Publications by authors named "Roza Khalmuratova"

31 Publications

DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition.

J Allergy Clin Immunol 2021 May 4. Epub 2021 May 4.

Obstructive Upper airway Research Laboratory, the Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea. Electronic address:

Background: Diesel exhaust particles (DEPs) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear.

Objective: We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model.

Methods: Gene set enrichment and weighted gene coexpression network analyses were performed. Cytotoxicity, epithelial-to-mesenchymal transition (EMT) markers, and nasal polyposis were assessed. Effects of DEP exposure on EMT were determined using epithelial cells from normal people or patients with chronic rhinosinusitis with or without NPs. BALB/c mice were exposed to DEP through either a nose-only exposure system or nasal instillation, with or without house dust mite, followed by zinc finger E-box-binding homeobox (ZEB)2 small hairpin RNA delivery.

Results: Bioinformatics analyses revealed that DEP exposure triggered EMT features in airway epithelial cells. Similarly, DEP-exposed human nasal epithelial cells exhibited EMT characteristics, which were dependent on ZEB2 expression. Human nasal epithelial cells derived from patients with chronic rhinosinusitis presented more prominent EMT features after DEP treatment, when compared with those from control subjects and patients with NPs. Coexposure to DEP and house dust mite synergistically increased the number of NPs, epithelial disruptions, and ZEB2 expression. Most importantly, ZEB2 inhibition prevented DEP-induced EMT, thereby alleviating NP formation in mice.

Conclusions: Our data show that DEP facilitated NP formation, possibly via the promotion of ZEB2-induced EMT. ZEB2 may be a therapeutic target for DEP-induced epithelial damage and related airway diseases, including NPs.
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http://dx.doi.org/10.1016/j.jaci.2021.04.024DOI Listing
May 2021

Bone morphogenetic protein-2 as a novel biomarker for refractory chronic rhinosinusitis with nasal polyps.

J Allergy Clin Immunol 2021 Mar 2. Epub 2021 Mar 2.

Department of Otorhinolaryngology-Head & Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea. Electronic address:

Background: Bone morphogenetic proteins (BMPs), which are members of the TGF-β superfamily, regulate bone remodeling by stimulating osteoblasts and osteoclasts. Although the association between osteitis and poor surgical outcomes is well known in patients with chronic rhinosinusitis (CRS), BMPs have not been fully investigated as potential biomarkers for the prognosis of CRS.

Objective: Our aim was to investigate the role of BMPs in osteitis in patients with CRS with nasal polyps (NPs) (CRSwNPs), as well as associations between BMPs and inflammatory markers in sinonasal tissues from patients with CRSwNP.

Methods: We investigated the expression of 6 BMPs (BMP-2, BMP-4, BMP-6, BMP-7, BMP-9, and BMP-10) and their cellular origins in NPs of human subjects by using immunohistochemistry and ELISA of NP tissues. Exploratory factor analysis was performed to identify associations between BMPs and inflammatory markers. Air-liquid interface cell culture of human nasal epithelial cells was performed to evaluate the induction of the epithelial-mesenchymal transition by BMPs.

Results: Of the 6 BMPs studied, BMP-2 and BMP-7 were associated with refractoriness. Only BMP-2 concentrations were higher in patients with severe osteitis and advanced disease extent according to the computed tomography findings. Eosinophils and some macrophages were identified as cellular sources of BMP-2 in immunofluorescence analysis. An in vitro experiment revealed that BMP-2 induced epithelial-mesenchymal transition in air-liquid interface-cultured human nasal epithelial cells, particularly in a T2 milieu.

Conclusion: BMP-2 could reflect the pathophysiology of mucosa and bone remodeling. and may be a novel biomarker for refractory CRSwNP.
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http://dx.doi.org/10.1016/j.jaci.2021.02.027DOI Listing
March 2021

Effect of lipopolysaccharide and polyinosinic:polycytidylic acid in a murine model of nasal polyp.

Sci Rep 2021 Jan 13;11(1):1021. Epub 2021 Jan 13.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehagro, Jongro-gu, Seoul, 03080, Korea.

Several factors, including bacterial and viral infections, have been associated with rhinosinusitis and nasal tissue remodelling that may result in nasal polyp formation. However, the potential role of bacterial or viral stimuli triggering polyp development is unclear. Here, we used lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid [poly(I:C)] in a murine model of allergic rhinosinusitis to compare different effects of bacterial- and virus-derived stimuli in the pathogenesis of nasal polyp formation. Briefly, BALB/c mice were sensitised and challenged with ovalbumin and staphylococcal enterotoxin, with or without LPS or poly(I:C), and the consequent histopathological profiles, cytokines, and systemic humoral responses were studied. While no significant differences in polyp formations and epithelial disruptions were observed among the experimental groups, the local cell recruitment patterns slightly differed in animals that received either LPS or poly(I:C). Additionally, the local immune environments generated by LPS or poly(I:C) stimulation varied. LPS stimulation induced a marked Th1/Th17 response and predominantly neutrophilic nasal polyp formations, whereas poly(I:C) induced a Th2-skewed environment in neutrophilic nasal polyp development. Overall, our findings show that both cell recruitment patterns and local immune environments induced by these two stimuli differ, which may have implications in the physiopathology of rhinosinusitis with nasal polyp.
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http://dx.doi.org/10.1038/s41598-020-80483-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806732PMC
January 2021

Influence of the Genetic Background on Allergic Rhinitis Models in Mice.

Clin Exp Otorhinolaryngol 2020 Nov 1;13(4):322-323. Epub 2020 Nov 1.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.21053/ceo.2020.00892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669321PMC
November 2020

Crosstalk Between Mucosal Inflammation and Bone Metabolism in Chronic Rhinosinusitis.

