Mol. Cells

The Role of Proprotein Convertases in Upper Airway Remodeling

Additional article information


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: airway remodeling, chronic rhinosinusitis, endoproteolytic cleavage, human nasal epithelial cells, nasal polyps, proprotein convertase


Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and paranasal sinuses that lasts longer than 12 weeks and is the most common upper respiratory tract disease associated with tissue remodeling. CRS has been divided into two major subtypes based on the presence (CRSwNP) or absence (CRSsNP) of nasal polyps (NPs) (Fokkens et al., 2012; Meltzer et al., 2004). CRSsNP comprises more than two-thirds of cases and is less likely to be managed by surgical intervention, whereas CRSwNP represents 20%-25% of cases. NPs are outgrowths of swollen inflammatory tissue that infiltrate the middle or superior meatus. They are the most severe form of pathological tissue remodeling in CRS and require surgical intervention. Tos et al. (2010) hypothesized that NP pathogenesis involves epithelial rupture and necrosis, leading to protrusions from the lamina propria and epithelial repair. Furthermore, Takabayashi et al. (2013a; 2013b) clarified that NP growth is due to the deposition of fibrin mesh within the tissue. However, why NPs only develop in some patients with CRS remains unclear.

The recent identification of appropriate CRS biomarkers has revealed new classification methods, such as the characterization of the CRS patient immune response, known as endotyping. Endotypes are classified according to distinct subsets of CD4+ T cells, namely T helper (Th)1, Th2, and Th17 cells, T cell products, infiltrating eosinophilic and noneosinophilic inflammatory cells, and remodeling markers (Schleimer, 2017; Staudacher et al., 2020). Age, as well as environmental and genetic factors, also influence CRS patient inflammatory endotypes (Mahdavinia et al., 2015; Stevens et al., 2019; Wang et al., 2016b; Zhang et al., 2017). However, some clusters cannot be classified using currently available endotype classification methods, highlighting the necessity for more specific biomarkers and indicating that CRS pathophysiology and pathogenesis remain to be fully understood. Comprehensive tissue remodeling processes, in particular, require further investigation, highlighting the necessity of elucidating regulatory mechanisms underlying tissue remodeling based on endotype classification.

Tissue remodeling is a secondary phenomenon, beginning in early-stage CRS development due to persistent inflammation (Bassiouni et al., 2013; Meng et al., 2013; Watelet et al., 2015). Tissue remodeling in CRS is the reorganization or renovation of nasal mucosa, which can be either physiological or pathological. Nasal mucosal inflammation induces remodeling processes within the mucosa characterized by changes in extracellular matrix (ECM) protein deposition, macrophage and lymphocyte infiltration, and histological structure. Structural alterations in the nasal epithelium include goblet cell hyperplasia, squamous metaplasia, epithelial–mesenchymal transition (EMT), epithelial barrier disruption, epithelial exfoliation, and basement membrane thickening. Structural changes in the lamina propria include stromal edema, bone thickening, fibrosis, angiogenesis, and submucosal gland hyperplasia. The various CRS subgroups can be differentiated by distinct remodeling features; for example, the eosinophilic forms of both CRSwNP and CRSsNP are characterized by increased edema, resulting in more severe disease presentation than the noneosinophilic forms of CRSwNP, which are characterized by increased glandular hyperplasia and dense collagen deposition (Kountakis et al., 2004). Furthermore, fibrosis and collagen deposition, which are Th-1 biased inflammatory responses, are commonly observed in CRSsNP but not in CRSwNP. However, edema is a prominent feature of Th2-biased eosinophilic inflammation (Van Bruaene et al., 2009; 2012). Eosinophilic CRS shows heightened basement membrane thickening compared with noneosinophilic CRS (Lee et al., 2021). Previous studies have reported differences in tissue remodeling between polyps obtained from white and Asian patients (Shi et al., 2013; Van Bruaene and Bachert, 2011). Eosinophilic CRS is typically more common in the EU and USA, whereas noneosinophilic CRS is more common in Asia. However, the prevalence of eosinophilic CRS has increased in Asia due to an increasingly westernized lifestyle. Interestingly, a large histopathologic study of CRS in Wuhan, China, confirmed the link between eosinophilic infiltration and edema and the association of neutrophils with fibrosis (Cao et al., 2009).

Numerous mediators are implicated in airway tissue remodeling, including growth factors, enzymes, adhesion molecules, and ECM components (Ashley et al., 2017; Bassiouni et al., 2013; Maxfield et al., 2018; Samitas et al., 2018; Van Bruaene et al., 2012; Watelet et al., 2015) (Fig. 1). For example, insulin-like growth factor-1 (IGF-1) and its receptor are involved in epithelial cell hyperplasia, mucus overproduction, and ECM deposition (Chand et al., 2012; Krein et al., 2003). Notch signaling plays a critical role in the lineage selection of airway basal cells (BCs) during differentiation into either secretory or ciliated cells in many adults and embryonic tissues (Chiba, 2006; Koch and Radtke, 2010; Rock et al., 2011). However, the sustained activation of Notch signaling promotes the transition of airway BCs to a goblet cell fate (Gerovac et al., 2014; Gomi et al., 2015; Guseh et al., 2009; Rock et al., 2011). Transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF), fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor (VEGF), and matrix metalloproteinase (MMP) all induce the pathological conversion of epithelial cells into fibroblasts, resulting in tissue fibrosis (Câmara and Jarai, 2010; Davies, 2009; Strutz et al., 2002). Furthermore, VEGF promotes edema, angiogenesis, and epithelial cell growth in NPs (Fruth et al., 2012). Upregulation of epidermal growth factor (EGF) skews the airway BC fate toward the squamous and EMT-like phenotypes with decreased epithelial junctional barrier integrity (Shaykhiev et al., 2013). Additionally, bone morphogenetic protein 2 (BMP-2) is associated with both osteitis (Kim et al., 2021) and squamous metaplasia (Lee et al., 2015) in patients with refractory CRSwNP. Importantly, numerous secreted and cell surface proteins, including the proteins mentioned above, are initially synthesized as inactive precursor proteins, requiring endoproteolytic cleavage by proprotein convertases (PCs) for activation (Fig. 1, Table 1) (Artenstein and Opal, 2011; Seidah and Chrétien, 1999). Earlier work by our lab indicated that the expression of four PCs (furin, PC1/3, PC5/6, and PACE4) is significantly upregulated in CRS patient NP mucosa (Fig. 2). These results indicate that these enzymes may play important roles in NP pathogenesis. Furthermore, PCs show promise as diagnostic markers for CRS and may ultimately be targeted by molecular therapy. We summarize the general properties and biological relevance of PCs, as well as current discoveries regarding the pathophysiological roles of furin, PC1/3, PC5/6, and PACE4 in CRS.

