Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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The Role of Proprotein Convertases in Upper Airway Remodeling

  • Lee, Sang-Nam (The Airway Mucus Institute, Yonsei University College of Medicine) ;
  • Yoon, Joo-Heon (The Airway Mucus Institute, Yonsei University College of Medicine)
  • Received : 2022.02.02
  • Accepted : 2022.02.27
  • Published : 2022.06.30
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Abstract

Chronic rhinosinusitis (CRS) is a multifactorial, heterogeneous disease characterized by persistent inflammation of the sinonasal mucosa and tissue remodeling, which can include basal/progenitor cell hyperplasia, goblet cell hyperplasia, squamous cell metaplasia, loss or dysfunction of ciliated cells, and increased matrix deposition. Repeated injuries can stimulate airway epithelial cells to produce inflammatory mediators that activate epithelial cells, immune cells, or the epithelial-mesenchymal trophic unit. This persistent inflammation can consequently induce aberrant tissue remodeling. However, the molecular mechanisms driving disease within the different molecular CRS subtypes remain inadequately characterized. Numerous secreted and cell surface proteins relevant to airway inflammation and remodeling are initially synthesized as inactive precursor proteins, including growth/differentiation factors and their associated receptors, enzymes, adhesion molecules, neuropeptides, and peptide hormones. Therefore, these precursor proteins require post-translational cleavage by proprotein convertases (PCs) to become fully functional. In this review, we summarize the roles of PCs in CRS-associated tissue remodeling and discuss the therapeutic potential of targeting PCs for CRS treatment.

Keywords

Acknowledgement

This research was supported by the Global Research Lab Program of the National Research Foundation of Korea, funded by the Ministry of Science, ICT (Information and Communication Technologies), and Future Planning (2016K1A1A2910779 to J.-H.Y.), and by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Education (2016R1D1A1B01007747 to S.-N.L.).

References

  1. Araya, J., Cambier, S., Markovics, J.A., Wolters, P., Jablons, D., Hill, A., Finkbeiner, W., Jones, K., Broaddus, V.C., Sheppard, D., et al. (2007). Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients. J. Clin. Invest. 117, 3551-3562. https://doi.org/10.1172/JCI32526
  2. Artenstein, A.W. and Opal, S.M. (2011). Proprotein convertases in health and disease. N. Engl. J. Med. 365, 2507-2518. https://doi.org/10.1056/NEJMra1106700
  3. Ashley, S.L., Wilke, C.A., Kim, K.K., and Moore, B.B. (2017). Periostin regulates fibrocyte function to promote myofibroblast differentiation and lung fibrosis. Mucosal Immunol. 10, 341-351. https://doi.org/10.1038/mi.2016.61
  4. Auerbach, O., Stout, A.P., Hammond, E.C., and Garfinkel, L. (1961). Changes in bronchial epithelium in relation to cigarette smoking and in relation to lung cancer. N. Engl. J. Med. 265, 253-267. https://doi.org/10.1056/NEJM196108102650601
  5. Bassiouni, A., Chen, P.G., and Wormald, P.J. (2013). Mucosal remodeling and reversibility in chronic rhinosinusitis. Curr. Opin. Allergy Clin. Immunol. 13, 4-12. https://doi.org/10.1097/ACI.0b013e32835ad09e
  6. Becker, G.L., Lu, Y., Hardes, K., Strehlow, B., Levesque, C., Lindberg, I., Sandvig, K., Bakowsky, U., Day, R., Garten, W., et al. (2012). Highly potent inhibitors of proprotein convertase furin as potential drugs for treatment of infectious diseases. J. Biol. Chem. 287, 21992-22003. https://doi.org/10.1074/jbc.M111.332643