Clin Exp Otorhinolaryngol 2021 Feb 4;14(1):43-49. Epub 2020 Sep 4.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Chronic rhinosinusitis (CRS) is a multifactorial and highly heterogeneous upper airway disease that affects approximately 12% of the general population. There is increasing evidence supporting the impact of osteitis on the pathophysiology of CRS. Osteitis is frequently observed in patients with CRS, and is associated with severe sinonasal inflammation and recalcitrant cases. The overlying inflammatory sinonasal mucosa plays a critical role in the initiation of osteitis; however, the underlying molecular mechanisms and functional significance remain unclear. Increasingly many studies have suggested that immune cells play a crucial role in the bone remodeling process in CRS. The purpose of this review is to summarize the current state of knowledge regarding the specific role of sinonasal inflammation in bone remodeling in CRS patients.
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http://dx.doi.org/10.21053/ceo.2020.00416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904438PMC
February 2021

Evaluation of Neo-Osteogenesis in Eosinophilic Chronic Rhinosinusitis Using a Nasal Polyp Murine Model.

Allergy Asthma Immunol Res 2020 03;12(2):306-321

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Osteitis refers to the development of new bone formation and remodeling of bone in chronic rhinosinusitis (CRS) patients; it is typically associated with eosinophilia, nasal polyps (NPs), and recalcitrant CRS. However, the roles of ossification in CRS with or without NPs remain unclear due to the lack of appropriate animal models. Thus, it is necessary to have a suitable animal model for greater advances in the understanding of CRS pathogenesis.

Methods: BALB/c mice were administered ovalbumin (OVA) and staphylococcal enterotoxin B (SEB). The numbers of osteoclasts and osteoblasts and bony changes were assessed. Micro computed tomography (micro-CT) scans were conducted to measure bone thickness. Immunofluorescence, immunohistochemistry, and quantitative polymerase chain reaction were performed to evaluate runt-related transcription factor 2 (RUNX2), osteonectin, interleukin (IL)-13, and RUNX2 downstream gene expression. Gene set enrichment analysis was performed in mucosal tissues from control and CRS patients. The effect of resveratrol was evaluated in terms of osteogenesis in a murine eosinophilic CRS NP model.

Results: The histopathologic changes showed markedly thickened bones with significant increase in osteoblast numbers in OVA/SEB-treated mice compared to the phosphate-buffered saline-treated mice. The structural changes in bone on micro-CT were consistent with the histopathological features. The expression of RUNX2 and IL-13 was increased by the administration of OVA/SEB and showed a positive correlation. RUNX2 expression mainly co-localized with osteoblasts. Bioinformatic analysis using human CRS transcriptome revealed that IL-13-induced bony changes via RUNX2. Treatment with resveratrol, a candidate drug against osteitis, diminished the expression of IL-13 and RUNX2, and the number of osteoblasts in OVA/SEB-treated mice.

Conclusions: In the present study, we found the histopathological and radiographic evidence of osteogenesis using a previously established murine eosinophilic CRS NP model. This animal model could provide new insights into the pathophysiology of neo-osteogenesis and provide a basis for developing new therapeutics.
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http://dx.doi.org/10.4168/aair.2020.12.2.306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997277PMC
March 2020

Impact of the Long-Lived Plasma Cells in Patients With Chronic Rhinosinusitis With Nasal Polyps.

Allergy Asthma Immunol Res 2020 03;12(2):173-175

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.4168/aair.2020.12.2.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997286PMC
March 2020

Superantigen-related T2 CD4 T cells in nonasthmatic chronic rhinosinusitis with nasal polyps.

J Allergy Clin Immunol 2020 05 25;145(5):1378-1388.e10. Epub 2020 Jan 25.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea; BioMedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, Korea. Electronic address:

Background: Staphylococcus aureus enterotoxin (SAE) superantigens are detected in nasal polyps (NPs), and SAE-specific IgE predicts asthma comorbidity in patients with NPs. However, roles of SAE superantigens and superantigen-related T-cell responses remain to be elucidated in nonasthmatic patients.

Objective: We investigated the presence of SAEs and SAE-related T-cell receptor (TCR) Vβ (TCRVβ) in nonasthmatic NPs, the phenotypes and functions of SAE-related T cells, and the clinical implication of SAE-related T-cell expansion.

Methods: Sinonasal tissue samples were obtained from patients with nonasthmatic chronic rhinosinusitis (CRS) with NPs (CRSwNP), patients with CRS without NPs (CRSsNP), and control subjects. SAE genes were detected by PCR, and the TCRVβ distribution and T-cell phenotypes were examined by flow cytometry.

Results: Various SAE genes were detected not only in NPs but also in sinonasal mucosa from patients with CRSsNP and from controls. The S aureus enterotoxin I (SEI) gene was detected in all NPs. The fraction of SEI-responsive TCRVβ (TCRVβ1 and Vβ5.1) CD4 T cells was significantly increased only in NPs and the ethmoidal mucosa of patients with CRSwNP, indicating superantigen-induced expansion. The expanded TCRVβ5.1 CD4 T cells expressed proliferation marker Ki-67 and the T2 transcription factor GATA3. Furthermore, TCRVβ5.1 CD4 T cells in NPs highly expressed T2 markers, including IL-17RB, thymic stromal lymphoprotein receptor, and chemoattractant receptor-homologous molecule expressed on T2 cells, with a potent T2 cytokine-producing ability. Moreover, the expansion of TCRVβ1 or Vβ5.1 CD4 T cells was associated with the Lund-Mackay computed tomography score, indicating disease extent.

Conclusion: In nonasthmatic patients with CRSwNP, superantigen-related expansion of CD4 T cells with T2 differentiation was associated with the disease extent.
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http://dx.doi.org/10.1016/j.jaci.2019.12.915DOI Listing
May 2020

α-Helical cell-penetrating peptide-mediated nasal delivery of resveratrol for inhibition of epithelial-to-mesenchymal transition.

J Control Release 2020 01 27;317:181-194. Epub 2019 Nov 27.

Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:

In the present study, we examined the potential of cell-penetrating peptide (CPP)-based intranasal drug delivery for the treatment of localized nasal diseases. Many charged or non-hydrophobic drugs have difficulty penetrating into the nasal epithelium due to intrinsic membrane impermeability and rapid mucociliary clearance in the nasal cavity. To treat chronic rhinosinusitis with nasal polyps (CRSwNP), one of the most common localized nasal diseases, we conjugated resveratrol (RSV) to an amphiphilic α-helical leucine (L)- and lysine (K)-rich CPP (LK) and intranasally delivered it to the interior of nasal epithelial cells for inhibiting epithelial-to-mesenchymal transition (EMT) caused by hypoxia-inducible factor 1α. The RSV-LK conjugate could penetrate into the nasal epithelium and efficiently inhibit EMT, nasal polyp formation, epithelial disruption, and related inflammation in an eosinophilic CRSwNP mouse model, at 10-fold lower doses and with 3-fold less frequent administration than free RSV. Due to the rapid penetration into the nasal epithelium and the therapeutic effect of the RSV-LK conjugate at much lower doses than free RSV, this CPP-based delivery system, with the ability to overcome the tight nasal epithelial barrier, may provide a new strategy for the treatment of localized nasal diseases without the systemic side effects of cargo drugs.
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http://dx.doi.org/10.1016/j.jconrel.2019.11.034DOI Listing
January 2020

Interleukin (IL)-13 and IL-17A contribute to neo-osteogenesis in chronic rhinosinusitis by inducing RUNX2.

EBioMedicine 2019 Aug 19;46:330-341. Epub 2019 Jul 19.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Ischemic/hypoxic disease institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: There is increasing evidence supporting the impact of neoosteogenesis in the pathophysiology of chronic rhinosinusitis (CRS), especially in the recalcitrant group of patients. Runt-related transcription factor 2 (RUNX2), a member of the RUNX family, controls osteoblast differentiation and bone formation. However, the role and regulation of RUNX2 in CRS patients with neoosteogenesis remain unclear. The aim of the study is to determine the role of RUNX2 in neoosteogenesis of CRS patients.

Methods: Sinonasal bone and overlying mucosa samples were obtained from CRS patients with or without neoosteogenesis (n = 67) and healthy controls (n = 11). Double immunofluorescence, immunohistochemistry, and immunoblotting were used to evaluate RUNX2 expression in CRS patients with and without neoosteogenesis. In addition, the osteogenic activity of pro-inflammatory cytokines was examined by measuring alkaline phosphatase (ALP) activity and bone mineralisation in vitro.

Findings: RUNX2 was highly expressed in osteoblasts of CRS patients with neoosteogenesis compared with tissues from control subjects and those with CRS without neoosteogenesis. Mucosal extracts from CRS patients with neoosteogenesis showed increased RUNX2 expression and ALP activity in C2C12 cells, whereas those from patients without neoosteogenesis did not. Expression of interleukin (IL)-13 and IL-17A was upregulated in CRS patients with neoosteogenesis. ALP activity and Alizarin Red staining showed IL-13 and IL-17A dose-dependent osteoblast differentiation and mineralisation in vitro.

Interpretation: These findings suggested that IL-13- or IL-17A-induced RUNX2 contributed to new bone formation in CRS patients through its effect on the activity of osteoblasts. RUNX2 may be a novel target for preventing neoosteogenesis in CRS patients.
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http://dx.doi.org/10.1016/j.ebiom.2019.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710985PMC
August 2019

The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition.

Mucosal Immunol 2019 05 25;12(3):601-611. Epub 2019 Feb 25.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammatory disease characterized by involvement of diverse types of inflammatory cells. Asian CRS patients frequently show infiltration of neutrophils and an elevated level of interferon (IFN)-γ; by contrast, western patients exhibit eosinophil infiltration and enhanced levels of Th2-related cytokines. Neutrophilia in tissues decreases sensitivity to corticosteroids, but the mechanisms underlying the progression of neutrophilic CRS are unclear. In this study, we investigated the role of IFN-γ in CRS patients with marked neutrophil infiltration. We report that the IFN-γ level is upregulated in the tissues of these patients, particularly those with non-eosinophilic nasal polyps. The level of IFN-γ was significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT). We further demonstrated that IFN-γ induced the EMT via the p38 and extracellular signal-regulated kinase (ERK) pathways in a manner distinct from the hypoxia-inducible factor (HIF)-1α, SMAD, and NF-κB signaling pathways. In a murine nasal polyp (NP) model, blocking the p38 and ERK signaling pathways prevented NP formation and chemotactic cytokine secretion by neutrophils but not eosinophils. Taken together, our results suggest that IFN-γ can induce the EMT in nasal epithelial cells, and thus blocking the p38 and ERK pathways could be an effective therapeutic strategy against neutrophil-dominant CRS.
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http://dx.doi.org/10.1038/s41385-019-0149-1DOI Listing
May 2019

Intermittent hypoxia promotes carcinogenesis in azoxymethane and dextran sodium sulfate-induced colon cancer model.

Mol Carcinog 2019 05 20;58(5):654-665. Epub 2019 Jan 20.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Intermittent hypoxia (IH), a characteristic of obstructive sleep apnea, is known to promote cancer progression and aggressiveness in mouse models. However, little is known regarding the effect of IH on cancer initiation. Here, the effect of IH on carcinogenesis was explored in azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced colon cancer models with three different protocols. In the first protocol, two other application time points (early or late initiation of IH) were applied. In the second protocol, mice were divided into only two groups, and then exposed to either N or IH conditions for 14 days. In the third protocol, a pharmacological inhibition study for anti-inflammation (5-aminosalicylate) or anti-oxidative stress (N-acetylcysteine [NAC]) was performed. The number of tumors was significantly higher in the IH-1 than in the N or IH-2 groups. 8-oxo-2'-deoxyguanosine (8-OHdG) levels were higher in tumors of the IH-1 group than in that of the N and IH-2 groups. Gene expression related to reactive oxygen species production was higher in the IH-1 group than in the N and IH-2 groups, and it showed a positive correlation with 8-OHdG levels. Prior to cancer development 8-OHdG levels were already elevated in colonic epithelial regions in the IH group, possibly due to an imbalance between oxidative stress and antioxidant systems. NAC treatment resulted in a significant reduction in the number of tumors in mice exposed to IH. In conclusion, IH promotes carcinogenesis in a chemically-induced colon cancer model where elevated 8-OHdG may contribute to the increased tumor induction.
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http://dx.doi.org/10.1002/mc.22957DOI Listing
May 2019

Wogonin attenuates nasal polyp formation by inducing eosinophil apoptosis through HIF-1α and survivin suppression.

