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Mucus composition abnormalities in sinonasal mucosa of chronic rhinosinusitis with and without nasal polyps

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Abstract

Mucus secretion and its composition are vital in the maintenance of airway health, among which hypoxia-inducible factors (HIFs) are thought to be involved in the regulation of mucin synthesis and regulation. Nasal mucus composition difference between healthy individuals and chronic rhinosinusitis (CRS) patients may contribute to the pathology of chronic nasal diseases, but so far, their role has yet to be completely understood. Nasal biopsy specimens were obtained from 24 healthy subjects and 99 patients with CRS without (CRSsNP, n=36) or with (CRSwNP, n=63) nasal polyps. Immunohistochemical (IHC) and immunofluorescent (IF) staining, quantitative real-time PCR, and western blot were performed to compare the nasal mucus composition between the subjects. Areas of the serous gland and mucous gland were both significantly increased in CRSsNP patients. In CRSwNP patients, a decrease in submucosal gland density and a marked increase in goblet cells were observed. The major gel-forming mucins in the sinonasal mucosa of CRSsNP and CRSwNP are MUC5B and MUC5AC respectively. Mucous cells are found in a higher proportion in both CRSsNP and CRSwNP. The proportion of MUC5AC-positive goblet cells was increased in CRSwNP. The mRNA level of HIF-2α was significantly increased in CRS, and both HIF-1α and HIF-2α were expressed in serous cell but not mucous cell. Over secretion and altered composition of mucus are observed in sinonasal mucosa of CRS, which was mainly associated with glandular hyperplasia in CRSsNP and goblet cell hyperplasia in CRSwNP. Mucus abnormality compromised both non-specific and specific antimicrobial capabilities in the sinonasal mucosa. HIF expression may contribute to differences in mucin synthesis and serous gland regulation, which needs further investigation to understand the pathology of CRS.

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References

  1. Kaliner, M., Z. Marom, C. Patow, and J. Shelhamer. 1984. Human respiratory mucus. The Journal of Allergy and Clinical Immunology 73: 318–323.

    Article  CAS  PubMed  Google Scholar 

  2. Lee, R.J., and J.K. Foskett. 2010. Mechanisms of Ca2+-stimulated fluid secretion by porcine bronchial submucosal gland serous acinar cells. American Journal of Physiology. Lung Cellular and Molecular Physiology 298: L210–L231.

    Article  CAS  PubMed  Google Scholar 

  3. May, A.J., T.H.N. Teshima, A. Noble, and A.S. Tucker. 2019. FGF10 is an essential regulator of tracheal submucosal gland morphogenesis. Developmental Biology 451: 158–166.

    Article  CAS  PubMed  Google Scholar 

  4. Raphael, G.D., E.V. Jeney, J.N. Baraniuk, I. Kim, S.D. Meredith, and M.A. Kaliner. 1989. Pathophysiology of rhinitis. Lactoferrin and lysozyme in nasal secretions. The Journal of Clinical Investigation 84: 1528–1535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Finkbeiner, W.E. 1999. Physiology and pathology of tracheobronchial glands. Respiration Physiology 118: 77–83.

    Article  CAS  PubMed  Google Scholar 

  6. Lundgren, J.D., and J.H. Shelhamer. 1990. Pathogenesis of airway mucus hypersecretion. The Journal of Allergy and Clinical Immunology 85: 399–417.

    Article  CAS  PubMed  Google Scholar 

  7. Schraven, S.P., M. Wehrmann, W. Wagner, G. Blumenstock, and A. Koitschev. 2011. Prevalence and histopathology of chronic polypoid sinusitis in pediatric patients with cystic fibrosis. Journal of Cystic Fibrosis 10: 181–186.

    Article  PubMed  Google Scholar 

  8. Wu, X., M.M. Amorn, P.K. Aujla, S. Rice, R. Mimms, A.M. Watson, J.R. Peters-Hall, M.C. Rose, and M.T. Peña. 2011. Histologic characteristics and mucin immunohistochemistry of cystic fibrosis sinus mucosa. Archives of Otolaryngology – Head & Neck Surgery 137: 383–389.