Figure F1
Depicted are proforms of the numerous PC substrates that are associated with tissue remodeling, their mature forms, and their effects on upper airway remodeling.
Figure F2
Western blot analysis reveals that furin, PC1/3, PC5/6, and PACE4 are expressed in both control nasal mucosa and nasal polyps, and the expression of four PCs is significantly upregulated in ...
Table 1


PCs are a family of calcium-dependent serine endoproteases. Examples of these enzymes include furin, PC1/3, PC2, PC4, PC5/6, PACE4, and PC7 (Artenstein and Opal, 2011). These enzymes activate precursor proteins through cleavage at doublets of the basic amino acids arginine (R) or lysine (K) or at paired basic motifs [R/K-(X)n-R/K-R↓, where the arrow indicates the cleavage site, X represents any amino acid except cysteine and n = 0, 2, 4, or 6] (Seidah and Chrétien, 1999; Steiner et al., 1967). In various organs, PCs are essential for key physiological functions, such as embryonic development and tissue homeostasis, due to their involvement in the proteolytic activation of many secretory proteins, including growth/differentiation factors and their receptors, adhesion molecules, enzymes, neuropeptides, and peptide hormones (Table 1) (Artenstein and Opal, 2011; Thomas, 2002; Turpeinen et al., 2013). Although PC inactivation in mice and humans has revealed specific phenotypes caused by unique, tissue-specific processing events (Seidah et al., 2013), additional investigation into the specific physiologic substrates for PCs is required. Furthermore, some PCs are associated with various pathophysiological states, including endocrinopathies, cancer, viral/bacterial/parasitic infection, atherosclerosis, and neurodegenerative (Table 2) (Artenstein and Opal, 2011; Chrétien et al., 2008; Seidah and Prat, 2012; Thomas, 2002; Turpeinen et al., 2013). These PCs therefore, represent potential therapeutic targets for the treatment of various human diseases. We summarize the reported PC inhibitors that are expected to affect human pathologies (Table 2). It should be noted that none of these PC inhibitors is highly specific to only one PC.

Table 2


Airway BCs are a long-lived, multipotent stem cell population responsible for normal epithelium homeostasis and regeneration after injury, which is accomplished through their capacities for self-renewal and differentiation into multiple cell types, including secretory and ciliated cells (Rock et al., 2010). However, chronic repetitive injuries disrupt the balance between BC proliferation and differentiation and ultimately lead to pathological tissue remodeling, such as BC hyperplasia, goblet cell hyperplasia, squamous cell metaplasia, loss or dysfunction of ciliated cells, and increased matrix deposition (Araya et al., 2007; Rock et al., 2010; Samitas et al., 2018). These dramatic structural and functional changes contribute to disease susceptibility, initiation, and progression in the airway. Therefore, clarifying the fundamental mechanisms underlying BC lineage choice and differentiation during airway inflammation and remodeling is clinically relevant.

The Notch signaling pathway plays an essential role in regulating the differentiation of airway BCs into secretory and ciliated cells in both the developmental and adult phases (Chiba, 2006; Koch and Radtke, 2010; Rock et al., 2011). Four mammalian Notch receptors (Notch1-4) have been identified (Chiba, 2006). Steady-state Notch signaling is present in relatively few BCs due to low epithelial turnover. However, Notch signaling is greatly increased during repair after epithelial injury (Rock et al., 2011). In vivo studies have shown that the sustained activation of Notch1 signaling promotes luminal differentiation of airway BCs, primarily toward goblet cell lineages (Gerovac et al., 2014; Gomi et al., 2015; Guseh et al., 2009; Rock et al., 2011). A similar result was obtained from in vitro experiments using Notch signaling agonists and antagonists in air-liquid interface (ALI)-human bronchial epithelial cell cultures initiated with BCs (Guseh et al., 2009). Importantly, the Notch receptor is activated after cleavage by a furin-like convertase (Logeat et al., 1998; Rand et al., 2000). Using an in vitro ALI-human nasal epithelial (HNE) cell culture model of airway injury (Puchelle et al., 2006; Whitcutt et al., 1988), we found that inhibiting PC activity during BC differentiation using decanoyl-RVKR-chloromethylketone (CMK) treatment (Hallenberger et al., 1992) skews differentiation toward the ciliated cell phenotype. This skewed differentiation was evidenced by increased numbers of ciliated cells and the upregulation of various genes associated with ciliated cell differentiation (Lee et al., 2017). Furthermore, furin knockdown resulted in suppressed Notch1 processing and increased ciliated cell numbers in ALI-HNE cell culture, indicating that furin is the enzyme responsible for Notch1 activation in HNE cells. These observations and previous studies collectively suggest that furin may play a critical role in BC lineage choice toward goblet cell lineages, as well as the pathogenesis of goblet cell hyperplasia during chronic injury. Therefore, targeting furin has potential as an attractive therapeutic approach for airway epithelial repair and regeneration after injury.