  7. Becker, G.L., Sielaff, F., Than, M.E., Lindberg, I., Routhier, S., Day, R., Lu, Y., Garten, W., and Steinmetzer, T. (2010). Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics. J. Med. Chem. 53, 1067-1075. https://doi.org/10.1021/jm9012455
  8. Botchkarev, V.A. (2003). Bone morphogenetic proteins and their antagonists in skin and hair follicle biology. J. Invest. Dermatol. 120, 36-47. https://doi.org/10.1046/j.1523-1747.2003.12002.x
  9. Boudreault, A., Gauthier, D., and Lazure, C. (1998). Proprotein convertase PC1/3-related peptides are potent slow tight-binding inhibitors of murine PC1/3 and Hfurin. J. Biol. Chem. 273, 31574-31580. https://doi.org/10.1074/jbc.273.47.31574
  10. Byun, S., Tortorella, M.D., Malfait, A.M., Fok, K., Frank, E.H., and Grodzinsky, A.J. (2010). Transport and equilibrium uptake of a peptide inhibitor of PACE4 into articular cartilage is dominated by electrostatic interactions. Arch. Biochem. Biophys. 499, 32-39. https://doi.org/10.1016/j.abb.2010.04.019
  11. Camara, J. and Jarai, G. (2010). Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-α. Fibrogenesis Tissue Repair 3, 2. https://doi.org/10.1186/1755-1536-3-2
  12. Cao, P.P., Li, H.B., Wang, B.F., Wang, S.B., You, X.J., Cui, Y.H., Wang, D.Y., Desrosiers, M., and Liu, Z. (2009). Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J. Allergy Clin. Immunol. 124, 478-484.e2. https://doi.org/10.1016/j.jaci.2009.05.017
  13. Chand, H.S., Woldegiorgis, Z., Schwalm, K., McDonald, J., and Tesfaigzi, Y. (2012). Acute inflammation induces insulin-like growth factor-1 to mediate Bcl-2 and Muc5ac expression in airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 47, 784-791. https://doi.org/10.1165/rcmb.2012-0079OC
  14. Cheng, M., Xu, N., Iwasiow, B., Seidah, N., Chretien, M., and Shiu, R.P. (2001). Elevated expression of proprotein convertases alters breast cancer cell growth in response to estrogen and tamoxifen. J. Mol. Endocrinol. 26, 95-105. https://doi.org/10.1677/jme.0.0260095
  15. Chiba, S. (2006). Concise review: Notch signaling in stem cell systems. Stem Cells 24, 2437-2447. https://doi.org/10.1634/stemcells.2005-0661
  16. Chretien, M., Seidah, N.G., Basak, A., and Mbikay, M. (2008). Proprotein convertases as therapeutic targets. Expert Opin. Ther. Targets 12, 1289-1300. https://doi.org/10.1517/14728222.12.10.1289
  17. Constam, D.B., Calfon, M., and Robertson, E.J. (1996). SPC4, SPC6, and the novel protease SPC7 are coexpressed with bone morphogenetic proteins at distinct sites during embryogenesis. J. Cell Biol. 134, 181-191. https://doi.org/10.1083/jcb.134.1.181
  18. Coppola, J.M., Bhojani, M.S., Ross, B.D., and Rehemtulla, A. (2008). A small-molecule furin inhibitor inhibits cancer cell motility and invasiveness. Neoplasia 10, 363-370. https://doi.org/10.1593/neo.08166
  19. Couture, F., D'Anjou, F., Desjardins, R., Boudreau, F., and Day, R. (2012). Role of proprotein convertases in prostate cancer progression. Neoplasia 14, 1032-1042. https://doi.org/10.1593/neo.121368
  20. Dahms, S.O., Haider, T., Klebe, G., Steinmetzer, T., and Brandstetter, H. (2021). OFF-state-specific inhibition of the proprotein convertase furin. ACS Chem. Biol. 16, 1692-1700. https://doi.org/10.1021/acschembio.1c00411
  21. Davies, D.E. (2009). The role of the epithelium in airway remodeling in asthma. Proc. Am. Thorac. Soc. 6, 678-682. https://doi.org/10.1513/pats.200907-067DP
  22. Fokkens, W.J., Lund, V.J., Mullol, J., Bachert, C., Alobid, I., Baroody, F., Cohen, N., Cervin, A., Douglas, R., Gevaert, P., et al. (2012). EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 50, 1-12. https://doi.org/10.4193/Rhino50E2