    Article  Google Scholar 

  9. Fokkens, W.J., V.J. Lund, C. Hopkins, P.W. Hellings, R. Kern, S. Reitsma, et al. 2020. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology 58: 1–464.

    Article  PubMed  Google Scholar 

  10. Van Bruaene, N., and C. Bachert. 2011. Tissue remodeling in chronic rhinosinusitis. Current Opinion in Allergy and Clinical Immunology 11: 8–11.

    Article  PubMed  Google Scholar 

  11. Cummins, E.P., E. Berra, K.M. Comerford, A. Ginouves, K.T. Fitzgerald, F. Seeballuck, C. Godson, J.E. Nielsen, P. Moynagh, J. Pouyssegur, and C.T. Taylor. 2006. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proceedings of the National Academy of Sciences of the United States of America 103: 18154–18159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kaelin, W.G., Jr., and P.J. Ratcliffe. 2008. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Molecular Cell 30: 393–402.

    Article  CAS  PubMed  Google Scholar 

  13. Khalmuratova, R., M. Lee, J.H. Mo, Y. Jung, J.W. Park, and H.W. Shin. 2018. Wogonin attenuates nasal polyp formation by inducing eosinophil apoptosis through HIF-1alpha and survivin suppression. Scientific Reports 8: 6201.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Shin, H.W., K. Cho, D.W. Kim, D.H. Han, R. Khalmuratova, S.W. Kim, S.Y. Jeon, Y.G. Min, C.H. Lee, C.S. Rhee, and J.W. Park. 2012. Hypoxia-inducible factor 1 mediates nasal polypogenesis by inducing epithelial-to-mesenchymal transition. American Journal of Respiratory and Critical Care Medicine 185: 944–954.

    Article  CAS  PubMed  Google Scholar 

  15. Lee, M., D.W. Kim, H. Yoon, D. So, R. Khalmuratova, C.S. Rhee, et al. 2016. Sirtuin 1 attenuates nasal polypogenesis by suppressing epithelial-to-mesenchymal transition. The Journal of Allergy and Clinical Immunology 137: 87–98 e7.

    Article  CAS  PubMed  Google Scholar 

  16. Song, G., J. Kim, F.W. Bazer, and T.E. Spencer. 2008. Progesterone and interferon tau regulate hypoxia-inducible factors in the endometrium of the ovine uterus. Endocrinology 149: 1926–1934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Terrizzi, A.R., M.I. Conti, M.P. Martinez, and J. Fernandez-Solari. 2018. The process of acclimation to chronic hypoxia leads to submandibular gland and periodontal alterations: an insight on the role of inflammatory mediators. Mediators of Inflammation 2018: 6794508.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Leopold, D.A., D. Elkayam, J.C. Messina, C. Kosik-Gonzalez, P.G. Djupesland, and R.A. Mahmoud. 2019. NAVIGATE II: Randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis. The Journal of Allergy and Clinical Immunology 143: 126–34 e5.

    Article  CAS  PubMed  Google Scholar 

  19. Lildholdt, T., H. Rundcrantz, and N. Lindqvist. 1995. Efficacy of topical corticosteroid powder for nasal polyps: a double-blind, placebo-controlled study of budesonide. Clinical Otolaryngology and Allied Sciences 20: 26–30.

    Article  CAS  PubMed  Google Scholar 

  20. Payne, S.C., S.B. Early, P. Huyett, J.K. Han, L. Borish, and J.W. Steinke. 2011. Evidence for distinct histologic profile of nasal polyps with and without eosinophilia. Laryngoscope 121: 2262–2267.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kiwamoto, T., T. Katoh, C.M. Evans, W.J. Janssen, M.E. Brummet, S.A. Hudson, et al. 2015. Endogenous airway mucins carry glycans that bind Siglec-F and induce eosinophil apoptosis. The Journal of Allergy and Clinical Immunology 135: 1329–40 e9.

    Article  CAS  PubMed  Google Scholar 

  22. Berger, G., T. Kogan, D. Ophir, E. Skutelsky, and K. Pitaro. 2008. Glycoconjugate expression of sinus mucosa in chronic rhinosinusitis: a lectin histochemical study. American Journal of Rhinology 22: 349–355.