EMT is a process for an epithelial cell to undergo profound biochemical changes to acquire a mesenchymal phenotype, which includes the loss of epithelial cell–cell junctions, the generation of apicobasal polarity, interactions with the basement membrane, and the upregulation of mesenchymal markers, such as α-smooth muscle actin (α-SMA), vimentin, MMPs, collagen I, and epithelial transcriptional suppressors (Snail and Twist) (Câmara and Jarai, 2010; Davies, 2009; Kalluri and Neilson, 2003; Willis and Borok, 2007). Disrupting cell–cell adhesions during EMT allows contact between ligand/receptor pairs that do not typically interact due to segregation into either the apical or basolateral membrane domains. Additionally, this disruption initiates signal transduction cascades that affect epithelial cell activation and differentiation, resulting in tissue remodeling (Georas and Rezaee, 2014; Gibson and Perrimon, 2003; Vermeer et al., 2003). Furthermore, airway epithelial injury and abnormal epithelial repair responses induce persistent epithelial cell activation by undergoing EMT, leading to a pathological process associated with fibrogenesis (Hackett, 2012; Hackett et al., 2009; Shin et al., 2012; Willis and Borok, 2007). Thus, understanding the precise molecular interactions underlying EMT could lead to the identification of novel therapeutic targets to treat tissue fibrosis in chronic inflammatory airway diseases. Hackett et al. (2009) demonstrated that TP63+ KRT5+ BCs in a multilayered, differentiated ALI-airway epithelial cell culture derived from asthmatic subjects undergo EMT after exposure to TGF-β1, which is a known major inducer of EMT. EMT was evidenced by the loss of epithelial markers, E-cadherin and zonular occludin-1, and the upregulation of mesenchymal markers, EDA-fibronectin, vimentin, α-SMA, and collagen-1 (Hackett et al., 2009). Another study reported that hypoxic conditions present in inflamed sinus tissue drive EMT through a Smad3-dependent mechanism (Shin et al., 2012). Importantly, results from our lab revealed that both NP epithelium and ALI-HNE cell cultures undergoing TNF-α/IL-1β–induced EMT highly express PC1/3, together with the mesenchymal marker proteins N-cadherin, collagen I, and MMP-2 (Lee et al., 2013). Specifically, PC1/3 expression was mostly confined to the basal and suprabasal layers in healthy control nasal epithelium but was upregulated in the entire NP epithelial layer (Lee et al., 2013). Because EMT is intimately linked with the acquisition of epithelial stem cell properties with greater phenotypic plasticity (Mani et al., 2008), differentiated epithelial cells may dedifferentiate into regressed basal/progenitor cells in disease states (Tata et al., 2013). Moreover, overexpressing PC1/3 in stably transfected human lung mucoepidermoid carcinoma HCI-H292 cells resulted in decreased E-cadherin expression and increased mesenchymal marker expression (N-cadherin, vimentin, collagen I, α5 integrin, fibronectin, MMP2, Snail, and Twist), concurrent with the transition to a fibroblast-like morphology driven by actin cytoskeleton remodeling (Lee et al., 2013). Taken together, these observations suggest that PC1/3 contributes to tissue remodeling and CRSwNP pathogenesis and play crucial roles in EMT and fibrosis. PC1/3 likely contributes to CRSwNP pathogenesis due to altered processing of integrins, collagen I, fibronectin, neuropeptides, and MMPs (Artenstein and Opal, 2011; Cheng et al., 2001). Further research is required to fully define the precise molecular mechanisms underlying PC1/3-mediated EMT. Greater clarification is also needed to identify the physiological PC1/3 substrates that could provide new therapeutic targets for CRSwNP treatment.


Squamous metaplasia of the airway is a pathologic process by which normal, pseudostratified epithelium transdifferentiates into stratified epithelium consisting of flattened, squamous cells (Auerbach et al., 1961; Puchelle et al., 2006; Rock et al., 2010). Thus, squamous differentiation in airway epithelial cells and epidermal differentiation share many morphological and biochemical characteristics (Jetten, 1989). Chronic repetitive injuries to the airway epithelium induce tissue remodeling, such as epithelial cell hyperproliferation and squamous metaplasia, resulting in impaired mucociliary clearance (Puchelle et al., 2006). Interestingly, results from our lab revealed the significant upregulation of PC5/6A and BMP-2 in both the metaplastic squamous epithelium of NPs and a retinoic acid (RA) deficiency–induced squamous metaplasia model of ALI-HNE cells (Lee et al., 2015). RA deficiency is well-known to induce conversion from normal pseudostratified epithelium into stratified squamous airway epithelium (McDowell et al., 1984; Wolbach and Howe, 1925; Yoon et al., 2000). In a study by Pearton et al. (2001), four PCs, including furin, PACE4, PC5/6, and PC7, had significant roles in terminal keratinocyte differentiation in the epidermis. Additionally, BMP signaling is implicated in pathophysiological processes including wound-healing, fibrosis, and allergic inflammation in the skin and lungs (Botchkarev, 2003; Rosendahl et al., 2002; Sountoulidis et al., 2012; Yan et al., 2010). BMP signaling is also known to be involved in the regulation of embryonic development and adult homeostasis (Botchkarev, 2003; Hogan, 1999; Sountoulidis et al., 2012). Yan et al. (2010) demonstrated that TNF-α–induced EMT is mediated by the BMP-2 signaling pathway in wound-healing and fibrosis of human skin. A study from the Zou lab revealed the induction of a smoking-related abnormal phenotype in human airway BCs mediated by exaggerated BMP-4/BMPR1A/Smad signaling, generating squamous metaplasia (Zuo et al., 2019). Importantly, BMPs are known to be physiological substrates for PACE4 and PC5/6A (Table 1) (Constam et al., 1996; Tsuji et al., 2003). Our lab demonstrated that PC5/6A knockdown and pharmacological inhibition of PC activity in RA-deficient ALI cultures resulted in significant reductions in BMP-2 protein expression and processing, accompanied by the downregulation of squamous cell marker genes (cornifin/SPRR1 and involucrin) and the upregulation of secretory (MUC5AC, TFF3, and MUC5B) and ciliated cell marker genes (Tektin and DNAI1) (Lee et al., 2015). Conversely, PC5/6A overexpression using adenoviral-mediated transduction and exogenous BMP-2 resulted in the upregulation of squamous cell marker genes and the broad downregulation of ciliated and secretory cell differentiation genes (Lee et al., 2015) under RA-sufficient culture conditions for the mucociliary differentiation of HNE cells (Yoon et al., 2000). These observations suggest that PC5/6A-mediated BMP-2 maturation contributes to squamous metaplasia on the NP mucosal surface. Furthermore, Kim et al. (2021) reported that in CRSwNP, BMP-2 is upregulated in NP tissues, associated with osteitis severity, advanced disease extent, and disease refractoriness after surgery. Taken together, these results indicate that PC5/6A can serve as a new CRSwNP biomarker reflecting the pathophysiology of nasal mucosa with squamous metaplasia. Targeting PC5/6A may, therefore, be a viable therapeutic strategy for treating refractory CRSwNP.