Sci Rep 2018 04 18;8(1):6201. Epub 2018 Apr 18.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.

Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is an inflammatory sinonasal disorder characterized by eosinophilic inflammation and T-helper 2 skewing. Eosinophil accumulation in sinonasal mucosa comprises a major feature of CRSwNP. The study aimed to investigate the effect of the flavone wogonin in nasal polyposis by assessing its ability to induce eosinophil apoptosis in vitro and attenuate eosinophilic CRSwNP in mice. Double immunofluorescence, immunohistochemistry, flow cytometry, and immunoblotting were performed to evaluate hypoxia-inducible factor (HIF)-1α, survivin, and apoptotic markers in the human eosinophilic EoL-1 cell line or sinonasal tissues from patients with CRS with or without NPs. In sinonasal specimens from patients with CRS, HIF-1α and survivin were up-regulated in eosinophils from patients with NPs compared with levels in patients without NPs. Under hypoxia, HIF-1α and survivin expression was up-regulated in EoL-1 cells. Wogonin down-regulated both HIF-1α and survivin in EoL-1 cells. In addition, overexpression of survivin protected EoL-1 cells against apoptosis in response to wogonin. Moreover, wogonin attenuated nasal polyp formation in a murine model. Our findings suggest that wogonin could induce caspase-3 activation by suppressing HIF-1α and survivin expression in EoL-1 cells. Further studies regarding novel therapeutic options for CRSwNP targeting eosinophil apoptosis are needed.
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http://dx.doi.org/10.1038/s41598-018-24356-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906673PMC
April 2018

Fibrinogen cleavage products and Toll-like receptor 4 promote the generation of programmed cell death 1 ligand 2-positive dendritic cells in allergic asthma.

J Allergy Clin Immunol 2018 08 14;142(2):530-541.e6. Epub 2017 Oct 14.

Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea. Electronic address:

Background: Inhaled protease allergens preferentially trigger T2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on induction of T2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce T2-favorable DCs in the airway remains unclear.

Objective: We sought to determine a subset of DCs responsible for T2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway.

Methods: Mice were challenged intranasally with protease allergens or fibrinogen cleavage products (FCPs) to induce allergic airway inflammation. DCs isolated from mediastinal lymph nodes were analyzed for surface phenotype and T-cell stimulatory function. Anti-Thy1.2 and Mas-TRECK mice were used to deplete innate lymphoid cells and mast cells, respectively. Adoptive cell transfer, bone marrow DC culture, anti-IL-13, and Toll-like receptor (TLR) 4-deficient mice were used for further mechanistic studies.

Results: Protease allergens induced a remarkable accumulation of T2-favorable programmed cell death 1 ligand 2 (PD-L2) DCs in mediastinal lymph nodes, which was significantly abolished in mice depleted of mast cells and, to a lesser extent, innate lymphoid cells. Mechanistically, FCPs generated by protease allergens triggered IL-13 production from wild-type mast cells but not from TLR4-deficient mast cells, which resulted in an increase in the number of PD-L2 DCs. Intranasal administration of FCPs induced an increase in numbers of PD-L2 DCs in the airway, which was significantly abolished in TLR4- and mast cell-deficient mice. Injection of IL-13 restored the PD-L2 DC population in mice lacking mast cells.

Conclusion: Our findings unveil the "protease-FCP-TLR4-mast cell-IL-13" axis as a molecular mechanism for generation of T2-favorable PD-L2 DCs in allergic asthma and suggest that targeting the PD-L2 DC pathway might be effective in suppressing allergic T-cell responses in the airway.
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http://dx.doi.org/10.1016/j.jaci.2017.09.019DOI Listing
August 2018

Accelerated tumor growth under intermittent hypoxia is associated with hypoxia-inducible factor-1-dependent adaptive responses to hypoxia.

Oncotarget 2017 Sep 27;8(37):61592-61603. Epub 2017 Jun 27.

Obstructive Upper Airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul 03080, Korea.

Mounting evidence has revealed a causative role of intermittent hypoxia (IH) in cancer progression in mouse models of obstructive sleep apnea (OSA), but most studies have focused on the effects of IH following tumor implantation using an exposure to single IH frequency. Thus, we aimed to investigate 1) the potential effect of IH on the initial tumor growth in patients with OSA without an interaction with other mechanisms induced by IH in mice and 2) the influence of the IH frequency on tumor growth, which were tested using pre-conditioning with IH (Pre-IH) and 2 different IH frequencies, respectively. Pre-IH was achieved by alternatively maintaining melanoma cells between normoxia (10 min, 21% O) and hypoxia (50 min, 1% O) for 7 days (12 cycles per day) before administering them to mice. The conditions for IH-1 and IH-2 were 90 s of 12% FiO followed by 270s of 21% FiO (10 cycles/h), and 90 s of 12% FiO and 90 s of 21% FiO (20 cycles/h), respectively, for 8 h per day. Tumor growth was significantly higher in the Pre-IH group than in the normoxia group. In addition, the IH-2 group showed more accelerated tumor growth compared to the normoxia and IH-1 groups. Immunohistochemistry and gene-expression results consistently showed the up-regulation of molecules associated with HIF-1α-dependent hypoxic adaptation in tumors of the Pre-IH and IH-2 groups. Our findings reveal that IH increased tumor progression in a frequency-dependent manner, regardless of whether it was introduced before or after tumor cell implantation.
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http://dx.doi.org/10.18632/oncotarget.18644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617448PMC
September 2017

Serial Analysis of Tracheal Restenosis After 3D-Printed Scaffold Implantation: Recruited Inflammatory Cells and Associated Tissue Changes.

Tissue Eng Regen Med 2017 Oct 13;14(5):631-639. Epub 2017 Sep 13.

1Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080 Korea.