  23. Fruth, K., Zhu, C., Schramek, E., Angermair, J., Kassem, W., Haxel, B.R., Schneider, A., Mann, W.J., and Brieger, J. (2012). Vascular endothelial growth factor expression in nasal polyps of aspirin-intolerant patients. Arch. Otolaryngol. Head Neck Surg. 138, 286-293. https://doi.org/10.1001/archoto.2011.1474
  24. Georas, S.N. and Rezaee, F. (2014). Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation. J. Allergy Clin. Immunol. 134, 509-520. https://doi.org/10.1016/j.jaci.2014.05.049
  25. Gerovac, B.J., Valencia, M., Baumlin, N., Salathe, M., Conner, G.E., and Fregien, N.L. (2014). Submersion and hypoxia inhibit ciliated cell differentiation in a Notch-dependent manner. Am. J. Respir. Cell Mol. Biol. 51, 516-525. https://doi.org/10.1165/rcmb.2013-0237OC
  26. Gibson, M.C. and Perrimon, N. (2003). Apicobasal polarization: epithelial form and function. Curr. Opin. Cell Biol. 15, 747-752. https://doi.org/10.1016/j.ceb.2003.10.008
  27. Gomi, K., Arbelaez, V., Crystal, R.G., and Walters, M.S. (2015). Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway. PLoS One 10, e0116507. https://doi.org/10.1371/journal.pone.0116507
  28. Guseh, J.S., Bores, S.A., Stanger, B.Z., Zhou, Q., Anderson, W.J., Melton, D.A., and Rajagopal, J. (2009). Notch signaling promotes airway mucous metaplasia and inhibits alveolar development. Development 136, 1751-1759. https://doi.org/10.1242/dev.029249
  29. Hackett, T.L. (2012). Epithelial-mesenchymal transition in the pathophysiology of airway remodelling in asthma. Curr. Opin. Allergy Clin. Immunol. 12, 53-59. https://doi.org/10.1097/ACI.0b013e32834ec6eb
  30. Hackett, T.L., Warner, S.M., Stefanowicz, D., Shaheen, F., Pechkovsky, D.V., Murray, L.A., Argentieri, R., Kicic, A., Stick, S.M., Bai, T.R., et al. (2009). Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-β. Am. J. Respir. Crit. Care Med. 180, 122-133. https://doi.org/10.1164/rccm.200811-1730OC
  31. Hallenberger, S., Bosch, V., Angliker, H., Shaw, E., Klenk, H.D., and Garten, W. (1992). Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gpl60. Nature 360, 358-361. https://doi.org/10.1038/360358a0
  32. Hogan, B.L.M. (1999). Morphogenesis. Cell 96, 225-233. https://doi.org/10.1016/S0092-8674(00)80562-0
  33. Jackson, A.D. (2001). Airway goblet-cell mucus secretion. Trends Pharmacol. Sci. 22, 39-45. https://doi.org/10.1016/S0165-6147(00)01600-X
  34. Jetten, A.M. (1989). Multistep process of squamous differentiation in tracheobronchial epithelial cells in vitro: analogy with epidermal differentiation. Environ. Health Perspect. 80, 149-160. https://doi.org/10.1289/ehp.8980149
  35. Jiao, G.S., Cregar, L., Wang, J., Millis, S.Z., Tang, C., O'Malley, S., Johnson, A.T., Sareth, S., Larson, J., and Thomas, G. (2006). Synthetic small molecule furin inhibitors derived from 2, 5-dideoxystreptamine. Proc. Natl. Acad. Sci. U. S. A. 103, 19707-19712. https://doi.org/10.1073/pnas.0606555104
  36. Jiao, J., Zhang, T., Zhang, Y., Li, J., Wang, M., Wang, M., Li, Y., Wang, X., and Zhang, L. (2020). Epidermal growth factor upregulates expression of MUC5AC via TMEM16A, in chronic rhinosinusitis with nasal polyps. Allergy Asthma Clin. Immunol. 16, 40. https://doi.org/10.1186/s13223-020-00440-2
  37. Kalluri, R. and Neilson, E.G. (2003). Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 112, 1776-1784. https://doi.org/10.1172/JCI200320530
