Skip to main content

Advertisement

SpringerLink
Log in

Gene Expression Signatures: A New Approach to Understanding the Pathophysiology of Chronic Rhinosinusitis

  • SINUSITIS (ML KOWALSKI, SECTION EDITOR)
  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Chronic rhinosinusitis (CRS) is a complex inflammatory disease with variable disease manifestation. Though external risk factors are associated with development and/or persistence of CRS, the host mucosal response is also important, as nasal epithelium acts as a physical and immune barrier. Under inflammatory stress, the nasal epithelium can undergo injury, followed by a rapid remodeling response ranging from epithelial hyperplasia, to goblet-cell metaplasia, to denudation, loss of cilia, fibrosis, and basement membrane thickening. Identification of gene expression signatures and molecular pathways in CRS pathogenesis have now begun to contribute significantly to a better understanding of the genetic and molecular alterations underlying CRS development and progression. Genetic studies are especially illuminating when multiple gene variants synergize within a permissive environmental context, and are expected to guide development of more effective therapeutic targets for CRS treatment.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Fokkens WJ, Lund VJ, Mullol J, et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology. 2012;23:1–298. This is the most up-to-date position paper on epidemiology, pathogenesis, diagnosis, and treatment of chronic rhinosinusitis.

    Google Scholar 

  2. Larsen PL, Tos M. Origin of nasal polyps: an endoscopic autopsy study. Laryngoscope. 2004;114:710–9.

    Article  PubMed  Google Scholar 

  3. Larsen K. The clinical relationship of nasal polyps to asthma. Allergy Asthma Proc. 1996;17:243–9.

    Article  PubMed  CAS  Google Scholar 

  4. Peterson S, Poposki JA, Nagarkar DR, et al. Increased expression of CC chemokine ligand 18 in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2012;129:119–27. This study demonstrated clearly the relationship between M2 machrophage and eosinophil infiltration in CRSwNP.

    Article  PubMed  CAS  Google Scholar 

  5. Krysko O, Holtappels G, Zhang N, et al. Alternatively activated macrophages and impaired phagocytosis of S. aureus in chronic rhinosinusitis. Allergy. 2011;66:396–403.

    Article  PubMed  CAS  Google Scholar 

  6. Poposki JA, Uzzaman A, Nagarkar DR, et al. Increased expression of the chemokine CCL23 in eosinophilic chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2011;128:73–81.

    Article  PubMed  CAS  Google Scholar 

  7. Keswani A, Chustz RT, Suh L, et al. Differential expression of interleukin-32 in chronic rhinosinusitis with and without nasal polyps. Allergy. 2012;67:25–32.

    Article  PubMed  CAS  Google Scholar 

  8. Kimura S, Pawankar R, Mori S, et al. Increased expression and role of thymic stromal lymphopoietin in nasal polyposis. Allergy Asthma Immunol Res. 2011;3:186–93.

    Article  PubMed  Google Scholar 

  9. • Allakhverdi Z, Comeau MR, Smith DE, et al. CD34+ hemopoietic progenitor cells are potent effectors of allergic inflammation. J Allergy Clin Immunol. 2009;123:472–8. The paper demonstrated the functional role of epithelium derived gene TSLP in activating inflammatory effector cells such as CD34+ cells.

  10. Miyata M, Nakamura Y, Shimokawa N, et al. Thymic stromal lymphopoietin is a critical mediator of IL-13-driven allergic inflammation. Eur J Immunol. 2009;39:3078–83.

    Article  PubMed  CAS  Google Scholar 

  11. Reh DD, Wang Y, Ramanathan Jr M, Lane AP. Treatment-recalcitrant chronic rhinosinusitis with polyps is associated with altered epithelial cell expression of interleukin-33. Am J Rhinol Allergy. 2010;24:105–9.

    Article  PubMed  Google Scholar 

  12. Bulek K, Swaidani S, Aronica M, Li X. Epithelium: the interplay between innate and Th2 immunity. Immunol Cell Biol. 2010;88:257–68.

    Article  PubMed  CAS  Google Scholar 

  13. Tsicopoulos A, Shimbara A, de Nadai P, et al. Involvement of IL-9 in the bronchial phenotype of patients with nasal polyposis. J Allergy Clin Immunol. 2004;113:462–9.