    Article  PubMed  Google Scholar 

  23. Burgel, P.R., E. Escudier, A. Coste, T. Dao-Pick, I.F. Ueki, K. Takeyama, J.J. Shim, A.H. Murr, and J.A. Nadel. 2000. Relation of epidermal growth factor receptor expression to goblet cell hyperplasia in nasal polyps. The Journal of Allergy and Clinical Immunology 106: 705–712.

    Article  CAS  PubMed  Google Scholar 

  24. Liu, J., Y.Y. Li, A.K. Andiappan, Y. Yan, K.S. Tan, H.H. Ong, K.T. Thong, Y.K. Ong, F.G. Yu, H.B. Low, Y.L. Zhang, L. Shi, and D.Y. Wang. 2018. Role of IL-13Ralpha2 in modulating IL-13-induced MUC5AC and ciliary changes in healthy and CRSwNP mucosa. Allergy 73: 1673–1685.

    Article  CAS  PubMed  Google Scholar 

  25. Kirkham, S., J.K. Sheehan, D. Knight, P.S. Richardson, and D.J. Thornton. 2002. Heterogeneity of airways mucus: variations in the amounts and glycoforms of the major oligomeric mucins MUC5AC and MUC5B. Biochemical Journal 361: 537–546.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Zhao, J., B. Maskrey, S. Balzar, K. Chibana, A. Mustovich, H. Hu, J.B. Trudeau, V. O'Donnell, and S.E. Wenzel. 2009. Interleukin-13-induced MUC5AC is regulated by 15-lipoxygenase 1 pathway in human bronchial epithelial cells. American Journal of Respiratory and Critical Care Medicine 179: 782–790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mansson, A., M. Adner, U. Hockerfelt, and L.O. Cardell. 2006. A distinct Toll-like receptor repertoire in human tonsillar B cells, directly activated by PamCSK, R-837 and CpG-2006 stimulation. Immunology 118: 539–548.

    PubMed  PubMed Central  Google Scholar 

  28. Rousseau, K., C. Wickstrom, D.B. Whitehouse, I. Carlstedt, and D.M. Swallow. 2003. New monoclonal antibodies to non-glycosylated domains of the secreted mucins MUC5B and MUC7. Hybridoma and Hybridomics 22: 293–299.

    Article  CAS  PubMed  Google Scholar 

  29. Ramsey KA, Rushton ZL, Ehre C (2016) Mucin agarose gel electrophoresis: western blotting for high-molecular-weight glycoproteins. Journal of Visualized Experiments 112: e54153.

  30. Basbaum, C.B., B. Jany, and W.E. Finkbeiner. 1990. The serous cell. Annual Review of Physiology 52: 97–113.

    Article  CAS  PubMed  Google Scholar 

  31. Jolles, P., and J. Jolles. 1984. What's new in lysozyme research? Always a model system, today as yesterday. Molecular and Cellular Biochemistry 63: 165–189.

    Article  CAS  PubMed  Google Scholar 

  32. Woods, C.M., V.S. Lee, D.J. Hussey, S. Irandoust, E.H. Ooi, L.W. Tan, and A.S. Carney. 2012. Lysozyme expression is increased in the sinus mucosa of patients with chronic rhinosinusitis. Rhinology 50: 147–156.

    Article  CAS  PubMed  Google Scholar 

  33. De Rose, V., K. Molloy, S. Gohy, C. Pilette, and C.M. Greene. 2018. Airway epithelium dysfunction in cystic fibrosis and COPD. Mediators of Inflammation 2018: 1309746.

    PubMed  PubMed Central  Google Scholar 

  34. Land, L.M., P. Li, and P.M. Bummer. 2005. The influence of water content of triglyceride oils on the solubility of steroids. Pharmaceutical Research 22: 784–788.

    Article  CAS  PubMed  Google Scholar 

  35. Van Crombruggen, K., N. Zhang, P. Gevaert, P. Tomassen, and C. Bachert. 2011. Pathogenesis of chronic rhinosinusitis: inflammation. The Journal of Allergy and Clinical Immunology 128: 728–732.