  38. Kim, J.Y., Lim, S., Lim, H.S., Kim, Y.S., Eun, K.M., Khalmuratova, R., Seo, Y., Kim, J.K., Kim, Y.S., Kim, M.K., et al. (2021). Bone morphogenetic protein-2 as a novel biomarker for refractory chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 148, 461-472.e13. https://doi.org/10.1016/j.jaci.2021.02.027
  39. Klein-Szanto, A.J. and Bassi, D.E. (2017). Proprotein convertase inhibition: paralyzing the cell's master switches. Biochem. Pharmacol. 140, 8-15. https://doi.org/10.1016/j.bcp.2017.04.027
  40. Koch, U. and Radtke, F. (2010). Notch signaling in solid tumors. Curr. Top. Dev. Biol. 92, 411-455. https://doi.org/10.1016/S0070-2153(10)92013-9
  41. Komiyama, T., Coppola, J.M., Larsen, M.J., van Dort, M.E., Ross, B.D., Day, R., Rehemtulla, A., and Fuller, R.S. (2009). Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules. J. Biol. Chem. 284, 15729-15738. https://doi.org/10.1074/jbc.M901540200
  42. Kountakis, S.E., Arango, P., Bradley, D., Wade, Z.K., and Borish, L. (2004). Molecular and cellular staging for the severity of chronic rhinosinusitis. Laryngoscope 114, 1895-1905. https://doi.org/10.1097/01.mlg.0000147917.43615.c0
  43. Kowalska, D., Liu, J., Appel, J.R., Ozawa, A., Nefzi, A., Mackin, R.B., Houghten, R.A., and Lindberg, I. (2009). Synthetic small-molecule prohormone convertase 2 inhibitors. Mol. Pharmacol. 75, 617-625. https://doi.org/10.1124/mol.108.051334
  44. Krein, P.M., Sabatini, P.J.B., Tinmouth, W., Green, F.H.Y., and Winston, B.W. (2003). Localization of insulin-like growth factor-I in lung tissues of patients with fibroproliferative acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 167, 83-90. https://doi.org/10.1164/rccm.2201012
  45. Lee, H.Y., Pyo, J.S., and Kim, S.J. (2021). Distinct patterns of tissue remodeling and their prognostic role in chronic rhinosinusitis. ORL J. Otorhinolaryngol. Relat. Spec. 83, 457-463. https://doi.org/10.1159/000515005
  46. Lee, S.N., Choi, I.S., Kim, H.J., Yang, E.J., Min, H.J., and Yoon, J.H. (2017). Proprotein convertase inhibition promotes ciliated cell differentiation - a potential mechanism for the inhibition of Notch1 signalling by decanoylrvkr-chloromethylketone. J. Tissue Eng. Regen. Med. 11, 2667-2680. https://doi.org/10.1002/term.2240
  47. Lee, S.N., Lee, D.H., Lee, M.G., and Yoon, J.H. (2015). Proprotein convertase 5/6A is associated with bone morphogenetic protein-2-induced squamous cell differentiation. Am. J. Respir. Cell Mol. Biol. 52, 749-761. https://doi.org/10.1165/rcmb.2014-0029OC
  48. Lee, S.N., Lee, D.H., Sohn, M.H., and Yoon, J.H. (2013). Overexpressed proprotein convertase 1/3 induces an epithelial-mesenchymal transition in airway epithelium. Eur. Respir. J. 42, 1379-1390. https://doi.org/10.1183/09031936.00100412
  49. Levesque, C., Fugere, M., Kwiatkowska, A., Couture, F., Desjardins, R., Routhier, S., Moussette, P., Prahl, A., Lammek, B., Appel, J.R., et al. (2012). The Multi-Leu peptide inhibitor discriminates between PACE4 and furin and exhibits antiproliferative effects on prostate cancer cells. J. Med. Chem. 55, 10501-10511. https://doi.org/10.1021/jm3011178
  50. Logeat, F., Bessia, C., Brou, C., LeBail, O., Jarriault, S., Seidah, N.G., and Israel, A. (1998). The Notch1 receptor is cleaved constitutively by a furinlike convertase. Proc. Natl. Acad. Sci. U. S. A. 95, 8108-8112. https://doi.org/10.1073/pnas.95.14.8108
  51. Mahdavinia, M., Suh, L.A., Carter, R.G., Stevens, W.W., Norton, J.E., Kato, A., Tan, B.K., Kern, R.C., Conley, D.B., Chandra, R., et al. (2015). Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia. J. Allergy Clin. Immunol. 135, 576-579. https://doi.org/10.1016/j.jaci.2014.08.031