    Article  PubMed  CAS  Google Scholar 

  14. Jahnsen FL, Haye R, Gran E, Brandtzaeg P, Johansen FE. Glucocorticosteroids inhibit mRNA expression for eotaxin, eotaxin-2, and monocyte-chemotactic protein-4 in human airway inflammation with eosinophilia. J Immunol. 1999;163:1545–51.

    PubMed  CAS  Google Scholar 

  15. Lamkhioued B, Garcia-Zepeda EA, Abi-Younes S, et al. Monocyte chemoattractant protein (MCP)-4 expression in the airways of patients with asthma. Induction in epithelial cells and mononuclear cells by proinflammatory cytokines. Am J Respir Crit Care Med. 2000;162:723–32.

    PubMed  CAS  Google Scholar 

  16. Kato A, Peters A, Suh L, et al. Evidence of a role for B cell-activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2008;121:1385–92.

    Article  PubMed  CAS  Google Scholar 

  17. Park WS, Jung WK, Park SK, et al. Expression of galectin-9 by IFN-γ stimulated human nasal polyp fibroblasts through MAPK, PI3K, and JAK/STAT signaling pathways. Biochem Biophys Res Commun. 2011;411:259–64.

    Article  PubMed  CAS  Google Scholar 

  18. Van Zele T, Coppieters F, Gevaert P, Holtappels G, Van Cauwenberge P, Bachert C. Local complement activation in nasal polyposis. Laryngoscope. 2009;119:1753–8.

    Article  PubMed  Google Scholar 

  19. Schlosser RJ, Mulligan RM, Casey SE, Varela JC, Harvey RJ, Atkinson C. Alterations in gene expression of complement components in chronic rhinosinusitis. Am J Rhinol Allergy. 2010;24:21–5.

    Article  PubMed  Google Scholar 

  20. Cao PP, Li HB, Wang BF, et al. Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J Allergy Clin Immunol. 2009;124:478–84.

    Article  PubMed  CAS  Google Scholar 

  21. Shen Y, Tang XY, Yang YC, et al. Impaired balance of Th17/Treg in patients with nasal polyposis. Scand J Immunol. 2011;74:176–85.

    Article  PubMed  CAS  Google Scholar 

  22. Palomares O, Yaman G, Azkur AK, Akkoc T, Akdis M, Akdis CA. Role of Treg in immune regulation of allergic diseases. Eur J Immunol. 2010;40:1232–40.

    Article  PubMed  CAS  Google Scholar 

  23. Bellinghausen I, Klostermann B, Knop J, Saloga J. Human CD4 + CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production. J Allergy Clin Immunol. 2003;111:862–8.

    Article  PubMed  CAS  Google Scholar 

  24. Van Bruaene N, Pérez-Novo CA, Basinski TM, et al. T-cell regulation in chronic paranasal sinus disease. J Allergy Clin Immunol. 2008;121:1435–41.

    Article  PubMed  Google Scholar 

  25. Li CW, Zhang KK, Li TY, et al. Expression profiles of regulatory and helper T-cell-associated genes in nasal polyposis. Allergy. 2012;67:732–40. This study indicated that increased T-reg cell infiltration may not be sufficient to control Th2 inflammatory responses in CRSwNP.

    Article  PubMed  CAS  Google Scholar 

  26. Thunberg S, Akdis M, Akdis CA, et al. Immune regulation by CD4 + CD25+ T cells and interleukin-10 in birch pollen-allergic patients and non-allergic controls. Clin Exp Allergy. 2007;37:1127–36.

    Article  PubMed  CAS  Google Scholar 

  27. Malmhäll C, Bossios A, Pullerits T, Lötvall J. Effects of pollen and nasal glucocorticoid on FOXP3+, GATA-3+ and T-bet+ cells in allergic rhinitis. Allergy. 2007;62:1007–13.

    Article  PubMed  Google Scholar 

  28. Smyth LJ, Eustace A, Kolsum U, Blaikely J, Singh D. Increased airway T regulatory cells in asthmatic subjects. Chest. 2010;138:905–12.

    Article  PubMed  Google Scholar 

  29. Soyka MB, Wawrzyniak P, Eiwegger T, et al. Defective epithelial barrier in chronic rhinosinusitis: The regulation of tight junctions by IFN-γ and IL-4. J Allergy Clin Immunol. 2012;Epud. This study demonstrated the down-regulation of tight junction proteins in epithelium from CRS mucosa, indicating the defect of epithelial barrier function.