Goblet cell hyperplasia is a common feature of chronic airway diseases, which include asthma, allergic rhinitis, and CRSwNP (Jackson, 2001; Jiao et al., 2020; Tomazic et al., 2020). Recent unpublished results from our lab revealed that in the human nasal epithelium within a Th2 milieu, PACE4 upregulation is associated with goblet cell hyperplasia and mucus overproduction. In both NP epithelium and ALI-HNE cells treated with the Th2 cytokine IL-4, which induces goblet cell hyperplasia (Park et al., 2007), PACE4 expression was mostly confined to the basal and suprabasal layers. Furthermore, PACE4 knockdown in ALI-cultured BCs inhibited IL-4–induced goblet cell differentiation, which implies this enzyme is an attractive therapeutic target for CRSwNP treatment. Supporting this finding, a microarray-based study of the transcriptomes of eosinophilic CRSwNP (ECRSwNP) and noneosinophilic CRSwNP (non-ECRSwNP) showed that mRNA levels of Th2 cytokines and PCSK6, which is the gene PACE4, are significantly increased in ECRSwNP (Wang et al., 2016a). These results suggest PACE4 involvement in Th2 inflammation in ECRSwNP. ECRSwNP exhibits a poorer outcome compared to non-ECRSwNP. Indeed, ECRSwNP exhibits greater objective disease severity and a high recurrence rate after surgery (Nakayama et al., 2011; Szucs et al., 2002). Therefore, PACE4 may increase the risk of ECRSwNP, making it a potential diagnostic and prognostic biomarker and treatment target. Further investigation into the mechanism of how PACE4 is involved in ECRSwNP and the potential therapeutic benefits of targeting PACE4 in ECRSwNP is required.


There is still much more to learn about pathological endotyping or subphenotyping of tissue remodeling features in CRS patients, which has the potential to identify patients at a higher risk of recurrent or persistent disease. Here, we assert that PCs have crucial impacts on various types of CRS pathological tissue remodeling, including goblet cell hyperplasia, fibrosis, and squamous metaplasia. Therefore, PCs could be considered promising diagnostic and prognostic biomarkers in CRS patients. Targeting PCs has great potential to treat CRS. However, PC substrate specificity remains unknown in both the physiological and pathophysiological context. This lack of knowledge is largely due to substantial redundancies in the substrates and functions among PCs and the co-expression of some PCs in cells. Therefore, further studies to elucidate the precise mechanisms of PC activity and PC substrate specificity in tissue remodeling and CRS pathogenesis will enable the development of specific biomarkers for disease progression and more individualized treatment strategies. The challenge of identifying potent and safe PC inhibitors has great potential to yield an alternative CRS therapeutic option that could ultimately improve human health.

Article information

Mol. Cells.Jun 30, 2020; 45(6): 353-361.
Published online 2022-05-23. doi:  10.14348/molcells.2022.0019
1The Airway Mucus Institute, Yonsei University College of Medicine, Seoul 03722, Korea
2Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 03722, Korea
Received February 2, 2022; Accepted February 27, 2022.
Articles from Mol. Cells are provided here courtesy of Mol. Cells


