10.18093/0869-0189-2021-31-1-7-19 (in Russian)

7. Wynne M., Atkinson C., Schlosser R.J., Mulligan J.K. Contribution of epithelial cell dysfunction to the pathogenesis of chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2019; 33 (6): 782–90. DOI: https://doi.org/10.1177/1945892419868588

8. Savlevich E.L., Gaganov L.E., Gerasimov A.N., Kurbacheva O.M., Egorov V.I., Zurochka A.V. Analysis of clinical course of chronic rhinosinusitis with nasal polyp (CRSWNP) and pathomorphological composition of nasal polyp tissue in patients living in different regions of the Russian Federation. Head and neck. Russian Journal. 2021; 9 (3): 15–24. DOI: https://doi.org/10.25792/HN.2021.9.3.15–24 (in Russian)

9. Radajewski K., Wierzchowska M., Grzanka D., Antosik P., Zdrenka M., Burduk P. Tissue remodelling in chronic rhinosinusitis – review of literature. Otolaryngol Pol. 2019; 73 (5): 1–4. DOI: https://doi.org/10.1016/j.anai.2020.01.018

10. Bankova L.G., Barrett N.A. Epithelial cell function and remodeling in nasal polyposis. Ann Allergy Asthma Immunol. 2020; 124 (4): 333–41. DOI: https://doi.org/10.1016/j.anai.2020.01

11. Bankova L.G., Dwyer D.F., Yoshimoto E., Ualiyeva S., McGinty J.W., Raff H., von Moltke J., Kanaoka Y., Frank Austen K., Barrett N.A. The cysteinyl leukotriene 3 receptor regulates expansion of IL-25-producing airway brush cells leading to type 2 inflammation. Sci Immunol. 2018; 3 (28): eaat9453. DOI: https://doi.org/10.1126/sciimmunol.aat9453

12. Nagashima H., Mahlakõiv T., Shih H.Y., Davis F.P., Meylan F., Huang Y., Harrison O.J., Yao C., Mikami Y., Urban J.F. Jr, Caron K.M., Belkaid Y., Kanno Y., Artis D., O’Shea J.J. Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrains type 2 inflammation. Immunity. 2019; 51 (4): 682–95. DOI: https://doi.org/10.1016/j.immuni.2019.06.009

13. Wallrapp A., Burkett P.R., Riesenfeld S.J., Kim S.J., Christian E., Abdulnour R.E., Thakore P.I., Schnell A., Lambden C., Herbst R.H., Khan P., Tsujikawa K., Xavier R. J., Chiu I.M., Levy B.D., Regev A., Kuchroo V.K. Calcitonin gene-related peptide negatively regulates alarmin-driven type 2 innate lymphoid cell responses. Immunity. 2019; 51 (4): 709–23. DOI: https://doi.org/10.1016/j.immuni.2019.09.005

14. Egorov V.I., Savlevich E.L. Тhe role of innate immunity in the development of chronic rhinosinusitis and perspectives of its conservative management. Almanac of Clinical Medicine. 2016; 44 (7): 850–6. DOI: https://doi.org/10.18786/2072-0505-2016-44-7-850-856 (in Russian)

15. Gusniev S.A., Polner S.A., Mikhaleva L.M., Ilina N.I., Esakova A.P., Kurbacheva O.M., Shilovskiy I.P., Khaitov M.R. Influence of interleukin-33 gene expression on clinical and morphological characteristics of the nasal mucosa in allergic rhinitis. Immunologiya. 2021; 42 (1): 68–79. DOI: https://doi.org/10.33029/0206-4952-2021-42-1-68-79 (in Russian)

16. Laoukili J., Perret E., Willems T., Minty A., Parthoens E., Houcine O., Coste A., Jorissen M., Marano F., Caput D., Tournier F. IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. The Journal of clinical investigation. 2001; 108 (12): 1817–24. DOI: https://doi.org/10.1172/JCI13557

17. Gudis D., Zhao K.Q., Cohen N.A. Acquired cilia dysfunction in chronic rhinosinusitis. Am J Rhinol Allergy. 2012; 26 (1): 1–6. DOI: https://doi.org/10.2500/ajra.2012.26.3716

18. Savlevich E.L., Kurbacheva O.M., Egorov V.I., Dyneva M.E., Shilovskiy I.P., Khaitov M.R. Gene expression levels of cytokines in different phenotypes of CRSwNP. Bulletin of Otorhinolaryngology. 2019; 84 (6): 42–7. DOI: https://doi.org/10.17116/otorino20198406142 (in Russian)