  30. Tieu DD, Peters AT, Carter RG, et al. Evidence for diminished levels of epithelial psoriasin and calprotectin in chronic rhinosinusitis. J Allergy Clin Immunol. 2010;125:667–75.

    Article  PubMed  CAS  Google Scholar 

  31. Månsson A, Bogefors J, Cervin A, Uddman R, Cardell LO. NOD-like receptors in the human upper airways: a potential role in nasal polyposis. Allergy. 2011;66:621–8.

    Article  PubMed  Google Scholar 

  32. Dong Z, Yang Z, Wang C. Expression of TLR2 and TLR4 messenger RNA in the epithelial cells of the nasal airway. Am J Rhinol Allergy. 2005;19:236–9.

    Google Scholar 

  33. Lane AP, Truong-Tran QA, Schleimer RP. Altered expression of genes associated with innate immunity and inflammation in recalcitrant rhinosinusitis with polyps. Am J Rhinol Allergy. 2006;20:138–44.

    Google Scholar 

  34. Ramanathan Jr M, Lee WK, Dubin MG, Lin S, Spannhake EW, Lane AP. Sinonasal epithelial cell expression of toll-like receptor 9 is decreased in chronic rhinosinusitis with polyps. Am J Rhinol. 2007;21:110–6.

    Article  PubMed  Google Scholar 

  35. Lai Y, Chen B, Shi J, Palmer JN, Kennedy DW, Cohen NA. Inflammation-mediated upregulation of centrosomal protein 110, a negative modulator of ciliogenesis, in patients with chronic rhinosinusitis. J Allergy Clin Immunol. 2011;128:1207–51. This study showed an increase of ciliogenesis inhibitor CP110 in epithelial cells isolated from CRS muocsa, indicating the poor ciliation in CRS.

    Article  PubMed  CAS  Google Scholar 

  36. Yu F, Zhao X, Li C, et al. Airway stem cells: review of potential impact on understanding of upper airway diseases. Laryngoscope. 2012;122:1463–9. This review paper summarized the updated information on the roles of airway stem cells in epithelial repair and remodeling in healthy and pathological conditions.

    Article  PubMed  Google Scholar 

  37. Rock JR, Gao X, Xue Y, Randell SH, Kong YY, Hogan BL. Notch-dependent differentiation of adult airway basal stem cells. Cell Stem Cell. 2011;8:639–48.

    Article  PubMed  CAS  Google Scholar 

  38. Li C, Li A, Li M, et al. Stabilized beta-catenin in lung epithelial cells changes cell fate and leads to tracheal and bronchial polyposis. Dev Biol. 2009;334:97–108.

    Article  PubMed  CAS  Google Scholar 

  39. • Li CW, Cheung W, Lin ZB, Li TY, Lim JT, Wang DY. Oral steroids enhance epithelial repair in nasal polyposis via upregulation of the AP-1 gene network. Thorax. 2009;64:306–12. This study provided an evidence that a decrease of AP-1 gene network in CRSwNP which could be related to damage of epithelium and suggested the wound healing effects of steroid treatment.

  40. Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol. 1997;9:240–6.

    Article  PubMed  CAS  Google Scholar 

  41. Grose R. Epithelial migration: open your eyes to c-Jun. Curr Biol. 2003;13:R678–680.

    Article  PubMed  CAS  Google Scholar 

  42. Li G, Gustafson-Brown C, Hanks SK, et al. c-Jun is essential for organization of the epidermal leading edge. Dev Cell. 2003;4:865–77.

    Article  PubMed  CAS  Google Scholar 

  43. Savla U, Appel HJ, Sporn PH, Waters CM. Prostaglandin E(2) regulates wound closure in airway epithelium. Am J physiol Lung Cell Mol Physiol. 2001;280:L421–431.

    PubMed  CAS  Google Scholar 

  44. •• Holgate ST. Epithelial damage and response. Clin Exp Allergy. 2000;30:37–41. The review discussed comprehensively the molecular pathways and concenpt of epithelial remodeling process in chronic inflammatory airway tissues.

  45. Kolliputi N, Waxman AB. IL-6 cytoprotection in hyperoxic acute lung injury occurs via suppressor of cytokine signaling-1-induced apoptosis signal-regulating kinase-1 degradation. Am J Respir Cell Mol Biol. 2009;40:314–24.

    Article  PubMed  CAS  Google Scholar 

  46. Gallucci RM, Simeonova PP, Matheson JM, et al. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J. 2000;14:2525–31.