  • Araya, J., Cambier, S., Markovics, J.A., Wolters, P., Jablons, D., Hill, A., Finkbeiner, W., Jones, K., Broaddus, V.C., Sheppard, D. (2007). Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients. J. Clin. Invest.. 117, 3551-3562.
  • Artenstein, A.W., Opal, S.M. (2011). Proprotein convertases in health and disease. N. Engl. J. Med.. 365, 2507-2518.
  • Ashley, S.L., Wilke, C.A., Kim, K.K., Moore, B.B. (2017). Periostin regulates fibrocyte function to promote myofibroblast differentiation and lung fibrosis. Mucosal Immunol.. 10, 341-351.
  • Auerbach, O., Stout, A.P., Hammond, E.C., 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.
  • Bassiouni, A., Chen, P.G., Wormald, P.J. (2013). Mucosal remodeling and reversibility in chronic rhinosinusitis. Curr. Opin. Allergy Clin. Immunol.. 13, 4-12.
  • Becker, G.L., Lu, Y., Hardes, K., Strehlow, B., Levesque, C., Lindberg, I., Sandvig, K., Bakowsky, U., Day, R., Garten, W. (2012). Highly potent inhibitors of proprotein convertase furin as potential drugs for treatment of infectious diseases. J. Biol. Chem.. 287, 21992-22003.
  • Becker, G.L., Sielaff, F., Than, M.E., Lindberg, I., Routhier, S., Day, R., Lu, Y., Garten, W., Steinmetzer, T. (2010). Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics. J. Med. Chem.. 53, 1067-1075.
  • Botchkarev, V.A. (2003). Bone morphogenetic proteins and their antagonists in skin and hair follicle biology. J. Invest. Dermatol.. 120, 36-47.
  • Boudreault, A., Gauthier, D., 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.
  • Byun, S., Tortorella, M.D., Malfait, A.M., Fok, K., Frank, E.H., 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.
  • Câmara, J., 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.
  • Cao, P.P., Li, H.B., Wang, B.F., Wang, S.B., You, X.J., Cui, Y.H., Wang, D.Y., Desrosiers, M., Liu, Z. (2009). Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J. Allergy Clin. Immunol.. 124, 478-484.e2.
  • Chand, H.S., Woldegiorgis, Z., Schwalm, K., McDonald, J., 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.
  • Cheng, M., Xu, N., Iwasiow, B., Seidah, N., Chrétien, M., 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.
  • Chiba, S. (2006). Concise review: Notch signaling in stem cell systems. Stem Cells. 24, 2437-2447.
  • Chrétien, M., Seidah, N.G., Basak, A., Mbikay, M. (2008). Proprotein convertases as therapeutic targets. Expert Opin. Ther. Targets. 12, 1289-1300.
  • Constam, D.B., Calfon, M., 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.
  • Coppola, J.M., Bhojani, M.S., Ross, B.D., Rehemtulla, A. (2008). A small-molecule furin inhibitor inhibits cancer cell motility and invasiveness. Neoplasia. 10, 363-370.
  • Couture, F., D'Anjou, F., Desjardins, R., Boudreau, F., Day, R. (2012). Role of proprotein convertases in prostate cancer progression. Neoplasia. 14, 1032-1042.
  • Dahms, S.O., Haider, T., Klebe, G., Steinmetzer, T., Brandstetter, H. (2021). OFF-state-specific inhibition of the proprotein convertase furin. ACS Chem. Biol.. 16, 1692-1700.
  • Davies, D.E. (2009). The role of the epithelium in airway remodeling in asthma. Proc. Am. Thorac. Soc.. 6, 678-682.
  • Fokkens, W.J., Lund, V.J., Mullol, J., Bachert, C., Alobid, I., Baroody, F., Cohen, N., Cervin, A., Douglas, R., Gevaert, P. (2012). EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology. 50, 1-12.
  • Fruth, K., Zhu, C., Schramek, E., Angermair, J., Kassem, W., Haxel, B.R., Schneider, A., Mann, W.J., Brieger, J. (2012). Vascular endothelial growth factor expression in nasal polyps of aspirin-intolerant patients. Arch. Otolaryngol. Head Neck Surg.. 138, 286-293.
  • Georas, S.N., Rezaee, F. (2014). Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation. J. Allergy Clin. Immunol.. 134, 509-520.
  • Gerovac, B.J., Valencia, M., Baumlin, N., Salathe, M., Conner, G.E., 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.
  • Gibson, M.C., Perrimon, N. (2003). Apicobasal polarization: epithelial form and function. Curr. Opin. Cell Biol.. 15, 747-752.
  • Gomi, K., Arbelaez, V., Crystal, R.G., Walters, M.S. (2015). Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway. PLoS One. 10, e0116507.
  • Guseh, J.S., Bores, S.A., Stanger, B.Z., Zhou, Q., Anderson, W.J., Melton, D.A., Rajagopal, J. (2009). Notch signaling promotes airway mucous metaplasia and inhibits alveolar development. Development. 136, 1751-1759.
  • Hackett, T.L. (2012). Epithelial-mesenchymal transition in the pathophysiology of airway remodelling in asthma. Curr. Opin. Allergy Clin. Immunol.. 12, 53-59.
  • 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. (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.
  • Hallenberger, S., Bosch, V., Angliker, H., Shaw, E., Klenk, H.D., Garten, W. (1992). Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gpl60. Nature. 360, 358-361.
  • Hogan, B.L.M. (1999). Morphogenesis. Cell. 96, 225-233.
  • Jackson, A.D. (2001). Airway goblet-cell mucus secretion. Trends Pharmacol. Sci.. 22, 39-45.
  • 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.
  • Jiao, G.S., Cregar, L., Wang, J., Millis, S.Z., Tang, C., O'Malley, S., Johnson, A.T., Sareth, S., Larson, J., Thomas, G. (2006). Synthetic small molecule furin inhibitors derived from 2, 5-dideoxystreptamine. Proc. Natl. Acad. Sci. U. S. A.. 103, 19707-19712.
  • Jiao, J., Zhang, T., Zhang, Y., Li, J., Wang, M., Wang, M., Li, Y., Wang, X., Zhang, L. (2020). Epidermal growth factor upregulates expression of MUC5AC via TMEM16A, in chronic rhinosinusitis with nasal polyps. Allergy Asthma Clin. Immunol.. 16, 40.
  • Kalluri, R., Neilson, E.G. (2003). Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest.. 112, 1776-1784.
  • 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. (2021). Bone morphogenetic protein-2 as a novel biomarker for refractory chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol.. 148, 461-472.e13.
  • Klein-Szanto, A.J., Bassi, D.E. (2017). Proprotein convertase inhibition: paralyzing the cell's master switches. Biochem. Pharmacol.. 140, 8-15.