    Article  PubMed  CAS  Google Scholar 

  36. Fitzpatrick, S.F., M.M. Tambuwala, U. Bruning, B. Schaible, C.C. Scholz, A. Byrne, A. O’Connor, W.M. Gallagher, C.R. Lenihan, J.F. Garvey, K. Howell, P.G. Fallon, E.P. Cummins, and C.T. Taylor. 2011. An intact canonical NF-kappaB pathway is required for inflammatory gene expression in response to hypoxia. Journal of Immunology 186: 1091–1096.

    Article  CAS  Google Scholar 

  37. Rius, J., M. Guma, C. Schachtrup, K. Akassoglou, A.S. Zinkernagel, V. Nizet, R.S. Johnson, G.G. Haddad, and M. Karin. 2008. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453: 807–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Murdoch, C., A. Giannoudis, and C.E. Lewis. 2004. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104: 2224–2234.

    Article  CAS  PubMed  Google Scholar 

  39. Peyssonnaux, C., V. Datta, T. Cramer, A. Doedens, E.A. Theodorakis, R.L. Gallo, N. Hurtado-Ziola, V. Nizet, and R.S. Johnson. 2005. HIF-1alpha expression regulates the bactericidal capacity of phagocytes. The Journal of Clinical Investigation 115: 1806–1815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Polosukhin, V.V., J.M. Cates, W.E. Lawson, A.P. Milstone, A.G. Matafonov, P.P. Massion, J.W. Lee, S.H. Randell, and T.S. Blackwell. 2011. Hypoxia-inducible factor-1 signalling promotes goblet cell hyperplasia in airway epithelium. The Journal of Pathology 224: 203–211.

    Article  CAS  PubMed  Google Scholar 

  41. Zhou, X., J. Tu, Q. Li, V.P. Kolosov, and J.M. Perelman. 2012. Hypoxia induces mucin expression and secretion in human bronchial epithelial cells. Translational Research 160: 419–427.

    Article  CAS  PubMed  Google Scholar 

  42. Yu, H., Q. Li, V.P. Kolosov, J.M. Perelman, and X. Zhou. 2012. Regulation of cigarette smoke-mediated mucin expression by hypoxia-inducible factor-1alpha via epidermal growth factor receptor-mediated signaling pathways. Journal of Applied Toxicology 32: 282–292.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by grants from the National Medical Research Council (NMRC/CIRG/1458/2016), Singapore (to D-YW); The Major Research Development Program of Shandong Province No.2016GSF201084 (to LS), National Nature Science Foundation of China No.81873692 (to LS); Dr Tan Kai Sen is a recipient of fellowship support from European Allergy and Clinical Immunology (EAACI) Research Fellowship 2019.

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Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital Affiliated to Shandong University, No. 4 Duanxing West Road, Jinan, 250000, Shandong, China

    Yanyi Tu, Tao Li, Xiangmin Zhou, Kaiyue Sun, Yi Ouyang, Xu Liang & Li Shi

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

    Yanyi Tu, Jing Liu, Tao Li, Xiangmin Zhou, Kai Sen Tan, Hsiao Hui Ong & De-Yun Wang

  3. Department of Otolaryngology, Head & Neck Surgery, National University Health System, Singapore, Singapore

    Yew Kwang Ong & Mark Thong

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  1. Yanyi Tu
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Contributions

Experiments design: D-y W, LS, JL, and Y-y T. Sample collection: K-y S, YO, XL, Y-k O, and MT. Conducting experiments: Y-y T, TL, and X-m Z. Data analysis: Y-y T, KS T, and H-h O. Drafting and revising the manuscript: All authors have read and agreed to the final version of the manuscript.

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Correspondence to Li Shi or De-Yun Wang.

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The Institutional Review Boards of the Second Hospital of Shandong University in China (KYLL-2018(KJ) P-0025), and the National Healthcare Group Domain-Specific Board of Singapore (DSRB Ref: D/11/228) both approved this study.

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Tu, Y., Liu, J., Li, T. et al. Mucus composition abnormalities in sinonasal mucosa of chronic rhinosinusitis with and without nasal polyps. Inflammation 44, 1937–1948 (2021). https://doi.org/10.1007/s10753-021-01471-6

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