    Article  PubMed  CAS  Google Scholar 

  47. Nechemia-Arbely Y, Barkan D, Pizov G, et al. IL-6/IL-6R axis plays a critical role in acute kidney injury. J Am Soc Nephrol. 2008;19:1106–15.

    Article  PubMed  CAS  Google Scholar 

  48. Liu L, Tsai JC, Aird WC. Egr-1 gene is induced by the systemic administration of the vascular endothelial growth factor and the epidermal growth factor. Blood. 2000;96:1172–81.

    Google Scholar 

  49. Warburton G, Nares S, Angelov N, Brahim JS, Dionne RA, Wahl SM. Transcriptional events in a clinical model of oral mucosal tissue injury and repair. Wound Repair Regen. 2005;13:19–26.

    Article  PubMed  Google Scholar 

  50. Pace E, Scafidi V, Di Bona D, et al. Increased expression of IL-19 in the epithelium of patients with chronic rhinosinusitis and nasal polyps. Allergy. 2012;67:878–86.

    Article  PubMed  CAS  Google Scholar 

  51. Gosepath J, Brieger J, Lehr HA, Mann WJ. Expression, localization, and significance of vascular permeability/vascular endothelial growth factor in nasal polyps. Am J Rhinol Allergy. 2005;19:7–13.

    Google Scholar 

  52. Wittekindt C, Hess A, Bloch W, Sultanie S, Michel O. Immunohistochemical expression of VEGF and VEGF receptors in nasal polyps as compared to normal turbinate mucosa. Eur Arch Otorhinolaryngol. 2002;259:294–8.

    PubMed  Google Scholar 

  53. Lee HS, Myers A, Kim J. Vascular endothelial growth factor drives autocrine epithelial cell proliferation and survival in chronic rhinosinusitis with nasal polyposis. Am J Respir Crit Care Med. 2009;180:1056–67.

    Article  PubMed  CAS  Google Scholar 

  54. Li CW, Shi L, Zhang KK, et al. Role of p63/p73 in epithelial remodeling and their response to steroid treatment in nasal polyposis. J Allergy Clin Immunol. 2011;127:765–72. This study demonstrated for the first time that the increase of p63 was related to epithelial remodeling in CRSwNP, which can be suppressed by steroid treatment.

    Article  PubMed  CAS  Google Scholar 

  55. Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294:1871–5.

    Article  PubMed  CAS  Google Scholar 

  56. Steinke JW, Bradley D, Arango P, et al. Cysteinyl leukotriene expression in chronic hyperplastic sinusitis-nasal polyposis: importance to eosinophilia and asthma. J Allergy Clin Immunol. 2003;111:342–9.

    Article  PubMed  CAS  Google Scholar 

  57. • Pérez-Novo CA, Watelet JB, Claeys C, Van Cauwenberge P, Bachert C. Prostaglandin, leukotriene, and lipoxin balance in chronic rhinosinusitis with and without nasal polyposis. J Allergy Clin Immunol. 2005;115:1189–96. The study showed the alterations of eicosanoid metabolism molecules in CRS.

  58. Sousa AR, Parikh A, Scadding G, Corrigan CJ, Lee TH. Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med. 2002;347:1493–9.

    Article  PubMed  CAS  Google Scholar 

  59. Pérez-Novo CA, Claeys C, Van Cauwenberge P, Bachert C. Expression of eicosanoid receptors subtypes and eosinophilic inflammation: implication on chronic rhinosinusitis. Respir Res. 2006;12:75.

    Article  Google Scholar 

  60. Holgate ST, Peters-Golden M, Panettieri RA, Jr Henderson WR. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J Allergy Clin Immunol. 2003;111:S18–34.

    Article  PubMed  CAS  Google Scholar 

  61. Gervais FG, Cruz RP, Chateauneuf A, et al. Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP. J Allergy Clin Immunol. 2001;108:982–8.

    Article  PubMed  CAS  Google Scholar 

  62. Pérez-Novo CA, Holtappels G, Vinall SL, et al. CRTH2 mediates the activation of human Th2 cells in response to PGD(2) released from IgE/anti-IgE treated nasal polyp tissue. Allergy. 2010;65:304–10.

    Article  PubMed  Google Scholar 

  63. Okano M, Fujiwara T, Yamamoto M, et al. Role of prostaglandin D2 and E2 terminal synthases in chronic rhinosinusitis. Clin Exp Allergy. 2006;36:1028–38.