  • Koch, U., Radtke, F. (2010). Notch signaling in solid tumors. Curr. Top. Dev. Biol.. 92, 411-455.
  • Komiyama, T., Coppola, J.M., Larsen, M.J., van Dort, M.E., Ross, B.D., Day, R., Rehemtulla, A., Fuller, R.S. (2009). Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules. J. Biol. Chem.. 284, 15729-15738.
  • Kountakis, S.E., Arango, P., Bradley, D., Wade, Z.K., Borish, L. (2004). Molecular and cellular staging for the severity of chronic rhinosinusitis. Laryngoscope. 114, 1895-1905.
  • Kowalska, D., Liu, J., Appel, J.R., Ozawa, A., Nefzi, A., Mackin, R.B., Houghten, R.A., Lindberg, I. (2009). Synthetic small-molecule prohormone convertase 2 inhibitors. Mol. Pharmacol.. 75, 617-625.
  • Krein, P.M., Sabatini, P.J.B., Tinmouth, W., Green, F.H.Y., 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.
  • Lee, H.Y., Pyo, J.S., Kim, S.J. (2021). Distinct patterns of tissue remodeling and their prognostic role in chronic rhinosinusitis. ORL J. Otorhinolaryngol. Relat. Spec.. 83, 457-463.
  • Lee, S.N., Choi, I.S., Kim, H.J., Yang, E.J., Min, H.J., Yoon, J.H. (2017). Proprotein convertase inhibition promotes ciliated cell differentiation - a potential mechanism for the inhibition of Notch1 signalling by decanoyl-rvkr-chloromethylketone. J. Tissue Eng. Regen. Med.. 11, 2667-2680.
  • Lee, S.N., Lee, D.H., Lee, M.G., 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.
  • Lee, S.N., Lee, D.H., Sohn, M.H., Yoon, J.H. (2013). Overexpressed proprotein convertase 1/3 induces an epithelial-mesenchymal transition in airway epithelium. Eur. Respir. J.. 42, 1379-1390.
  • Levesque, C., Fugère, M., Kwiatkowska, A., Couture, F., Desjardins, R., Routhier, S., Moussette, P., Prahl, A., Lammek, B., Appel, J.R. (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.
  • Logeat, F., Bessia, C., Brou, C., LeBail, O., Jarriault, S., Seidah, N.G., Israël, A. (1998). The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc. Natl. Acad. Sci. U. S. A.. 95, 8108-8112.
  • 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. (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.
  • Majumdar, S., Mohanta, B.C., Chowdhury, D.R., Banik, R., Dinda, B., Basak, A. (2010). Proprotein convertase inhibitory activities of flavonoids isolated from Oroxylum indicum. Curr. Med. Chem.. 17, 2049-2058.
  • 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. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133, 704-715.
  • Maxfield, A.Z., Landegger, L.D., Brook, C.D., Lehmann, A.E., Campbell, A.P., Bergmark, R.W., Stankovic, K.M., Metson, R. (2018). Periostin as a biomarker for nasal polyps in chronic rhinosinusitis. Otolaryngol. Head Neck Surg.. 158, 181-186.
  • McDowell, E.M., Keenan, K.P., 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.
  • 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. (2004). Rhinosinusitis: establishing definitions for clinical research and patient care. J. Allergy Clin. Immunol.. 114, 155-212.
  • Meng, J., Zhou, P., Liu, Y., Liu, F., Yi, X., Liu, S., Holtappels, G., Bachert, C., Zhang, N. (2013). The development of nasal polyp disease involves early nasal mucosal inflammation and remodelling. PLoS One. 8, .
  • Muller, L., Cameron, A., Fortenberry, Y., Apletalina, E.V., Lindberg, I. (2000). Processing and sorting of the prohormone convertase 2 propeptide. J. Biol. Chem.. 275, 39213-39222.
  • Nakayama, T., Yoshikawa, M., Asaka, D., Okushi, T., Matsuwaki, Y., Otori, N., Hema, T., Moriyama, H. (2011). Mucosal eosinophilia and recurrence of nasal polyps-new classification of chronic rhinosinusitis. Rhinology. 49, 392-396.
  • Park, K.S., Korfhagen, T.R., Bruno, M.D., Kitzmiller, J.A., Wan, H., Wert, S.E., Khurana Hershey, G.K., Chen, G., Whitsett, J.A. (2007). SPDEF regulates goblet cell hyperplasia in the airway epithelium. J. Clin. Invest.. 117, 978-988.
  • Pearton, D.J., Nirunsuksiri, W., Rehemtulla, A., Lewis, S.P., Presland, R.B., Dale, B.A. (2001). Proprotein convertase expression and localization in epidermis: evidence for multiple roles and substrates. Exp. Dermatol.. 10, 193-203.
  • Puchelle, E., Zahm, J.M., Tournier, J.M., Coraux, C. (2006). Airway epithelial repair, regeneration, and remodeling after injury in chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc.. 3, 726-733.
  • Rand, M.D., Grimm, L.M., Artavanis-Tsakonas, S., Patriub, V., Blacklow, S.C., Sklar, J., Aster, J.C. (2000). Calcium depletion dissociates and activates heterodimeric Notch receptors. Mol. Cell. Biol.. 20, 1825-1835.
  • Rock, J.R., Gao, X., Xue, Y., Randell, S.H., Kong, Y.Y., Hogan, B.L.M. (2011). Notch-dependent differentiation of adult airway basal stem cells. Cell Stem Cell. 8, 639-648.
  • Rock, J.R., Randell, S.H., 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.
  • Rose, M., Duhamel, M., Aboulouard, S., Kobeissy, F., Le Rhun, E., Desmons, A., Tierny, D., Fournier, I., Rodet, F., 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.
  • Rose, M., Duhamel, M., Rodet, F., Salzet, M. (2021). The role of proprotein convertases in the regulation of the function of immune cells in the oncoimmune response. Front. immunol. 12, .
  • Rosendahl, A., Pardali, E., Speletas, M., Ten Dijke, P., Heldin, C.H., 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.
  • Samitas, K., Carter, A., Kariyawasam, H.H., 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.
  • Schleimer, R.P. (2017). Immunopathogenesis of chronic rhinosinusitis and nasal polyposis. Annu. Rev. Pathol.. 12, 331-357.
  • Seidah, N.G., Chrétien, M. (1999). Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res.. 848, 45-62.
  • Seidah, N.G., Prat, A. (2012). The biology and therapeutic targeting of the proprotein convertases. Nat. Rev. Drug Discov.. 11, 367-383.
  • Seidah, N.G., Sadr, M.S., Chrétien, M., Mbikay, M. (2013). The multifaceted proprotein convertases: their unique, redundant, complementary, and opposite functions. J. Biol. Chem.. 288, 21473-21481.