19. Korkmazov M.Yu., Dubinets I.D., Lengina M.A., Solodovnik A.V. Local concentrations of secretory immunoglobulin A in patients with adenoiditis, rhinosinusitis and exacerbation of chronic suppurative otitis media against the background of the use of physical methods in complex therapy. Russian journal of immunology. 2021; 24 (2): 297–304. DOI: https://doi.org/10.46235/1028-7221-999-LCO (in Russian)

20. Saitoh T., Kusunoli T., Yao T., Kawano K., Kojima Y., Miyahara K., Onoda J., Yokoi H., Ikeda K. Relationship between epithelial damage or basement membrane thickness and eosinophilic infiltration in nasal polyps with chronic rhinosinusitis. Rhinology. 2009; 47 (3): 275–9. DOI: https://doi.org/10.4193/Rhin08.109

21. Savlevich E.L., Kozlov V.S., Kurbacheva O.M. The modern trends in the diagnostic search for and the treatment of chronic rhinosinusitis with nasal polyps. Russian Rhinology. 2018; 26 (2): 41–7. DOI: https://doi.org/10.17116/rosrino201826241 (in Russian)

22. Carroll W.W., O’Connell B.P., Schlosser R.J., Gudis D.A., Karnezis T.T., Lawrence L.A., Soler Z.M., Mulligan J.K. Fibroblast levels are increased in chronic rhinosinusitis with nasal polyps and are associated with worse subjective disease severity. Int Forum Allergy Rhinol. 2016; 6 (2): 162–8. DOI: https://doi.org/10.1002/alr.21636

23. Rehl R.M., Balla A.A., Cabay R.J., Hearp M.L., Pytynia K.B., Joe S.A. Mucosal remodeling in chronic rhinosinusitis. Am J Rhinol. 2007; 21 (6): 651–7. DOI: https://doi.org/10.2500/ajr.2007.21.3096

24. Wang F., Yang Y., Wu Q., Chen H. Histopathologic analysis in chronic rhinosinusitis: Impact on quality of life outcomes. Am J Otolaryngol. 2019; 40 (3): 423–6. DOI: https://doi.org/10.1016/j.amjoto.2019.03.014

25. Guerra G., Testa D., Salzano F.A., Tafuri D., Hay E., Schettino BsA., Iovine R., Marcuccio G., Motta G. Expression of matrix metalloproteinases and their tissue inhibitors in chronic rhinosinusitis with nasal polyps: etiopathogenesis and recurrence. Ear Nose Throat J. 2021; 100 (5 Suppl): 597S–605S. DOI: https://doi.org/10.1177/0145561319896635

26. Lee K., Tai J., Lee S.H., Kim T.H. Advances in the knowledge of the underlying airway remodeling mechanisms in chronic rhinosinusitis based on the endotypes: a review. Int J Mol Sci. 2021; 22 (2): 910. DOI: https://doi.org/10.3390/ijms22020910

27. Kostamo K., Tervahartiala T., Sorsa T., Richardson M., Toskala E. Metalloproteinase function in chronic rhinosinusitis with nasal polyposis. Laryngoscope. 2007; 117 (4): 638–43. DOI: https://doi.org/10.1097/MLG.0b013e318030aca6

28. Huang C.C., Wang C.H., Wu P.W., He J.R., Huang C.C., Chang P.H., Fu.C. H., Lee T.J. Increased nasal matrix metalloproteinase-1 and -9 expression in smokers with chronic rhinosinusitis and asthma. Sci Rep. 2019; 9 (1): 15357. DOI: https://doi.org/10.1038/s41598-019-51813-6

29. Wang L.F., Chien C.Y., Chiang F.Y., Chai C.Y., Tai C.F. Expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in recurrent chronic rhinosinusitis with nasal polyposis. Kaohsiung J Med Sci. 2013; 29 (1): 26–31. DOI: https://doi.org/10.1016/j.kjms.2012.08.004

30. Watelet J.B., Bachert C., Claeys C., Van Cauwenberge P. Matrix metalloproteinases MMP-7, MMP-9 and their tissue inhibitor TIMP-1: expression in chronic sinusitis vs nasal polyposis. Allergy. 2004; 59 (1): 54–60. DOI: https://doi.org/10.1046/j.1398-9995.2003.00364.x

31. Detwiller K.Y., Smith T.L., Mace J.C., Trune D.R., Sautter N.B. Steroid-independent upregulation of matrix metalloproteinase 9 in chronic rhinosinusitis patients with radiographic evidence of osteitis. Int Forum Allergy Rhinol. 2013; 3 (5): 364–8. DOI: https://doi.org/10.1002/alr.21135