    Article  PubMed  CAS  Google Scholar 

  64. Hyo S, Kawata R, Kadoyama K, et al. Expression of prostaglandin D2 synthase in activated eosinophils in nasal polyps. Arch Otolaryngol Head Neck Surg. 2007;133:693–700.

    Article  PubMed  Google Scholar 

  65. Yamamoto M, Okano M, Fujiwara T, et al. Expression and characterization of PGD2 receptors in chronic rhinosinusitis: modulation of DP and CRTH2 by PGD2. Int Arch Allergy Immunol. 2009;148:127–36.

    Article  PubMed  CAS  Google Scholar 

  66. Fortner CN, Breyer RM, Paul RJ. EP2 receptors mediate airway relaxation to substance P, ATP, and PGE2. Am J physiol Lung Cell Mol Physiol. 2001;281:L469–474.

    PubMed  CAS  Google Scholar 

  67. Picado C, Fernandez-Morata JC, Juan M, et al. Cyclooxygenase-2 mRNA is downexpressed in nasal polyps from aspirin-sensitive asthmatics. Am J Respir Crit Care Med. 1999;160:291–6.

    PubMed  CAS  Google Scholar 

  68. Mullol J, Fernàndez-Morata JC, Roca-Ferrer J, et al. Cyclooxygenase 1 and cyclooxygenase 2 expression is abnormally regulated in human nasal polyps. J Allergy Clin Immunol. 2002;109:824–30.

    Article  PubMed  CAS  Google Scholar 

  69. • Mastruzzo C, Greco LR, Nakano K, et al. Impact of intranasal budesonide on immune inflammatory responses and epithelial remodeling in chronic upper airway inflammation. J Allergy Clin Immunol. 2003;112:37–44. The study demonstrated the molecular pathways and benificial effects of steroid on epithelial remodeling in CRS.

  70. Woodworth BA, Joseph K, Kaplan AP, Schlosser RJ. Alterations in eotaxin, monocyte chemoattractant protein-4, interleukin-5, and interleukin-13 after systemic steroid treatment for nasal polyps. Otolaryngol Head Neck Surg. 2004;131:585–9.

    Article  PubMed  Google Scholar 

  71. Zhang XH, Lu X, Long XB, et al. Chronic rhinosinusitis with and without nasal polyps is associated with decreased expression of glucocorticoid-induced leucine zipper. Clin Exp Allergy. 2009;39:647–54.

    Article  PubMed  CAS  Google Scholar 

  72. Liu Z, Lu X, Zhang XH, et al. Clara cell 10-kDa protein expression in chronic rhinosinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy. 2009;64:149–57.

    Article  PubMed  CAS  Google Scholar 

  73. Pujols L, Benitez P, Alobid I, et al. Glucocorticoid therapy increases COX-2 gene expression in nasal polyps in vivo. Eur Respir J. 2009;33:502–8.

    Article  PubMed  CAS  Google Scholar 

  74. Wadsworth SJ, Nijmeh HS, Hall IP. Glucocorticoids increase repair potential in a novel in vitro human airway epithelial wounding model. J Clin Immunol. 2006;26:376–87.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Medical Research Council (NMRC, IRG10may086), from Singapore Immunology Network (SIgN, SIgN 10-028) of Singapore, and from the National Nature Science Foundation of China (no. 81170897).

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore, 119228, Singapore

    Chunwei Li, Yan Yan & De-Yun Wang

  2. Department of Otolaryngology, Qilu Hospital, Shandong University, 44 Wenhua West Road, Jinan, Shandong, People’s Republic of China, 250012

    Li Shi

  3. Department of Otology and Laryngology, Harvard University, Massachusetts Eye and Ear Infirmary, Boston, and Division of Otolaryngology, Cape Cod Hospital, Hyannis, MA, USA

    Bruce R. Gordon

  4. Department of Medicine and Biological Chemistry, University of California, Irvine, CA, USA

    William M. Gordon

Authors
  1. Chunwei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bruce R. Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William M. Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. De-Yun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Li Shi or De-Yun Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, C., Shi, L., Yan, Y. et al. Gene Expression Signatures: A New Approach to Understanding the Pathophysiology of Chronic Rhinosinusitis. Curr Allergy Asthma Rep 13, 209–217 (2013). https://doi.org/10.1007/s11882-012-0328-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-012-0328-6

Keywords

Search

Navigation