  • Senzer, N., Barve, M., Kuhn, J., Melnyk, A., Beitsch, P., Lazar, M., Lifshitz, S., Magee, M., Oh, J., Mill, S.W. (2012). Phase I trial of "bi-shRNAifurin/GMCSF DNA/autologous tumor cell" vaccine (FANG) in advanced cancer. Mol. Ther.. 20, 679-686.
  • Shaykhiev, R., Zuo, W.L., Chao, I., Fukui, T., Witover, B., Brekman, A., 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.
  • Shi, L.L., Xiong, P., Zhang, L., Cao, P.P., Liao, B., Lu, X., Cui, Y.H., Liu, Z. (2013). Features of airway remodeling in different types of Chinese chronic rhinosinusitis are associated with inflammation patterns. Allergy. 68, 101-109.
  • 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. (2012). Hypoxia-inducible factor 1 mediates nasal polypogenesis by inducing epithelial-to-mesenchymal transition. Am. J. Respir. Crit. Care Med.. 185, 944-954.
  • 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. (2012). Activation of the canonical bone morphogenetic protein (BMP) pathway during lung morphogenesis and adult lung tissue repair. PLoS One. 7, e41460.
  • Staudacher, A.G., Peters, A.T., Kato, A., 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.
  • Steiner, D.F., Cunningham, D., Spigelman, L., Aten, B. (1967). Insulin biosynthesis: evidence for a precursor. Science. 157, 697-700.
  • 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. (2019). Associations between inflammatory endotypes and clinical presentations in chronic rhinosinusitis. J. Allergy Clin. Immunol. Pract.. 7, 2812-2820.e3.
  • Strutz, F., Zeisberg, M., Ziyadeh, F.N., Yang, C.Q., Kalluri, R., Muller, G.A., Neilson, E.G. (2002). Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int.. 61, 1714-1728.
  • Szucs, E., Ravandi, S., Goossens, A., Beel, M., 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.
  • 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. (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.
  • 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. (2013b). Increased expression of factor XIII-A in patients with chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol.. 132, 584-592.e4.
  • Tata, P.R., Mou, H., Pardo-Saganta, A., Zhao, R., Prabhu, M., Law, B.M., Vinarsky, V., Cho, J.L., Breton, S., Sahay, A. (2013). Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature. 503, 218-223.
  • Thomas, G. (2002). Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat. Rev. Mol. Cell Biol.. 3, 753-766.
  • Tomazic, P.V., Darnhofer, B., Birner-Gruenberger, R. (2020). Nasal mucus proteome and its involvement in allergic rhinitis. Expert Rev. Proteomics. 17, 191-199.
  • Tos, M., Larsen, P.L., Larsen, K., Caye-Thomasen, P. (2010). Pathogenesis and pathophysiology of nasal polyps. , Önerci, T.M., Ferguson, B.J., ed. (Cham, Switzerland:Springer Nature Switzerland AG), pp. 53-63.
  • Tsuji, A., Sakurai, K., Kiyokage, E., Yamazaki, T., Koide, S., Toida, K., Ishimura, K., 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.
  • Turpeinen, H., Ortutay, Z., Pesu, M. (2013). Genetics of the first seven proprotein convertase enzymes in health and disease. Curr. Genomics. 14, 453-467.
  • Tzimas, G.N., Chevet, E., Jenna, S., Nguyên, D.T., Khatib, A.M., Marcus, V., Zhang, Y., Chrétien, M., Seidah, N., Metrakos, P. (2005). Abnormal expression and processing of the proprotein convertases PC1 and PC2 in human colorectal liver metastases. BMC Cancer. 5, 149.
  • Van Bruaene, N., Bachert, C. (2011). Tissue remodeling in chronic rhinosinusitis. Curr. Opin. Allergy Clin. Immunol.. 11, 8-11.
  • Van Bruaene, N., Derycke, L., Perez-Novo, C.A., Gevaert, P., Holtappels, G., De Ruyck, N., Cuvelier, C., Van Cauwenberge, P., Bachert, C. (2009). TGF-β signaling and collagen deposition in chronic rhinosinusitis. J. Allergy Clin. Immunol.. 124, 253-259.e2.
  • Van Bruaene, N., Perez-Novo, C., Van Crombruggen, K., De Ruyck, N., Holtappels, G., Van Cauwenberge, P., Gevaert, P., Bachert, C. (2012). Inflammation and remodelling patterns in early stage chronic rhinosinusitis. Clin. Exp. Allergy. 42, 883-890.
  • Vermeer, P.D., Einwalter, L.A., Moninger, T.O., Rokhlina, T., Kern, J.A., Zabner, J., Welsh, M.J. (2003). Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature. 422, 322-326.
  • Vivoli, M., Caulfield, T.R., Martínez-Mayorga, K., Johnson, A.T., Jiao, G.S., Lindberg, I. (2012). Inhibition of prohormone convertases PC1/3 and PC2 by 2, 5-dideoxystreptamine derivatives. Mol. Pharmacol.. 81, 440-454.
  • Wang, W., Gao, Z., Wang, H., Li, T., He, W., Lv, W., Zhang, J. (2016a). Transcriptome analysis reveals distinct gene expression profiles in eosinophilic and noneosinophilic chronic rhinosinusitis with nasal polyps. Sci. Rep.. 6, 26604.
  • Wang, X., Zhang, N., Bo, M., Holtappels, G., Zheng, M., Lou, H., Wang, H., Zhang, L., 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.
  • Watelet, J.B., Dogne, J.M., Mullier, F. (2015). Remodeling and repair in rhinosinusitis. Curr. Allergy Asthma Rep.. 15, 34.
  • Whitcutt, M.J., Adler, K.B., 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.
  • Willis, B.C., Borok, Z. (2007). TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol.. 293, L525-L534.
  • Wolbach, S.B., Howe, P.R. (1925). Tissue changes following deprivation of fat-soluble A vitamin. J. Exp. Med.. 42, 753-777.
  • Yan, C., Grimm, W.A., Garner, W.L., Qin, L., Travis, T., Tan, N., 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.
  • Yoon, J.H., Kim, K.S., Kim, S.S., Lee, J.G., 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.
  • Zhang, Y., Gevaert, E., Lou, H., Wang, X., Zhang, L., Bachert, C., Zhang, N. (2017). Chronic rhinosinusitis in Asia. J. Allergy Clin. Immunol.. 140, 1230-1239.
  • Zuo, W.L., Yang, J., Strulovici-Barel, Y., Salit, J., Rostami, M., Mezey, J.G., O'Beirne, S.L., Kaner, R.J., Crystal, R.G. (2019). Exaggerated BMP4 signalling alters human airway basal progenitor cell differentiation to cigarette smoking-related phenotypes. Eur. Respir. J.. 53, 1702553.