32. Videler W.J., Georgalas C., Menger D.J., Freling N.J., van Drunen C.M., Fokkens W.J. Osteitic bone in recalcitrant chronic rhinosinusitis. Rhinology. 2011; 49 (2): 139–47. DOI: https://doi.org/10.4193/Rhino10.158

33. Van Zele T., Gevaert P., Holtappels G., Beule A., Wormald P.J., Mayr S., Hens G., Hellings P., Ebbens F. A., Fokkens W., Van Cauwenberge P., Bachert C. Oral steroids and doxycycline: two different approaches to treat nasal polyps. J Allergy Clin Immunol. 2010; 125 (5): 1069–76. DOI: https://doi.org/10.1016/j.jaci.2010.02.020

34. Yeo N.K., Eom D.W., Oh M.Y., Lim H.W., Song Y.J. Expression of matrix metalloproteinase 2 and 9 and tissue inhibitor of metalloproteinase 1 in nonrecurrent vs recurrent nasal polyps. Ann Allergy Asthma Immunol. 2013; 111 (3): 205–10. DOI: https://doi.org/10.1016/j.anai.2013.06.023

35. Kim D.K., Eun K.M., Kim M.K., Cho D., Han S.A., Han S.Y., Seo Y., Lee D.H., Cho S.H., Kim D.W. Comparison between signature cytokines of nasal tissues in subtypes of chronic rhinosinusitis. Allergy Asthma Immunol Res. 2019; 11 (2): 201–11. DOI: https://doi.org/10.4168/aair.2019.11.2.201

36. Can I.H., Ceylan K., Caydere M., Samim E.E., Ustun H., Karasoy D.S. The expression of MMP-2, MMP-7, MMP-9, and TIMP-1 in chronic rhinosinusitis and nasal polyposis. Otolaryngol Head Neck Surg. 2008; 139 (2): 211–5. DOI: https://doi.org/10.1016/j.otohns.2008.04.032

37. Xiang R., Zhang Q.P., Zhang W., Kong Y.G., Tan L., Chen S.M., Deng Y.Q., Tao Z.Z., Xu Y. Different effects of allergic rhinitis on nasal mucosa remodeling in chronic rhinosinusitis with and without nasal polyps. Eur Arch Otorhinolaryngol. 2019; 276 (1): 115–30. DOI: https://doi.org/10.1007/s00405-018-5195-x

38. Kuwabara Y., Kobayashi T., D’Alessandro-Gabazza C.N., Toda M., Yasuma T., Nishihama K., Takeshita A., Fujimoto H., Nagao M., Fujisawa T., Gabazza E. C. Role of matrix metalloproteinase-2 in eosinophil-mediated airway remodeling. Front Immunol. 2018; 9: 2163. DOI: https://doi.org/10.3389/fimmu.2018.02163

39. Churg A., Zhou S., Wright J.L. Series «matrix metalloproteinases in lung health and disease»: Matrix metalloproteinases in COPD. Eur Respir J. 2012; 39 (1): 197–209. DOI: https://doi.org/10.1183/09031936.00121611

40. Bhandari A., Takeuchi K., Suzuki S., Harada T., Hayashi S., Imanaka-Yoshida K., Yoshida T., Majima Y. Increased expression of matrix metalloproteinase-2 in nasal polyps. Acta Otolaryngol. 2004; 124 (10): 1165–70. DOI: https://doi.org/0.1080/00016480410017152

41. Owen C.A., Hu Z., Lopez-Otin C., Shapiro S.D. Membrane-bound matrix metalloproteinase-8 on activated polymorphonuclear cells is a potent, tissue inhibitor of metalloproteinase-resistant collagenase and serpinase. J Immunol. 2004; 172 (12): 7791–803. DOI: https://doi.org/10.4049/jimmunol.172.12.7791

42. Kostamo K., Sorsa T., Leino M., Tervahartiala T., Alenius H., Richardson M., Toskala E. In vivo relationship between collagenase-2 and interleukin-8 but not tumour necrosis factor-alpha in chronic rhinosinusitis with nasal polyposis. Allergy. 2005; 60 (10): 1275–9. DOI: https://doi.org/10.1111/j.1398-9995.2005.00888.x

43. Gizinger O.A., Korkmazov A.M., Korkmazov M.Yu. State of antimicrobial protection factors of nasal secretion in patients operated on for deviated nasal septum in the early postoperative period. Russian Journal of Immunology. 2017; 2 (20): 117–9. (in Russian)

44. Prikk K., Maisi P., Pirilä E., Reintam M.A., Salo T., Sorsa T., Sepper R. Airway obstruction correlates with collagenase-2 (MMP-8) expression and activation in bronchial asthma. Lab Invest. 2002; 82 (11): 1535–45. DOI: https://doi.org/10.1097/01.lab.0000035023.53893.b6

