The Role of Activin-A in the Etiopathogenesis of Nasal Polyposis

Abstract

Objective: Nasal polyposis (NP) is defined as persistent inflammation of the sinonasal mucosa intractable to medical and surgical treatment. Activin-A, is a pleiotropic cytokine in the transforming growth factor-b (TGF-β) superfamily and was shown to orchestrate the allergic inflammation in asthma via suppression of T helper-2 (Th2) cells, induction of regulatory T cells, and tissue repair. The purpose of this study was to investigate the role of the activin-A in pathophysiology of NP.

Materials and Methods: According to the European Rhinosinusitis and Nasal Polyp criteria, 50 patients and 24 healthy subjects were included in the study. There were no significant differences across age and gender between the 2 groups (p>0.05). Samples from patients with NP (n=50; 11 women, 39 men) were acquired during endoscopic sinus surgeries. Middle turbinate specimens from patients without sinus disease and who were undergoing septoplasty were collected as controls (n=24; 3 women, 21 men).

Results: Immunohistochemical staining with activin-A showed an increase in the staining intensity, number of glands and inflammatory cells in polyp specimens compared to healthy nasal mucosa. In contrast, no differences were found in fibroblasts and vascular density.

Conclusion: We evaluated the expression of activin-A in NP tissue, which showed a slightly elevated expression compared to the controls. This might support the possible role of activin-A in the pathophysiology of NP. Clearer elucidation of the roles of activin-A and other mediators in tissue remodeling in NP may ensure more accurate targets for treatment and prevention of relapse.

Keywords

• Activin A
• Nasal polyps
• Sinusitis
• TGF-β

Supporting Institution

Selcuk University Scientific Research Projects

Project Number

13102029

References

1. 1. Stevens WW, Schleimer RP, Kern RC. Chronic Rhinosinusitis with Nasal Polyps. J Allergy Clin Immunol Pract 2016;4(4):565-72. google scholar
2. 2. Gelardi M, Iannuzzi L, Tafuri S, Passalacqua G, Quaranta N. Allergic and non-allergic rhinitis: relationship with nasal polyposis, asthma and family history. Acta Otorhinolaryngol Ital 2014;34(1):36-41. google scholar
3. 3. Cao PP, Li HB, Wang BF, Wang SB, You XJ, Cui YH, et al. Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J Allergy Clin Immunol 2009;124(3):478-84. google scholar
4. 4. Bachert C, Gevaert P, Holtappels G, Cuvelier C, van Cauwenberge P: Nasal polyposis: from cytokines to growth. Am J Rhinol 2000;14(5):279-90. google scholar
5. 5. Hammad H, Lambrecht BN. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol 2008;8(3):193-204. google scholar
6. 6. Alcorn JF, Rinaldi LM, Jaffe EF, van Loon M, Bates JH, Janssen-Heininger YM, et al. Transforming growth factor-beta1 suppresses airway hyperresponsiveness in allergic airway disease. Am J Respir Crit Care Med 2007;176(10):974-82. google scholar
7. 7. Kou W, Guo-Hua H, Yao H-B, Wang X, Shen Y, Kang H-Y, et al. Regulation of transforming growth factor-1 activation and expression in the tissue remodeling involved in chronic rhinosinusitis. ORLJOtorhinolaryngolRelatSpec 2012;74(3):172-8. google scholar
8. 8. Hirschberg A, Jokuti A, Darvas Z, Almay K, Repassy G, Falus A. Pathogenesis of nasal polyposis by immunoglobulin E and interleukin-5 is complete by transforming growth factor-B1. Laryngoscope 2003;113(1):120-4. google scholar

