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Chronic rhinosinusitis with nasal polyps (CRSwNP) is closely associated with tissue remodeling. Epithelial-to-mesenchymal transition (EMT), a process of tissue remodeling, can be a therapeutic target of CRSwNP. Glucocorticoids are a type of steroid hormone that is used primarily in medical therapy for patients with CRSwNP; however, their effects on EMT in the airway epithelium remain unknown. To investigate the effects of dexamethasone and fluticasone propionate, a class of glucocorticoids, on transforming growth factor-β1 (TGF-β1) -induced EMT, we used A549 cells, human primary nasal epithelial cells (hPNECs) and ex vivo organ culture of the inferior turbinate. TGF-β1 induced changes in cell morphology, suppressed the expression of E-cadherin and enhanced the expression of a-smooth muscle actin, vimentin and fibronectin in A549 cells. However, glucocorticoids inhibited EMT, migration and invasion enhancement by TGF-β1. We found that the induction of phosphorylated ERK, p38 and the activity of Snail and Slug transcription factors by TGF-β1 were suppressed by glucocorticoids. Glucocorticoids also had a similar effect in hPNECs and ex vivo organ cultures of the inferior turbinate. These findings suggest that glucocorticoids might be a useful therapy for preventing tissue remodeling by blocking the EMT initiated by TGF-β1-induced MAPK and Snail/Slug signaling pathways in CRSwNP.

Background: Diesel exhaust particles (DEP) are a major source of air pollution. Nasal fibroblasts are known to produce various cytokines and chemokines. The aim of this study was to evaluate DEP-induced cytokines and chemokines in nasal fibroblasts and to identify the signaling pathway involved., Methods: A cytokine and chemokine array performed after stimulation of nasal fibroblasts with DEP revealed that levels of IL-6 and IL-8 were increased most significantly among various cytokines and chemokines. RT-PCR and ELISA were used to determine the mRNA and protein expression levels of IL-6 and IL-8. Signaling pathways of p-38, Akt, and NF-κB were analyzed by western blotting, luciferase assay, and ELISA. Organ cultures of nasal interior turbinate were also developed to demonstrate the ex vivo effect of DEP on the expression of IL-6 and IL-8 and the associated signaling pathway., Results: DEP increased the expressions of IL-6 and IL-8 in nasal fibroblasts at mRNA and protein levels. DEP induced phosphorylation of p38, Akt, and NF-κB, whereas inhibitors of p38, Akt, and NF-κB blocked these phophorylations and the expressions of IL-6 and IL-8. These findings were also observed in ex vivo organ culture of nasal inferior turbinate., Conclusions: DEP induces expression of IL-6 and IL-8 via p38, Akt, and NF-κB signaling pathways in nasal fibroblasts. This finding suggests that air pollution might induce or aggravate allergic rhinitis or chronic rhinosinusitis.

Background: Diesel exhaust particles (DEPs), the major contributors to air pollution, induce inflammatory responses in the nasal epithelium. Overproduction of airway mucins is an important pathogenic finding in inflammatory airway diseases., Objective: The aims of the present study were to determine the effect of DEPs on the expression of the mucin gene MUC4 and to investigate the underlying mechanism of DEP-induced MUC4 expression in NCI-H292 cells and primary nasal epithelial cells (PNECs)., Methods: NCI-H292 cells were stimulated for 24 h with DEPs. Messenger RNA (mRNA) and protein expression of MUC4 was determined by real-time reverse transcription (RT) polymerase chain reaction (PCR) and Western blotting. NCI-H292 cells were exposed to 3 mitogen-activated protein kinase inhibitors (U0126, SB203580, and SP600125) and a CREB (cAMP response element-binding protein) inhibitor prior to stimulation with DEPs, and MUC4 expression was examined by RT-PCR and Western blotting. PNECs were pretreated with a p38 inhibitor and CREB inhibitor prior to stimulation with DEPs, and MUC4 expression was then determined by RT-PCR and/or Western blotting., Results: DEPs significantly increased the expression of MUC4 mRNA and protein. MUC4 mRNA and protein expression was inhibited by pretreatment with p38 and CREB inhibitors in NCI-H292 stimulated with DEPs. p38 and CREB inhibitors also blocked the expression of MUC4 mRNA and protein in DEP-stimulated PNECs., Conclusions: We demonstrated that DEPs stimulated the expression of MUC4 via the p38/CREB pathway in NCI-H292 cells and PNECs. The results of the present study pave the way for further studies on the role of MUC4 in DEP-induced hypersecretion in airway epithelium., (© 2017 S. Karger AG, Basel.)