Figure 1

Depicted are proforms of the numerous PC substrates that are associated with tissue remodeling, their mature forms, and their effects on upper airway remodeling.

Figure 2

Western blot analysis reveals that furin, PC1/3, PC5/6, and PACE4 are expressed in both control nasal mucosa and nasal polyps, and the expression of four PCs is significantly upregulated in nasal polyps compared to the control mucosa. Right panel shows densitometric analysis of furin, normalized to β-actin and relative to control mucosa. Data represent the mean ± SEM. *P < 0.05.

Table 1

Substrates activated by PCs

Typical substrates
PC1/3 Growth hormone-releasing hormone, insulin, glucagon, corticotropin, β-lipotropin, ACTH
PC2 Insulin, glucagon, α-MSH, met-enkephalin, somatostatin
PC4 Pituitary adenylate cyclase-activating polypeptide, IGF-2
Furin Albumin, factor IX, VWF, neurotophins, adhesins, α- and β-secretases, TNF-α, TGF-β, IGF-1, IGF-1R, integrins, Notchs, PDGF, VEGFs, MMPs, BMPs, bacterial toxins (anthrax toxin, dipteria toxin, pseudomonas exotoxin A, aerolysin toxin, Shiga toxins, Clostridium specum α-toxin), viral glycoproteins (HIV gp160, Evola gp, influenza HA, measles, cytomegalovirus, respiratory syncytial virus, coronavirus)
PC5/6 GDF11, PTPRM, L1CAM, α4 integrin, BMPs In vitro and ex vivo redundancy with furin and PACE4
PACE4 Nodal, Lefty, L1CAM, MMPs, BMPs In vitro and ex vivo redundancy with furin and PC5/6
PC7 Transferrin receptor 1 Partial redundancy with furin, PC5/6, and PACE4

Table 2

Therapeutic potential of PCs

Diseases Proposed therapies References
PC1/3 Neuroendocrine tumors (pheoch-romocytoma, pituitary adenoma, carcinoids, pancreatic cancer, small-cell lung carcinoma) Small-molecule inhibitors (2,5-dideoxystreptamine derivatives, peptidomimetic analogs, temozolomide), PC1/3 propeptide Becker et al., 2012; Boudreault et al., 1998; Chrétien et al., 2008; Rose et al., 2020; Vivoli et al., 2012
PC2 Neuroendocrine tumors, liver colorectal metastases Small-molecule inhibitors (bicyclic guanidines, pyrrolidine bis-piperazines, 2,5-dideoxystreptamine derivatives), PC2 propeptide Chrétien et al., 2008; Kowalska et al., 2009; Muller et al., 2000; Tzimas et al., 2005; Vivoli et al., 2012
PC4 Male contraceptive Small-molecule inhibitors (flavonoid derivatives) Becker et al., 2012; Majumdar et al., 2010
Furin Cancer and metastasis, viral, bacterial and parasitic infections Bi: shRNA-Furin GMCSF, locked nucleic acid (LNA), neutralizing antibodies, small-molecule inhibitors (2,5-dideoxystreptamine, dicoumarol derivatives, B3, phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide, decarboxylated P1 arginine peptide mimetics, guanidilated streptamine derivatives, peptidomimetic analogs, temozolomide, dicoumarol derivatives), alpha-1-antitrypsin derivatives, nanobodies, furin propeptide Becker et al., 2010; 2012; Coppola et al., 2008; Couture et al., 2012; Dahms et al., 2021; Jiao et al., 2006; Klein-Szanto and Bassi, 2017; Komiyama et al., 2009; Rose et al., 2020; 2021; Senzer et al., 2012
PC5/6 Atherosclerosis, cancer, viral infections, reproduction, dyslipidemia Small-molecule inhibitors (guanidilated streptamine derivatives, peptidomimetic analogs, dicoumarol derivatives), alpha-1-antitrypsin derivatives), PC5/6 propeptide Becker et al., 2012; Dahms et al., 2021; Klein-Szanto and Bassi, 2017; Rose et al., 2021
PACE4 Cancer and metastasis, arthritis, viral and pathogenic infections shRNA, Small-molecule inhibitors (Multi-Leu peptide, peptidomimetic analogs, temozolomide, guanidilated streptamine derivatives, dicoumarol derivatives), alpha-1-antitrypsin derivatives Becker et al., 2012; Byun et al., 2010; Couture et al., 2012; Klein-Szanto and Bassi, 2017; Levesque et al., 2012; Rose et al., 2020; 2021
PC7 Anxiety Small-molecule inhibitors (guanidilated streptamine derivatives, dicoumarol derivatives), PC7 propeptide Dahms et al., 2021; Klein-Szanto and Bassi, 2017; Rose et al., 2021