  52. Majumdar, S., Mohanta, B.C., Chowdhury, D.R., Banik, R., Dinda, B., and Basak, A. (2010). Proprotein convertase inhibitory activities of flavonoids isolated from Oroxylum indicum. Curr. Med. Chem. 17, 2049-2058. https://doi.org/10.2174/092986710791233643
  53. Mani, S.A., Guo, W., Liao, M.J., Eaton, E.N., Ayyanan, A., Zhou, A.Y., Brooks, M., Reinhard, F., Zhang, C.C., Shipitsin, M., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715. https://doi.org/10.1016/j.cell.2008.03.027
  54. Maxfield, A.Z., Landegger, L.D., Brook, C.D., Lehmann, A.E., Campbell, A.P., Bergmark, R.W., Stankovic, K.M., and Metson, R. (2018). Periostin as a biomarker for nasal polyps in chronic rhinosinusitis. Otolaryngol. Head Neck Surg. 158, 181-186. https://doi.org/10.1177/0194599817737967
  55. McDowell, E.M., Keenan, K.P., and Huang, M. (1984). Restoration of mucociliary tracheal epithelium following deprivation of vitamin A. A quantitative morphologic study. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 45, 221-240. https://doi.org/10.1007/BF02889866
  56. Meltzer, E.O., Hamilos, D.L., Hadley, J.A., Lanza, D.C., Marple, B.F., Nicklas, R.A., Bachert, C., Baraniuk, J., Baroody, F.M., Benninger, M.S., et al. (2004). Rhinosinusitis: establishing definitions for clinical research and patient care. J. Allergy Clin. Immunol. 114(6 Suppl), 155-212. https://doi.org/10.1016/j.jaci.2004.09.029
  57. Meng, J., Zhou, P., Liu, Y., Liu, F., Yi, X., Liu, S., Holtappels, G., Bachert, C., and Zhang, N. (2013). The development of nasal polyp disease involves early nasal mucosal inflammation and remodelling. PLoS One 8, e82373. https://doi.org/10.1371/journal.pone.0082373
  58. Muller, L., Cameron, A., Fortenberry, Y., Apletalina, E.V., and Lindberg, I. (2000). Processing and sorting of the prohormone convertase 2 propeptide. J. Biol. Chem. 275, 39213-39222. https://doi.org/10.1074/jbc.m003547200
  59. Nakayama, T., Yoshikawa, M., Asaka, D., Okushi, T., Matsuwaki, Y., Otori, N., Hema, T., and Moriyama, H. (2011). Mucosal eosinophilia and recurrence of nasal polyps-new classification of chronic rhinosinusitis. Rhinology 49, 392-396. https://doi.org/10.4193/Rhino10.261
  60. Park, K.S., Korfhagen, T.R., Bruno, M.D., Kitzmiller, J.A., Wan, H., Wert, S.E., Khurana Hershey, G.K., Chen, G., and Whitsett, J.A. (2007). SPDEF regulates goblet cell hyperplasia in the airway epithelium. J. Clin. Invest. 117, 978-988. https://doi.org/10.1172/JCI29176
  61. Pearton, D.J., Nirunsuksiri, W., Rehemtulla, A., Lewis, S.P., Presland, R.B., and Dale, B.A. (2001). Proprotein convertase expression and localization in epidermis: evidence for multiple roles and substrates. Exp. Dermatol. 10, 193-203. https://doi.org/10.1034/j.1600-0625.2001.010003193.x
  62. Puchelle, E., Zahm, J.M., Tournier, J.M., and Coraux, C. (2006). Airway epithelial repair, regeneration, and remodeling after injury in chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 3, 726-733. https://doi.org/10.1513/pats.200605-126SF
  63. Rand, M.D., Grimm, L.M., Artavanis-Tsakonas, S., Patriub, V., Blacklow, S.C., Sklar, J., and Aster, J.C. (2000). Calcium depletion dissociates and activates heterodimeric Notch receptors. Mol. Cell. Biol. 20, 1825-1835. https://doi.org/10.1128/MCB.20.5.1825-1835.2000
  64. Rock, J.R., Gao, X., Xue, Y., Randell, S.H., Kong, Y.Y., and Hogan, B.L.M. (2011). Notch-dependent differentiation of adult airway basal stem cells. Cell Stem Cell 8, 639-648. https://doi.org/10.1016/j.stem.2011.04.003
  65. Rock, J.R., Randell, S.H., and Hogan, B.L.M. (2010). Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Dis. Model. Mech. 3, 545-556. https://doi.org/10.1242/dmm.006031