Background: Although inverted papilloma (IP) is one of the most common sinonasal tumors, its etiology and factors associated with tumor progression have not been fully determined. Generally, tumorigenesis or tumor growth requires angiogenesis to feed tumor cells. Angiomotin is a recently discovered protein that regulates migration and tubule formation in endothelial cells. It has been reported that angiomotin affects angiostatin (circulating inhibitor of angiogenesis), resulting in promotion of angiogenesis. Thus, we evaluated the expression and distribution of angiomotin in sinonasal IP, compared to normal control tissue., Methods: The study included 10 subjects with sinonasal IP and 5 normal controls. Ethmoid sinus mucosa obtained during reduction of blowout fractures was used as a normal control. Reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR, immunohistochemistry, and Western blot analysis were used to assess the expression, intensity, and distribution of angiomotin in tissues., Results: Positive bands for angiomotin were seen in all specimens by RT-PCR. The expression level of angiomotin was significantly upregulated in IP tissues versus normal sinus mucosa by real-time PCR. Immunohistochemistry revealed positive reactions on endothelial cells of capillaries and small vessels within the tumor and normal tissues, but the positivity was significantly stronger in IP. Western blot analysis showed that expression levels of angiomotin were increased in IP compared to normal sinus mucosa., Conclusion: Angiomotin, a novel protein in angiogenesis, was overexpressed in IP. Although it is not an etiological or initiating factor in tumor development, it seems to be associated with progression and growth of IP via promoting angiogenesis., (© 2014 ARS-AAOA, LLC.)

Conclusion: Reconstruction of a large anterior skull base defect (SBD) with the nasoseptal flap (SF) is feasible in Asians. We consider the width of the SF to be the determining factor. Increasing flap width by incorporating the mucoperiosteum of the nasal floor can compensate for the relatively small septum in Asians., Objectives: To assess the feasibility of the SF for reconstruction of large anterior SBD in Koreans, and attempt to provide tips for improving its design., Methods: Radioanatomic measurements and intraoperative findings were analyzed. Specific skull base landmarks were measured to estimate the anticipated SBD and actual SBD. The length and width of the potential SF dimension was also measured and compared with the defect size to assess its feasibility., Results: The lengths of the actual SBDs were longer than those of anticipated SBDs in all patients, while the width of actual SBDs showed less discrepancy. Length and anterior width of the potential SF exceeded the needed SF dimensions in two patients, while the posterior width of potential SF fell short of the needed dimension. In both patients, the length of harvested SF was long enough to repair the entire length of SBD, while shortage of SF width was encountered in one patient.