Tracheal restenosis is a major obstacle to successful tracheal replacement, and remains the greatest challenge in tracheal regeneration. However, there have been no detailed investigations of restenosis. The present study was performed to analyze the serial changes in recruited inflammatory cells and associated histological changes after tracheal scaffold implantation. Asymmetrically porous scaffolds, which successfully prevented tracheal stenosis in a partial trachea defect model, designed with a tubular shape by electrospinning and reinforced by 3D-printing to reconstruct 2-cm circumferential tracheal defect. Serial rigid bronchoscopy, micro-computed tomography, and histology [H&E, Masson's Trichrome, IHC against α-smooth muscle actin (α-SMA)] were performed 1, 4, and 8 weeks after transplantation. Progressive stenosis developed especially at the site of anastomosis. Neutrophils were the main inflammatory cells recruited in the early stage, while macrophage infiltration increased with time. Recruitment of fibroblasts peaked at 4 weeks and deposition of α-SMA increased from 4 weeks and was maintained through 8 weeks. During the first 8 weeks post-transplantation, neutrophils and macrophages played significant roles in restenosis of the trachea. Antagonists to these would be ideal targets to reduce restenosis and thus play a pivotal role in successful tracheal regeneration.
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http://dx.doi.org/10.1007/s13770-017-0057-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171631PMC
October 2017

Immune Cell Responses and Mucosal Barrier Disruptions in Chronic Rhinosinusitis.

Immune Netw 2017 Feb 23;17(1):60-67. Epub 2017 Feb 23.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul 03080, Korea.; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea.; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul 03080, Korea.

Chronic rhinosinusitis (CRS) is one of the most common presentations of upper airway illness and severely affects patient quality of life. Its frequency is not surprising given levels of environmental exposure to microbes, pollutants, and allergens. Inflammatory cells, inflammatory cytokine and chemokine production, and airway remodeling have been detected in the sinonasal mucosae of CRS patients, although the precise pathophysiological mechanisms causing such persistent inflammation remain unclear. Given its high prevalence and considerable associated morbidity, continued research into CRS is necessary to increase our understanding of factors likely to contribute to its pathogenesis, and facilitate the development of novel therapeutic strategies to improve treatment. The purpose of this review is to summarize the current state of knowledge regarding immune cell responses and epithelial alterations in CRS.
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http://dx.doi.org/10.4110/in.2017.17.1.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334123PMC
February 2017

Sinonasal Delivery of Resveratrol via Mucoadhesive Nanostructured Microparticles in a Nasal Polyp Mouse Model.

Sci Rep 2017 01 10;7:40249. Epub 2017 Jan 10.

Institute of Medical &Biological Engineering, Medical Research Center, Seoul National University, Seoul, 03080, Republic of Korea.

Resveratrol (RSV) has been shown to effectively suppress chronic rhinosinusitis with nasal polyps in a mouse model; however, when locally administered to the sinonasal cavity, bolus RSV is limited by low drug bioavailability owing to its low aqueous solubility and relatively rapid clearance from the administration site. To address this limitation, we propose mucoadhesive nanostructured microparticles (PLGA/PEG NM) as a potential carrier for the sinonasal delivery of RSV. In this study, PLGA/PEG NM released RSV in a sustained manner. Owing to the enlarged specific surface area of the nanostructures, PLGA/PEG NM had synergistically enhanced mucoadhesiveness and thus showed improved in vivo retention properties in the sinonasal cavity. Therefore, when tested in a mouse nasal polyp model, PLGA/PEG NM mitigated polyp formation and restored epithelial integrity better than the control treatments. The therapeutic effect was similar at half the dose of PLGA/PEG NM, suggesting improved local bioavailability of RSV in the sinonasal cavity.
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http://dx.doi.org/10.1038/srep40249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223156PMC
January 2017

Chronic anosmia induces depressive behavior and reduced anxiety via dysregulation of glucocorticoid receptor and corticotropin-releasing hormone in a mouse model.

Rhinology 2016 03;54(1):80-7

Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: Olfactory loss is highly prevalent, and comorbid mood disorders are common. Considering olfactory input is highly interconnected with the limbic system, and that the limbic system manages mood, it is predictable that impairments in the sense of smell may result in mood changes.

Methodology: Chronic olfactory deficits were induced by repeated intranasal irrigation of ZnSO4 for 12 weeks in BALB/c mice. H&E staining, OMP staining, and potato chip finding test were performed to confirm olfactory loss. Tail suspension, forced swim, and splash tests were performed to evaluate depression, as well as open field, elevated plus maze tests were applied to assess anxiety. The mRNA levels of glucocorticoid receptor (GR) and corticotropin releasing hormone (CRH) were measured by real-time PCR to confirm relevant molecular changes.

Results: Disruption of the olfactory epithelium and olfactory loss was confirmed in histological studies and potato chip finding test. Behavioral tests show that the chronic anosmic state caused increased depression and reduced anxiety. PCR data showed that mRNA levels of GR in the hypothalamus and CRH in the amygdala were significantly decreased.

Conclusions: These results propose that ZnSO4-induced chronic anosmia can cause a depressive and anxiolytic state via decreased hypothalamic GR and amygdalar CRH.
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http://dx.doi.org/10.4193/Rhino15.209DOI Listing
March 2016

Sirtuin 1 attenuates nasal polypogenesis by suppressing epithelial-to-mesenchymal transition.

J Allergy Clin Immunol 2016 Jan 2;137(1):87-98.e7. Epub 2015 Sep 2.

Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea; Cancer Research Institute, Seoul National University, Seoul, Korea. Electronic address:

Background: Nasal polyps (NPs) imply a refractory clinical course in patients with chronic rhinosinusitis (CRS). Previously, we showed that hypoxia-inducible factor (HIF) 1 could mediate nasal polypogenesis through epithelial-to-mesenchymal transition (EMT). Sirtuin 1 (SIRT1), a histone deacetylase, reportedly suppresses the transcriptional activity of HIF-1. Thus we hypothesized that SIRT1 attenuates nasal polyposis by inhibiting HIF-1-induced EMT.

Objective: We sought to determine the role of SIRT1 in patients with nasal polyposis.

Methods: The effects of SIRT1 on nasal polypogenesis were investigated in previously developed murine models. Immunohistochemistry, immunoblotting, and immunoprecipitation were done to evaluate SIRT1, EMT, and hypoxic markers in human nasal epithelial cells or sinonasal tissues from the mice and the patients with CRS with or without NPs.