  66. Rose, M., Duhamel, M., Aboulouard, S., Kobeissy, F., Le Rhun, E., Desmons, A., Tierny, D., Fournier, I., Rodet, F., and Salzet, M. (2020). The role of a Proprotein Convertase inhibitor in reactivation of tumor-associated macrophages and inhibition of Glioma growth. Mol. Ther. Oncolytics 17, 31-46. https://doi.org/10.1016/j.omto.2020.03.005
  67. Rose, M., Duhamel, M., Rodet, F., and Salzet, M. (2021). The role of proprotein convertases in the regulation of the function of immune cells in the oncoimmune response. Front. immunol. 12, 667850. https://doi.org/10.3389/fimmu.2021.667850
  68. Rosendahl, A., Pardali, E., Speletas, M., Ten Dijke, P., Heldin, C.H., and Sideras, P. (2002). Activation of bone morphogenetic protein/Smad signaling in bronchial epithelial cells during airway inflammation. Am. J. Respir. Cell Mol. Biol. 27, 160-169. https://doi.org/10.1165/ajrcmb.27.2.4779
  69. Samitas, K., Carter, A., Kariyawasam, H.H., and Xanthou, G. (2018). Upper and lower airway remodelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: the one airway concept revisited. Allergy 73, 993-1002. https://doi.org/10.1111/all.13373
  70. Schleimer, R.P. (2017). Immunopathogenesis of chronic rhinosinusitis and nasal polyposis. Annu. Rev. Pathol. 12, 331-357. https://doi.org/10.1146/annurev-pathol-052016-100401
  71. Seidah, N.G. and Chretien, M. (1999). Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res. 848, 45-62. https://doi.org/10.1016/S0006-8993(99)01909-5
  72. Seidah, N.G. and Prat, A. (2012). The biology and therapeutic targeting of the proprotein convertases. Nat. Rev. Drug Discov. 11, 367-383. https://doi.org/10.1038/nrd3699
  73. Seidah, N.G., Sadr, M.S., Chretien, M., and Mbikay, M. (2013). The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions. J. Biol. Chem. 288, 21473-21481. https://doi.org/10.1074/jbc.R113.481549
  74. Senzer, N., Barve, M., Kuhn, J., Melnyk, A., Beitsch, P., Lazar, M., Lifshitz, S., Magee, M., Oh, J., Mill, S.W., et al. (2012). Phase I trial of "bi-shRNAifurin/GMCSF DNA/autologous tumor cell" vaccine (FANG) in advanced cancer. Mol. Ther. 20, 679-686. https://doi.org/10.1038/mt.2011.269
  75. Shaykhiev, R., Zuo, W.L., Chao, I., Fukui, T., Witover, B., Brekman, A., and Crystal, R.G. (2013). EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype. Proc. Natl. Acad. Sci. U. S. A. 110, 12102-12107. https://doi.org/10.1073/pnas.1303058110
  76. Shi, L.L., Xiong, P., Zhang, L., Cao, P.P., Liao, B., Lu, X., Cui, Y.H., and Liu, Z. (2013). Features of airway remodeling in different types of Chinese chronic rhinosinusitis are associated with inflammation patterns. Allergy 68, 101-109. https://doi.org/10.1111/all.12064
  77. Shin, H.W., Cho, K., Kim, D.W., Han, D.H., Khalmuratova, R., Kim, S.W., Jeon, S.Y., Min, Y.G., Lee, C.H., Rhee, C.S., et al. (2012). Hypoxia-inducible factor 1 mediates nasal polypogenesis by inducing epithelial-to-mesenchymal transition. Am. J. Respir. Crit. Care Med. 185, 944-954. https://doi.org/10.1164/rccm.201109-1706OC
  78. Sountoulidis, A., Stavropoulos, A., Giaglis, S., Apostolou, E., Monteiro, R., Chuva de Sousa Lopes, S.M., Chen, H., Stripp, B.R., Mummery, C., Andreakos, E., et al. (2012). Activation of the canonical bone morphogenetic protein (BMP) pathway during lung morphogenesis and adult lung tissue repair. PLoS One 7, e41460. https://doi.org/10.1371/journal.pone.0041460
  79. Staudacher, A.G., Peters, A.T., Kato, A., and Stevens, W.W. (2020). Use of endotypes, phenotypes, and inflammatory markers to guide treatment decisions in chronic rhinosinusitis. Ann. Allergy Asthma Immunol. 124, 318-325. https://doi.org/10.1016/j.anai.2020.01.013