Chronic rhinosinusitis (CRS) is an inflammation of the nasal and paranasal sinus mucosa, and eosinophilic CRS (eCRS) is a subtype characterized by significant eosinophil infiltration and immune response by T-helper-2 cells. The pathogenesis of eCRS is heterogeneous and involves various environmental and host factors. Proteases from external sources, such as mites, fungi, and bacteria, have been implicated in inducing type 2 inflammatory reactions. The balance between these proteases and endogenous protease inhibitors (EPIs) is considered important, and their imbalance can potentially lead to type 2 inflammatory reactions, such as eCRS. In this review, we discuss various mechanisms by which exogenous proteases influence eCRS and highlight the emerging role of endogenous protease inhibitors in eCRS pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Glycolytic reprogramming is a key feature of chronic inflammatory disease. Extracellular matrix (ECM) produced by myofibroblasts plays an important role in tissue remodeling of nasal mucosa in chronic rhinosinusitis (CRS). This study aimed to determine whether glycolytic reprogramming contributes to myofibroblast differentiation and ECM production in nasal fibroblasts. Methods: Primary nasal fibroblasts were isolated from the nasal mucosa of patients with CRS. Glycolytic reprogramming was assessed by measuring the extracellular acidification and oxygen consumption rates in nasal fibroblast, with and without transforming growth factor beta 1 (TGF-β1) treatment. Expression of glycolytic enzymes and ECM components was measured by real-time polymerase chain reaction, western blotting, and immunocytochemical staining. Gene set enrichment analysis was performed using whole RNA-sequencing data of nasal mucosa of healthy donors and patients with CRS. Result: Glycolysis of nasal fibroblasts stimulated with TGF-B1 was upregulated along with glycolytic enzymes. Hypoxia-inducing factor (HIF)-1α was a high-level regulator of glycolysis, and increased HIF-1α expression promoted glycolysis of nasal fibroblasts, and inhibition of HIF-1α down-regulated myofibroblasts differentiation and ECM production. Conclusion: This study suggests that inhibition of the glycolytic enzyme and HIF-1α in nasal fibroblasts regulates myofibroblast differentiation and ECM generation associated with nasal mucosa remodeling. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis is involved in tissue remodeling of nasal mucosa such as nasal myofibroblast differentiation and extracellular matrix production. Apigenin (4’,5,7-trihydroxyflavone) is a bioflavonoid compound and has anti-tissue remodeling characteristics. The aims of this study were to evaluate the effect of apigenin on TGF-β1-induced myofibroblast differentiation and extracellular matrix accumulation and to determine the underlying mechanism. Methods: Nasal fibroblasts and ex vivo nasal inferior turbinate tissues were stimulated with TGF-β1 with or without apigenin. The expression levels of α-SMA, fibronectin and collagen type I were determined by real-time PCR, western blot and immunocytochemical staining. Mitogen-activated protein kinase (MAPK) phosphorylation induced by TGF-β1 were determined by western blot analysis. The transcriptional activity of NF-κB was measured by luciferase assay. Migration effects of fibroblasts were evaluated by wound scratch and transwell migration assay. Contractile activity was determined by collagen gel contraction assay. Results: The expression levels of α-SMA, fibronectin, and collagen type I significantly increased in TGF-β1-stimulated nasal fibroblasts. In TGF-β1-stimulated nasal fibroblasts, apigenin inhibited the expressions of α-SMA, fibronectin, and collagen type I. Inhibitors of MAPK (p-38, JNK) and NF-κB blocked the expression of α-SMA, fibronectin and collagen type I. Apigenin suppressed the activation of MAPK (p-38, JNK) and NF-κB induced by TGF-β1 treatment. Apigenin also inhibited the functional activity of fibroblasts by reducing the migration and collagen contractile activities. Conclusions: These results suggests the possible use of apigenin as a chronic rhinosinusitis therapeutic agent which can suppress tissue remodeling in nasal mucosa. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) is an inflammation of the sinonasal mucosa and many inflammatory cells and cytokines are involved in its pathogenesis. High-mobility group protein B1 (HMGB1) is a DNA-binding protein that has a proinflammatory function when secreted into extracellular space. The purpose of this study was to evaluate the expression of HMGB1 in paranasal sinus mucosa and to determine the difference of HMGB1 expression between CRS patients and normal controls. Methods: Paranasal sinus mucosa was obtained from 10 patients with CRS and 10 patients without CRS. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR and Western blot analysis were performed to detect mRNA and protein. Sections of the mucosa were immunostained for localization of HMGB1 and image analysis was performed. Results: RT-PCR and real-time PCR showed that the expression level of HMGB1 mRNA was significantly increased in the tissues of patients with CRS compared with controls. Western blot analysis showed that the expression level of HMGB1 protein was significantly increased in the tissues of CRS. In immunohistochemical staining, the HMGB1 protein was expressed in epithelial cells and inflammatory cells and the expression intensity of HMGB1 protein was stronger in CRS. Conclusion: HMGB1 is increased in the paranasal sinus mucosa of patients with CRS. These results suggest a possible contribution of HMGB1 in the pathophysiology of CRS. [ABSTRACT FROM AUTHOR]

Background: Although mucosal cysts in the paranasal sinuses (PSMCs) are commonly detected, the long-term follow-up studies of PSMCs are sparse. This study evaluated the natural course of PSMCs and identified risk factors for the disease progression. Methods: A total of 133 subjects with PSMCs who underwent health checkup including brain magnetic resonance imaging more than two times with an interval of ≥24 months between January 2000 and December 2009 were included. The characteristics of PSMCs were analyzed on the initial and follow-up images. Nasal symptoms, smoking status, and comorbid medical conditions were evaluated using structured questionnaires and medical records. Results: The mean follow-up duration was 40.38 months (range, 24.0-109.8 months). The mean size of PSMCs decreased from 15.07 to 12.73 mm. Only 8.3% of subjects showed an increase in size, whereas the size of cysts was decreased or unchanged in the remaining 91.7% of subjects. Six (4.5%) subjects complained of nasal symptoms during follow-up and subsequent sinusitis was developed in 3% of subjects. An increase in cyst size was associated with development of sinusitis (odds ratio = 45.375). Initial size of cysts >20 mm and bilateral location were significant risk factors for progression (p = 0.019 and p = 0.039, respectively). Conclusion: The majority of PSMCs in this follow-up study were decreased or unchanged and most subjects were asymptomatic. Just observation is enough for most PSMCs. However, those who have a large cyst (>20 mm) or bilateral cysts at initial diagnosis were at risk for disease progression and should be regularly followed. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) is an inflammatory disease of the sinonasal mucosa. Thymic stromal lymphopoietin (TSLP) is associated with T‐helper 2 (Th2) response and induced by pathogen, allergen, toll‐like receptor (TLR) ligands, and cytokines. Fibroblasts are known to be modulators of wound‐healing, from inflammation to tissue remodeling. We examined effect of lipopolysaccharide (LPS) on TSLP production and the underlying mechanisms. We aimed to determine whether the effects of commonly used medications in CRS, namely corticosteroids, and macrolides, are related to LPS‐induced TSLP in nasal fibroblasts. Methods: Fibroblasts were isolated from inferior turbinate tissues of CRS patients. TSLP and TLR4 expressions were determined by reverse transcript‒polymerase chain reaction (RT‐PCR), Western blot, enzyme‐linked immunoassay, and immunofluorescence staining. Mitogen‐activated protein kinase (MAPK), protein kinase B (Akt), and nuclear factor‐kappaB (NF‐κB) phosphorylation was determined by Western blot and/or luciferase assay. Results: LPS increased TSLP expression in a dose‐ and time‐dependent manner. LPS antagonist and corticosteroids inhibited TLR4 expression in LPS‐stimulated fibroblasts. LPS‐RS, macrolides, corticosteroids, and specific inhibitors suppressed LPS‐induced alterations. Ex vivo culture showed similar results. Conclusion: LPS induces TSLP production via the TLR4, MAPK, Akt, and NF‐κB pathways. The effects of corticosteroids and macrolides are related to LPS‐induced TSLP expression. We explored new treatment modalities targeting LPS‐induced TSLP production that could replace the currently used corticosteroid and macrolides for treatment of CRS. [ABSTRACT FROM AUTHOR]