Results: SIRT1 transgenic mice had significantly fewer mucosal lesions with epithelial disruption and fewer NPs than wild-type (WT) mice. In addition, resveratrol (a SIRT1 activator) treatment suppressed nasal polypogenesis in WT mice; however, sirtinol (a SIRT1 inhibitor) administration increased the polyp burden in SIRT1 transgenic mice. In sinonasal specimens from patients with CRS, SIRT1 was downregulated in the mucosa from patients with polyps compared with levels seen in patients without polyps. SIRT1 overexpression or activation reversed hypoxia-induced EMT in human nasal epithelial cells. The intranasal transfection of a small hairpin SIRT1 lentiviral vector induced more nasal polypoid lesions in SIRT1 transgenic mice. Finally, mucosal extracts from patients with CRS without NPs increased SIRT1 expression in nasal epithelial cells, whereas those from patients with CRS with NPs did not.

Conclusion: SIRT1 suppressed NP formation, possibly because of inhibition of HIF-1-induced EMT. Thus nasal epithelium SIRT1 might be a therapeutic target for NPs.
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http://dx.doi.org/10.1016/j.jaci.2015.07.026DOI Listing
January 2016

Clinical and histologic studies of olfactory outcomes after nasoseptal flap harvesting.

Laryngoscope 2013 Jul 21;123(7):1602-6. Epub 2013 Mar 21.

Department of Otorhinolaryngology, Gyeongsang National University Hospital, Jinju, Korea.

Objectives/hypothesis: Since the introduction of an endonasal endoscopic approach in transsphenoidal pituitary surgery, reports of perioperative olfactory changes have presented conflicting results. We examined the incidence of olfactory loss in cases of endoscopic transsphenoidal pituitary surgery with skull base repair using the nasoseptal flap (NSF) and the effects of monopolar electrocautery commonly used in designing the NSF.

Study Design: Case-control study.

Methods: Fifteen patients who underwent endoscopic transsphenoidal pituitary surgery with skull base reconstruction using the NSF were divided into cold knife (n = 8) and electrocautery (n = 7) groups according to the device used in the superior incision of the NSF. Patients were followed regularly to monitor the need for dressing or adhesiolysis around the olfactory cleft. All subjects received olfactory tests before and 6 months after surgery. Septal mucosa specimens obtained during posterior septectomy were incised with different devices, and the degree of mucosal damage was evaluated.

Results: One patient in the electrocautery group demonstrated olfactory dysfunction postoperatively, but the other 14 patients showed no decrease in olfaction. In histologic analyses, 55.8% and 76.9% of the mucosal surface showed total epithelial loss when the mucosa was cut with cutting- and coagulation-mode electrocautery, respectively. In contrast, only 20% of the mucosal surface exhibited total epithelial loss when the mucosa was cut with a cold knife (P < .01).

Conclusions: Olfactory impairment is not common after use of the NSF. Use of the cold knife in making superior incision may reduce tissue damage with better olfactory outcomes.
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http://dx.doi.org/10.1002/lary.24107DOI Listing
July 2013

Roles of periostin in symptom manifestation and airway remodeling in a murine model of allergic rhinitis.

Allergy Asthma Immunol Res 2012 Jul 8;4(4):222-30. Epub 2012 Jun 8.

Department of Otorhinolaryngology, School of Medicine, Gyeongsang National University, Jinju, Korea.

Purpose: Periostin was originally identified as a secreted factor during screening of a mouse osteoblastic library. In a recent study, periostin was found to directly regulate eosinophil accumulation in allergic mucosal inflammation. Chronic eosinophilic inflammation is related to the development of remodeling. The present study examined the expression of periostin and evaluated its role in the inflammatory process and remodeling associated with allergic rhinitis.

Methods: A murine model of allergic rhinitis was established in periostin knockout mice. We analyzed the expression of periostin, manifestation of nasal symptoms, eosinophilic inflammation, and subepithelial fibrosis as well as the expression of MMP-2, TIMP-1, and type 1 collagen in nasal tissue.

Results: Periostin was mainly distributed in the subepithelial tissue of the nasal mucosa. The subepithelial tissue was thinner in the knockout group than in the control group. No differences in the expression of MMP-2 or TIMP-1 were found in the knockout group. However, after a month of allergen challenge, type I collagen in the nasal tissue was lower in the knockout group than in the control group. The number of eosinophils and the symptom score were also lower in the knockout group.

Conclusions: Periostin is expressed in nasal tissues of murine models of allergic rhinitis. Periostin deficiency may affect the remodeling of nasal tissue with reduced subepithelial fibrosis, and lead to less eosinophilic inflammation.
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http://dx.doi.org/10.4168/aair.2012.4.4.222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378929PMC
July 2012

Hypoxia-inducible factor 1 mediates nasal polypogenesis by inducing epithelial-to-mesenchymal transition.

Am J Respir Crit Care Med 2012 May 9;185(9):944-54. Epub 2012 Feb 9.

Department of Pharmacology and Biomedical Science, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.

Rationale: Nasal polyposis implies a refractory clinical course in case of chronic rhinosinusitis (CRS). Although hypoxia is believed to be associated with nasal polyposis, little is known about the mechanism underlying polypogenesis.

Objectives: To determine if hypoxia drives nasal polyposis by epithelial-to-mesenchymal transition (EMT).

Methods: Immunoblotting, immunofluorescence, flow cytometry, and real-time polymerase chain reaction were performed to evaluate EMT and hypoxic markers in human nasal epithelial cells (hNECs) and in sinonasal tissues from patients with CRS with or without polyps. In addition, the effects of hypoxia-inducible factor (HIF)-1α inhibitors on nasal polypogenesis were investigated in a murine model.