45. Zhou Y., Xu M., Gong W., Kang X., Guo R., Wen J., Zhou D., Wang M., Shi D., Jing Q. Circulating MMP-12 as potential biomarker in evaluating disease severity and efficacy of sublingual immunotherapy in allergic rhinitis. Mediators Inflamm. 2022; 2022: 3378035. DOI: https://doi.org/10.1155/2022/3378035

46. Lagente V., Le Quement C., Boichot E. Macrophage metalloelastase (MMP-12) as a target for inflammatory respiratory diseases. Expert Opin Ther Targets. 2009; 13 (3): DOI: https://doi.org/10.1517/14728220902751632

47. Lygeros S., Danielides G., Kyriakopoulos G.C., Grafanaki K., Tsapardoni F., Stathopoulos C., Danielides V. Evaluation of MMP-12 expression in chronic rhinosinusitis with nasal polyposis. Rhinology. 2022; 60 (1): 39–46. DOI: https://doi.org/10.4193/Rhin21.320

48. Du K., Wang M., Zhang N., Yu P., Wang P., Li Y., Wang X., Zhang L., Bachert C. Involvement of the extracellular matrix proteins periostin and tenascin C in nasal polyp remodeling by regulating the expression of MMPs. Clin Transl Allergy. 2021; 11 (7): e12059. DOI: https://doi.org/10.1002/clt2.12059

49. Wang M., Wang X., Zhang N., Wang H., Li Y., Fan E., Zhang L., Zhang L., Bachert C. Association of periostin expression with eosinophilic inflammation in nasal polyps. J Allergy Clin Immunol. 2015; 136 (6): 1700–03.e9. DOI: https://doi.org/10.1016/j.jaci.2015.09.005

50. Li X., Tao Y., Li X. Expression of MMP-9/TIMP-2 in nasal polyps and its functional implications. Int J Clin Exp Pathol. 2015; 8 (11): 14556–61.

51. Savlevich E.L., Zurochka A.V., Kurbacheva O.M., Egorov V.I., Gaganov L.E., Lyubimova E.V. Transforming growth factors TGF-β1, TGF-β2 and TGF-β3 in the tissue of nasal polyps in different phenotypes of chronic rhinosinusitis with nasal polyps. Medical Immunology (Russia) (Meditsinskaya Immunologiya). 2022; 24 (1): 147–56. DOI: https://doi.org/10.15789/1563-0625-TGF-2365 (in Russian)

52. Lygeros S., Danielides G., Grafanaki K., Riga M. Matrix metalloproteinases and chronic rhinosinusitis with nasal polyposis. Unravelling a puzzle through a systematic review. Rhinology. 2021; 59 (3): 245–57. DOI: https://doi.org/10.4193/Rhin20.578

53. Vandenbroucke R.E., Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov. 2014; 13 (12): 904–27. DOI: https://doi.org/10.1038/nrd4390

54. Watelet J.B., Dogne J.M., Mullier F. Remodeling and Repair in Rhinosinusitis. Curr Allergy Asthma Rep. 2015; 15 (6): 34. DOI: https://doi.org/10.1007/s11882-015-0531-3

55. Katainen E., Kostamo K., Virkkula P., Sorsa T., Tervahartiala T., Haapaniemi A., Toskala E. Local and systemic proteolytic responses in chronic rhinosinusitis with nasal polyposis and asthma. International forum of allergy & rhinology. 2015; 5 (4): 294–302. DOI: https://doi.org/10.1002/alr.21486

56. Savlevich E.L., Dyneva M.E., Gaganov L.E., Egorov V.I., Gerasimov A.N., Kurbacheva O.M. Diagnostic and treatment algorithm for different phenotypes of chronic rhinosinusitis with nasal polyps. Russian Journal of Allergy. 2019; 16 (2): 50–60. DOI: https://doi.org/10.36691/RJA1198 (in Russian)

57. Savlevich E.L., Kurbacheva O.M. Features of the course of polypous rhinosinusitis combined with allergic rhinitis. Medical Council. 2019; (20): 38–43. DOI: https://doi.org/10.21518/2079-701X-2019-20-38-43 (in Russian)

58. Shilovskiy I.P., Nikolskii A.A., Kurbacheva O.M., Khaitov M.R. Modern view of neutrophilic asthma molecular mechanisms and therapy. Biochemistry [Biokhimiia]. 2020; 85 (8): 854–68. DOI: https://doi.org/10.1134/S0006297920080027 (in Russian)

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