  80. Steiner, D.F., Cunningham, D., Spigelman, L., and Aten, B. (1967). Insulin biosynthesis: evidence for a precursor. Science 157, 697-700. https://doi.org/10.1126/science.157.3789.697
  81. Stevens, W.W., Peters, A.T., Tan, B.K., Klingler, A.I., Poposki, J.A., Hulse, K.E., Grammer, L.C., Welch, K.C., Smith, S.S., Conley, D.B., et al. (2019). Associations between inflammatory endotypes and clinical presentations in chronic rhinosinusitis. J. Allergy Clin. Immunol. Pract. 7, 2812-2820.e3. https://doi.org/10.1016/j.jaip.2019.05.009
  82. Strutz, F., Zeisberg, M., Ziyadeh, F.N., Yang, C.Q., Kalluri, R., Muller, G.A., and Neilson, E.G. (2002). Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 61, 1714-1728. https://doi.org/10.1046/j.1523-1755.2002.00333.x
  83. Szucs, E., Ravandi, S., Goossens, A., Beel, M., and Clement, P.A.R. (2002). Eosinophilia in the ethmoid mucosa and its relationship to the severity of inflammation in chronic rhinosinusitis. Am. J. Rhinol. 16, 131-134. https://doi.org/10.1177/194589240201600301
  84. Takabayashi, T., Kato, A., Peters, A.T., Hulse, K.E., Suh, L.A., Carter, R., Norton, J., Grammer, L.C., Cho, S.H., Tan, B.K., et al. (2013a). Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression. Am. J. Respir. Crit. Care Med. 187, 49-57. https://doi.org/10.1164/rccm.201207-1292OC
  85. Takabayashi, T., Kato, A., Peters, A.T., Hulse, K.E., Suh, L.A., Carter, R., Norton, J., Grammer, L.C., Tan, B.K., Chandra, R.K., et al. (2013b). Increased expression of factor XIII-A in patients with chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 132, 584-592.e4. https://doi.org/10.1016/j.jaci.2013.02.003
  86. Tata, P.R., Mou, H., Pardo-Saganta, A., Zhao, R., Prabhu, M., Law, B.M., Vinarsky, V., Cho, J.L., Breton, S., Sahay, A., et al. (2013). Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 503, 218-223. https://doi.org/10.1038/nature12777
  87. Thomas, G. (2002). Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat. Rev. Mol. Cell Biol. 3, 753-766. https://doi.org/10.1038/nrm934
  88. Tomazic, P.V., Darnhofer, B., and Birner-Gruenberger, R. (2020). Nasal mucus proteome and its involvement in allergic rhinitis. Expert Rev. Proteomics 17, 191-199. https://doi.org/10.1080/14789450.2020.1748502
  89. Tos, M., Larsen, P.L., Larsen, K., and Caye-Thomasen, P. (2010). Pathogenesis and pathophysiology of nasal polyps. In Nasal Polyposis, T.M. Onerci and B.J. Ferguson, eds. (Cham, Switzerland: Springer Nature Switzerland AG), pp. 53-63.
  90. Tsuji, A., Sakurai, K., Kiyokage, E., Yamazaki, T., Koide, S., Toida, K., Ishimura, K., and Matsuda, Y. (2003). Secretory proprotein convertases PACE4 and PC6A are heparin-binding proteins which are localized in the extracellular matrix: potential role of PACE4 in the activation of proproteins in the extracellular matrix. Biochim. Biophys. Acta 1645, 95-104. https://doi.org/10.1016/S1570-9639(02)00532-0
  91. Turpeinen, H., Ortutay, Z., and Pesu, M. (2013). Genetics of the first seven proprotein convertase enzymes in health and disease. Curr. Genomics 14, 453-467. https://doi.org/10.2174/1389202911314050010
  92. Tzimas, G.N., Chevet, E., Jenna, S., Nguyen, D.T., Khatib, A.M., Marcus, V., Zhang, Y., Chretien, M., Seidah, N., and Metrakos, P. (2005). Abnormal expression and processing of the proprotein convertases PC1 and PC2 in human colorectal liver metastases. BMC Cancer 5, 149. https://doi.org/10.1186/1471-2407-5-149
  93. Van Bruaene, N. and Bachert, C. (2011). Tissue remodeling in chronic rhinosinusitis. Curr. Opin. Allergy Clin. Immunol. 11, 8-11. https://doi.org/10.1097/ACI.0b013e32834233ef