Measurements And Main Results: E-cadherin and α-smooth muscle actin (α-SMA) were down-regulated and up-regulated, respectively, in patients with polyps as compared with patients without polyps. Under hypoxia, hNECs transformed to a mesenchymal shape, and demonstrated representative changes in EMT markers; that is, mesenchymal markers (α-SMA, vimentin, and twist) increased but epithelial markers (E-cadherin and β-catenin) decreased. Mechanistically, E-cadherin level was recovered in hypoxia by silencing HIF-1α and decreased in normoxia by expressing HIF-1α. Furthermore, hypoxia was found to down-regulate PP2Ac phosphatase and up-regulate pSmad3, which led to α-SMA induction. In CRS sinonasal specimens, HIF-1α expression was found to correlate with E-cadherin loss and α-SMA expression. Finally, HIF-1α inhibitors suppressed nasal polypogenesis in a murine model.

Conclusions: hNECs undergo EMT during hypoxia and this process is critically mediated by HIF-1α and pSmad3. This study shows that hypoxia-induced EMT is likely to contribute to nasal polyposis in CRS, and suggests that HIF-1α be viewed as a therapeutic target for nasal polyposis.
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http://dx.doi.org/10.1164/rccm.201109-1706OCDOI Listing
May 2012

Staphylococcus aureus enterotoxin B contributes to induction of nasal polypoid lesions in an allergic rhinosinusitis murine model.

Am J Rhinol Allergy 2011 Nov-Dec;25(6):e255-61

Department of Otorhinolaryngology, Gyeongsang National University, Jinju, Korea.

Background: Studies on the pathophysiology of nasal polyps in human subjects have been limited; thus an animal model is needed. There is increasing evidence supporting the role of Staphylococcus aureus enterotoxin B (SEB) in the pathogenesis of nasal polyposis. The aim of this study was to investigate the histological and immunologic effects of SEB on the formation of nasal polypoid lesions in an allergic rhinosinusitis murine model.

Methods: After induction of an ovalbumin (OVA)-induced allergic rhinosinusitis, OVA with SEB (5 or 500 ng) was instilled into the nasal cavity of mice for 8 weeks. Control mice did not receive SEB or OVA instillation. Histopathological changes were observed using hematoxylin and eosin, Sirius red, Giemsa, Masson's trichrome, and Alcian blue stains. The levels of interleukin (IL)-4, IL-5, IL-8, IL-13, eotaxin, interferon gamma, total IgE, and OVA-specific IgE from serum or nasal lavage fluid were measured using enzyme-linked immunosorbent assay.

Results: The group treated with OVA plus 5 ng of SEB had significantly more mucosal lesions with epithelial disruption and nasal polypoid lesions than mice treated with OVA only, showing a significant increase in the infiltration of total inflammatory cells, eosinophils, and lymphocytes than the other groups. Levels of IL-5, eotaxin, and OVA-specific IgE in nasal lavage fluid were increased in the group treated with OVA plus 5 ng of SEB than in the other groups. A higher number of secretory cells in the groups treated with OVA plus SEB was observed than in other groups.

Conclusion: Low-dose SEB induced nasal polypoid lesions with an increased eosinophilic infiltration in an allergic rhinosinusitis murine model.
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http://dx.doi.org/10.2500/ajra.2011.25.3727DOI Listing
May 2012

Immunohistochemical and biomolecular identification of melatonin 1a and 1b receptors in rat vestibular nuclei.

Auris Nasus Larynx 2012 Oct 4;39(5):479-83. Epub 2011 Nov 4.

Department of Otolaryngology, School of Medicine, Gyeongsang National University, Jinju, South Korea.

Objective: The aim of this study was to examine the localizations and expressions of melatonin 1a (MT1a) and 1b (MT1b) receptors in rat vestibular nuclei by immunohistochemical staining and reverse transcriptase-polymerase chain reaction.

Materials And Methods: Twenty male Sprague-Dawley rats were used in this study. Antibodies for the MT1a and MT1b receptors were used in 10 rats, respectively. A further 10 animals were sacrificed for RT-PCR. Tissues containing medial vestibular nuclei were selectively isolated from brain stem slices for RT-PCR.

Results: MT1a and MT1b receptor immunopositive neurons were found to be distributed throughout the four major vestibular nuclei. Both receptors were primarily detected in neuronal somata and their proximal dendrites. The presences of the mRNAs of the MT1a and MT1b receptors were confirmed by RT-PCR in medial vestibular nuclei and trigeminal ganglia.

Conclusions: The present study demonstrates, for the first time, that MT1a and MT1b receptors are localized and expressed in rat vestibular nuclei. This study provides additional insight into the role of melatonin receptors during vestibular signal processing.
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http://dx.doi.org/10.1016/j.anl.2011.09.007DOI Listing
October 2012

Effect of dexamethasone on wound healing of the septal mucosa in the rat.

Am J Rhinol Allergy 2011 May-Jun;25(3):112-6

Department of Otorhinolaryngology, College of Medicine, Gyeongsang National University, Jinju, Korea.

Background: Postoperative treatment after functional endoscopic sinus surgery (FESS) aims to modulate the wound healing process. Systemic or topically applied corticosteroids have been reported to be beneficial for improving nasal wound healing after FESS. However, few studies have investigated the effects of postoperative systemic steroids on nasal wound healing with regard to histological changes. The aim of this study was to evaluate the effect of systemic dexamethasone on nasal wound healing after mechanical injury in the rat.

Methods: A unilateral wound in the nasal cavity was induced using the brushing technique in 4-week-old, Sprague-Dawley rats (n = 70). Dexamethasone (0.15 mg/kg daily for 7 days) and normal saline were administered i.p. to the experimental and control groups (n = 35 for each) after the injury. The rats (n = 7 for each) were killed on days 2, 5, 14, 28, and 42 after the injury. Histological changes in the nasal mucosa were examined and compared using hematoxylin and eosin and Masson's trichrome staining.

Results: The experimental group showed less subepithelial edema formation and epithelial disarray at the early phase of the wound healing period. There were statistically significant differences in the subepithelial thickness and epithelial thickness indices between the experimental and control groups (p < 0.05). Ciliary and goblet cell indices were lower in the experimental group, which means that ciliary and goblet cell regeneration may be delayed by dexamethasone (p < 0.05). There were no differences in the subepithelial fibrosis index between the two groups. Adhesion formation between the nasal septum and turbinate were found only in the control group.