9. 9. Yang Y, Zhang N, Lan F, Van Crombruggen K, Fang L, Hu G, et al. Transforming growth factorbeta1 pathways in inflammatory airway diseases. Allergy 2014;69(6):699-707. google scholar
10. 10. Hedger MP, Kretser de DM. The activins and their binding protein, follistatin-Diagnostic and therapeutic targets in inflammatory disease and fibrosis. Cytokine Growth Factor Rev 2013;24(3):285-95. google scholar
11. 11. Gregory LG, Mathie SA, Walker SA, Pegorier S, Jones CP, Lloyd CM. Overexpression of Smad2 drives house dust mite-mediated airway remodeling and airway hyperresponsiveness via activin and IL-25. Am J Respir Crit Care Med 2010;182(2):143-54. google scholar
12. 12. Karagiannidis C, Hense G, Martin C, Epstein M, Ruckert B, Mantel PY et al. Activin A is an acute allergen-responsive cytokine and provides a link to TGF-beta-mediated airway remodeling in asthma. J Allergy Clin Immunol 2006;117(1):111-8. google scholar
13. 13. Kariyawasam HH, Pegorier S, Barkans J, Xanthou G, Aizen M, Ying S, et al. Activin and transforming growth factor-beta signaling pathways are activated after allergen challenge in mild asthma. J Allergy Clin Immunol 2009;124(3):454-62. google scholar
14. 14. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps. A summary for otorhinolaryngologists Rhinology 2012;50(Suppl S23):1-12. google scholar
15. 15. Muluk NB, Arikan OK, Atasoy P, Kiliç R, Yalçinozan ET. The role of endothelial nitric oxide synthase (eNOS) in the pathogenesis of sinonasal polyps. Eur Rev Med Pharmacol Sci 2014;18(6):918-29. google scholar
16. 16. Yan Y, Gordon WM, Wang DY. Nasal epithelial repair and remodeling in physical injury, infection, and inflammatory diseases. Curr Opin Otolaryngol Head Neck Surg 2013;21(3):263-70. google scholar
17. 17. Huvenne W, Van Bruaene N, Zhang N, van Zele T, Patou J, Gevaert P, et al. Chronic rhinosinusitis with and without nasal polyps: what is the difference? Curr Allergy Asthma Rep 2009;9(3):213-20. google scholar
18. 18. Hâkansson K, Bachert C, Konge L, Thomsen SF, Pedersen AE, Poulsen SS, et al. Airway Inflammation in Chronic Rhinosinusitis with Nasal Polyps and Asthma: The United Airways Concept Further Supported PLoS One 2015;10(7):e0127228. doi: 10.1371/ journal.pone.0127228. eCollection 2015. google scholar
19. 19. Van Bruaene N, Bachert C. Tissue remodeling in chronic rhinosinusitis. Curr Opin Allergy Clin Immunol 2011;11(1):8-11. google scholar
20. 20. Wang X, Zhao C, Ji W, Xu Y, Guo H. Relationship of TLR2, TLR4 and tissue remodeling in chronic rhinosinusitis. Int J Clin Exp Pathol 2015;8(2):1199-212. google scholar
21. 21. Tsuchida K, Nakatani M, Hitachi K, Uezumi A, Sunada Y, Ageta H, et al. Activin signaling as an emerging target for therapeutic interventions. Cell Commun Signal 2009;7:1-11. google scholar
22. 22. Cho SH, Yao Z, Wang SW, Alban RF, Barbers RG, French SW, Oh CK. Regulation of activin A expression in mast cells and asthma: its effect on the proliferation of human airway smooth muscle cells. J Immunol 2003;170(8):4045-52. google scholar
23. 23. Apostolou E, Stavropoulos A, Sountoulidis A, Xirakia C, Giaglis S, Protopapadakis E, et al. Activin-A overexpression in the murine lung causes pathology that simulates acute respiratory distress syndrome. A m J Respir Crit Care Med 2012;185(4):382-91. google scholar
24. 24. Hardy CL, Rolland JM, O’Hehir RE. The immunoregulatory and fibrotic roles of activin A in allergic asthma. Clin Exp Allergy 2015;45(10):1510-22. google scholar
25. 25. Kariyawasam HH, Semitekolou M, Robinson DS, Xanthou G. Activin-A: a novel critical regulator of allergic asthma. Clin Exp Allergy 2011;41(11):1505-14. google scholar
26. 26. Yang Y, Zhang N, Crombruggen KV, Lan F, Hu G, Hong S, Bachert C. Differential expression and release of Activin A and follistatin in chronic rhinosinusitis with and without nasal polyps. PLoS One 2015;10(6):e0128564. doi: 10.1371/journal. pone.0128564. eCollection 2015. google scholar
27. 27. Chaker AM, Zissler UM, Poulos N, Wagenmann M, Bas M, Gürth F, Xanthou G, Schmidt-Weber C. Activin-A Is a Pro-Inflammatory regulator in type-2-driven upper airway disease. Int Arch Allergy Immunol 2018;176:15-25. google scholar
28. 28. Yamin M, Holbrook EH, Gray ST, Busaba NY, Lovett B, Hamilos DL. Profibrotic transforming growth factor beta 1 and activin A are increased in nasal polyp tissue and induced in nasal polyp epithelium by cigarette smoke and Toll-like receptor 3 ligation. Int Forum Allergy Rhinol 2015;5(7):573-82. google scholar