  94. Van Bruaene, N., Derycke, L., Perez-Novo, C.A., Gevaert, P., Holtappels, G., De Ruyck, N., Cuvelier, C., Van Cauwenberge, P., and Bachert, C. (2009). TGF-β signaling and collagen deposition in chronic rhinosinusitis. J. Allergy Clin. Immunol. 124, 253-259.e2. https://doi.org/10.1016/j.jaci.2009.04.013
  95. Van Bruaene, N., Perez-Novo, C., Van Crombruggen, K., De Ruyck, N., Holtappels, G., Van Cauwenberge, P., Gevaert, P., and Bachert, C. (2012). Inflammation and remodelling patterns in early stage chronic rhinosinusitis. Clin. Exp. Allergy 42, 883-890. https://doi.org/10.1111/j.1365-2222.2011.03898.x
  96. Vermeer, P.D., Einwalter, L.A., Moninger, T.O., Rokhlina, T., Kern, J.A., Zabner, J., and Welsh, M.J. (2003). Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 422, 322-326. https://doi.org/10.1038/nature01440
  97. Vivoli, M., Caulfield, T.R., Martinez-Mayorga, K., Johnson, A.T., Jiao, G.S., and Lindberg, I. (2012). Inhibition of prohormone convertases PC1/3 and PC2 by 2, 5-dideoxystreptamine derivatives. Mol. Pharmacol. 81, 440-454. https://doi.org/10.1124/mol.111.077040
  98. Wang, W., Gao, Z., Wang, H., Li, T., He, W., Lv, W., and Zhang, J. (2016a). Transcriptome analysis reveals distinct gene expression profiles in eosinophilic and noneosinophilic chronic rhinosinusitis with nasal polyps. Sci. Rep. 6, 26604. https://doi.org/10.1038/srep26604
  99. Wang, X., Zhang, N., Bo, M., Holtappels, G., Zheng, M., Lou, H., Wang, H., Zhang, L., and Bachert, C.C. (2016b). Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: a multicenter study in Europe, Asia, and Oceania. J. Allergy Clin. Immunol. 138, 1344-1353. https://doi.org/10.1016/j.jaci.2016.05.041
  100. Watelet, J.B., Dogne, J.M., and Mullier, F. (2015). Remodeling and repair in rhinosinusitis. Curr. Allergy Asthma Rep. 15, 34. https://doi.org/10.1007/s11882-015-0531-3
  101. Whitcutt, M.J., Adler, K.B., and Wu, R. (1988). A biphasic chamber system for maintaining polarity of differentiation of culture respiratory tract epithelial cells. In Vitro Cell. Dev. Biol. 24, 420-428. https://doi.org/10.1007/BF02628493
  102. Willis, B.C. and Borok, Z. (2007). TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L525-L534. https://doi.org/10.1152/ajplung.00163.2007
  103. Wolbach, S.B. and Howe, P.R. (1925). Tissue changes following deprivation of fat-soluble A vitamin. J. Exp. Med. 42, 753-777. https://doi.org/10.1084/jem.42.6.753
  104. Yan, C., Grimm, W.A., Garner, W.L., Qin, L., Travis, T., Tan, N., and Han, Y.P. (2010). Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-α through bone morphogenic protein-2. Am. J. Pathol. 176, 2247-2258. https://doi.org/10.2353/ajpath.2010.090048
  105. Yoon, J.H., Kim, K.S., Kim, S.S., Lee, J.G., and Park, I.Y. (2000). Secretory differentiation of serially passaged normal human nasal epithelial cells by retinoic acid: expression of mucin and lysozyme. Ann. Otol. Rhinol. Laryngol. 109, 594-601. https://doi.org/10.1177/000348940010900612
  106. Zhang, Y., Gevaert, E., Lou, H., Wang, X., Zhang, L., Bachert, C., and Zhang, N. (2017). Chronic rhinosinusitis in Asia. J. Allergy Clin. Immunol. 140, 1230-1239. https://doi.org/10.1016/j.jaci.2017.09.009
  107. Zuo, W.L., Yang, J., Strulovici-Barel, Y., Salit, J., Rostami, M., Mezey, J.G., O'Beirne, S.L., Kaner, R.J., and Crystal, R.G. (2019). Exaggerated BMP4 signalling alters human airway basal progenitor cell differentiation to cigarette smoking-related phenotypes. Eur. Respir. J. 53, 1702553. https://doi.org/10.1183/13993003.02553-2017