Conclusion: Systemic dexamethasone after mucosal injury may lessen subepithelial edema, goblet cell hyperplasia, and adhesion formation; however, it may cause delayed mucosal ciliary regeneration.
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http://dx.doi.org/10.2500/ajra.2011.25.3595DOI Listing
November 2011

Immunohistochemical and biomolecular identification of 5-HT₇ receptor in rat vestibular nuclei.

J Vestib Res 2010 ;20(6):401-6

Department of Otolaryngology, School of Medicine, Gyeongsang National University, Jinju, South Korea.

The association between migraine and balance disorder morbidities has been a topic of interest for many years, and serotonin (5-HT) receptor is known to be closely related with migraine and also to be associated with vestibular symptoms. However, the mechanism underlying the pathogenesis of migrainous vertigo and its association with 5-HT has not been elucidated. Of the many 5-HT receptors, 5-HT₇ receptor has recently attracted attention in the context of migraine treatment. The purpose of this study was to investigate the localization and expression of 5-HT₇ receptor in the rat vestibular nuclei by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR). The present study might provide additional insight into the role of 5-HT₇ receptor in the pathogenesis of migraine-related vestibular symptoms.
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http://dx.doi.org/10.3233/VES-2010-0390DOI Listing
May 2011

Quantitative analysis of myosin heavy chain expression change in laryngeal muscle after irradiation in rats.

Yonsei Med J 2011 Jan;52(1):158-64

Department of Otorhinolaryngology, Institute of Health Science, College of Medicine, Gyeongsang National University, 90 Chilam-dong, Jinju 660-702, Korea.

Purpose: Radiotherapy for head and neck cancer does not impair the voice quality as much as laser treatment or surgery, but it can induce muscle wasting and fibrosis and symptoms of dry mouth. We investigated the effect of irradiation on the myosin heavy chain (MyHC) expression in laryngeal muscles.

Materials And Methods: Rats were irradiated with one dose of 10, 15, 20, 25, 30, or 35 Gy and other rats were irradiated with 20 Gy. The thyroarytenoid (TA), posterior cricoarytenoid (PCA), and cricothyroid (CT) muscles were subjected to reverse transcription-polymerase chain reaction (RT-PCR).

Results: Two weeks after irradiation with 10, 15, or 20 Gy, all the MyHC type expressions had decreased in a dose-dependent manner in the TA, PCA, and CT muscles, and especially the expression of MyHC IIa decreased much more than the expressions of the other MyHC isoforms in all muscles. In the 20 Gy-irradiated rats, almost all the MyHC isoform expressions declined over 12 weeks in the TA, PCA, and CT muscles, except for the MyHC I expression in the PCA and CT muscle. The MyHC IIa expression was markedly decreased in all the muscles.

Conclusion: The laryngeal muscles responded differently to radiation, but they showed a time-dependent and long-lasting decrease in the expressions of all the MyHC isoforms in the TA, PCA, and CT muscles. In particular, the expression of the MyHC IIa isoform in all the muscles may be more sensitive to irradiation than the expressions of the other MyHC isoforms.
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http://dx.doi.org/10.3349/ymj.2011.52.1.158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017692PMC
January 2011

Wound healing of nasal mucosa in a rat.

Am J Rhinol Allergy 2009 Nov-Dec;23(6):e33-7

Department of Otolaryngology, College of Medicine, Gyeongsang National University, Jinju, South Korea.

Background: Postoperative wound healing of the nasal mucosa is a highly organized process. However, this process still has not been fully understood. The present study aimed to establish a wound healing model in a rat and describe histomorphological changes of the nasal mucosa after mechanical injury.

Methods: Unilateral wound in the nasal cavity was induced using the brushing technique in 4-week-old, Sprague-Dawley rats. Experimental rats were divided into five groups (n = 7 for each group). Animals were killed 1 hour and 2, 5, 14, and 28 days after injury. The histological sections were examined for inflammatory cell infiltration, goblet, and ciliated cell formation in hematoxylin and eosin staining. The subepithelial and epithelial thicknesses were measured and expressed as the subepithelial thickness index (STI) and epithelial thickness index (ETI). Fibrosis was evaluated by subepithelial fibrosis index (SFI) in Masson's trichrome-stained sections.

Results: Respiratory epithelial discontinuity and hemorrhage were observed 1 hour after injury. On day 2, edematous subepithelium and infiltration of neutrophils could be found on the injured site. Day 5 was characterized by the infiltration of monocytes and granulation tissue. SFI and ETI values increased significantly at day 14. Goblet cells and ciliated cells began to regenerate from day 14 and restored to near normal at day 28.

Conclusion: Using mechanical injury, the wound healing model of the nasal mucosa was established in a rat. The regeneration of respiratory mucosa was completed on day 28 after injury.
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http://dx.doi.org/10.2500/ajra.2009.23.3390DOI Listing
June 2010

Colocalization of 5-HT1F receptor and calcitonin gene-related peptide in rat vestibular nuclei.

Neurosci Lett 2009 Nov 6;465(2):151-6. Epub 2009 Sep 6.

Department of Otolaryngology, College of Medicine, Gyeongsang National University, Jinju, South Korea.

The aim of this study was to determine whether calcitonin gene-related peptide (CGRP) colocalizes with 5-HT(1F) receptor in rat vestibular nuclei using a double immunohistochemical staining procedure. The frequent co-occurrence of migraine and balance disorders suggests a pathophysiologic link between the two. However, the mechanism of migrainous vertigo has not been elucidated, though serotonin (5-HT) and its receptors are believed to involve in the pathogenesis of migrainous vertigo. Furthermore, 5-HT(1F) receptor agonists and CGRP receptor antagonists have recently attracted attention as potential treatments for migraine, and CGRP release from trigeminal neurons has been associated with migraine. This study demonstrates the colocalization of 5-HT(1F) receptor and CGRP in the rat vestibular nuclei, which suggests that 5-HT(1F) receptor regulates the release of CGRP from vestibular nuclei. This finding indicates that 5-HT(1F) receptor agonists may ameliorate migrainous vertigo by attenuating elevated levels of CGRP release from vestibular nuclei.
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http://dx.doi.org/10.1016/j.neulet.2009.09.008DOI Listing
November 2009