Publications by authors named "Hyun-Jik Kim"

67 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

Correlation of site of obstruction between two dynamic evaluation modalities in obstructive sleep apnea patients: drug-induced sleep endoscopy and sleep videofluoroscopy.

Sleep Breath 2020 Oct 22. Epub 2020 Oct 22.

Department of Otorhinolaryngology-HNS, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Drug-induced sleep endoscopy (DISE) and sleep videofluoroscopy (SVF) are two dynamic modalities for evaluating the upper airway in patients with obstructive sleep apnea (OSA). We evaluated the correlation of obstructive sites determined by DISE and SVF in OSA patients and elucidate findings that can improve the accuracy of upper airway assessment.

Methods: A consecutive series of 63 patients with OSA who underwent DISE and SVF were the subjects of this study. The DISE and SVF findings were divided according to the anatomical structure responsible for the collapse, including the soft palate (SP), oropharyngeal lateral walls (LW), tongue base (TB), and larynx (LX). The obstruction was graded on the three-point scale: 0, no obstruction; 1, partial obstruction; or 2, complete obstruction. Additionally, grade 1.5 TB obstruction was designated when the posterior displacement of the anterior tongue was detected during simultaneous retropalatal obstruction. The agreement rate and Cohen's kappa test between the two modalities were also assessed.

Results: The agreement rate between the two modalities was highest in LX (88.9%) followed by SP (85.7%), TB (76.1%), and LW (74.6%) (Cohen's kappa value = 0.757 in LX, 0.642 in SP, 0.637 in TB, 0.612 in LW, respectively). When grade 1.5 and 2 TB obstructions were combined, the agreement rate increased to 88.9% (Cohen's kappa value = 0.757).

Conclusions: We found a good overall agreement between the two dynamic airway evaluation modalities during drug-induced sleep, and this correlation may be improved if the posterior displacement of the anterior tongue during DISE is used as a sign of TB obstruction.
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http://dx.doi.org/10.1007/s11325-020-02225-8DOI Listing
October 2020

Symbiotic microbiome Staphylococcus aureus from human nasal mucus modulates IL-33-mediated type 2 immune responses in allergic nasal mucosa.

BMC Microbiol 2020 10 7;20(1):301. Epub 2020 Oct 7.

Department of Otorhinolaryngology - Head and Neck Surgery, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Background: The host-microbial commensalism can shape the innate immune responses in respiratory mucosa and nasal microbiome also modulates front-line immune mechanism in the nasal mucosa. Inhaled allergens encounter the host immune system first in the nasal mucosa, and microbial characteristics of nasal mucus directly impact the mechanisms of initial allergic responses in nasal epithelium. However, the roles of the nasal microbiome in allergic nasal mucosa remain uncertain. We sought to determine the distribution of nasal microbiomes in allergic nasal mucosa and elucidate the interplay between nasal microbiome Staphylococcus species and Th2 cytokines in allergic rhinitis (AR) models.

Results: Staphylococcus aureus (AR-SA) and S. epidermidis (AR-SE) were isolated from the nasal mucosa of patients with AR. The influence of nasal microbiome Staphylococcus species on allergic nasal mucosa was also tested with in vitro and in vivo AR models. Pyrosequencing data showed that colonization by S. epidermidis and S. aureus was more dominant in nasal mucus of AR subjects. The mRNA and protein levels of IL-33 and TSLP were significantly higher in AR nasal epithelial (ARNE) cells which were cultured from nasal mucosa of AR subjects, and exposure of ARNE cells to AR-SA reduced IL-33 mRNA and secreted protein levels. Particularly, ovalbumin-driven AR mice inoculated with AR-SA by intranasal delivery exhibited significantly reduced IL-33 in their nasal mucosa. In the context of these results, allergic symptoms and Th2 cytokine levels were significantly downregulated after intranasal inoculation of AR-SA in vivo AR mice.

Conclusion: Colonization by Staphylococcus species was more dominant in allergic nasal mucosa, and nasal commensal S. aureus from subjects with AR mediates anti-allergic effects by modulating IL-33-dependent Th2 inflammation. The results demonstrate the role of host-bacterial commensalism in shaping human allergic inflammation.
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http://dx.doi.org/10.1186/s12866-020-01974-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542126PMC
October 2020

Human Rhinovirus Infection Enhances the Th2 Environment in Allergic and Non-allergic Patients with Chronic Rhinosinusitis.

Clin Exp Otorhinolaryngol 2021 May 11;14(2):217-224. Epub 2020 Sep 11.

Graduate School of Medicine, Seoul National University College of Medicine, Seoul, Korea.

Objectives: This study was conducted to determine whether patients with allergic rhinitis might be more susceptible to human rhinovirus (HRV) infection and whether the effects of infection on the elicited immune responses are different in allergic and non-allergic patients with chronic rhinosinusitis (CRS).

Methods: Uncinate process tissues were obtained from 61 CRS patients (of whom 39 had allergies and 22 did not) and were infected with HRV-16 using an air-liquid interface organ culture system. The expression levels of programmed cell death-ligand (PD-L)1, PD-L2, intracellular adhesion molecule 1, interferon-gamma (IFN-γ), interleukin (IL)-4, IL-5, and IL-10 were evaluated in the infected nasal mucosa.

Results: The HRV infection rates were not significantly different between the allergy (74.4%) and non-allergy (72.7%) groups. In the allergy group, the expression of PD-L1 (P=0.013) and IL-10 (P=0.040) was significantly elevated in the HRV-infected tissues, and there was a strong correlation between PD-L1 and IL-10 (r=0.868, P<0.001). In contrast, infected tissues from the non-allergy group displayed increased levels of IL-4 (P=0.039), IL-5 (P=0.023), and IFN-γ (P=0.031), as well as an increased IL-4/IFN-γ ratio, after HRV infection (P=0.043).

Conclusion: This study showed that HRV infection rates were similar in the nasal mucosa of patients with CRS regardless of the presence of allergic rhinitis. HRV infection enhanced the Th2 environment by modulating PD-L1 and PD-L2 expression levels in allergic mucosa and by increasing the IL-4/IFN-γ ratio in non-allergic mucosa.
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http://dx.doi.org/10.21053/ceo.2020.00444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111390PMC
May 2021

The influence of interferon-lambda on restricting Middle East Respiratory Syndrome Coronavirus replication in the respiratory epithelium.

Antiviral Res 2020 08 19;180:104860. Epub 2020 Jun 19.

Department of Otorhinolaryngology, Seoul National University Hospital, Seoul, Republic of Korea. Electronic address:

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe respiratory in human with high mortality and it has been a challenge to determine optimum treatment for MERS-CoV-induced respiratory infection. Here, we observed the distribution of MERS-CoV receptors using human respiratory mucosa and also evaluated the contribution of interferon-lambdas (IFN-λs) in response to MERS-CoV infection using in vitro normal human nasal epithelial (NHNE) and bronchial epithelial (NHBE) cells. We found that the gene and protein expression of DPPIV, MERS-CoV receptor, were more dominantly located in nasal and bronchial epithelium although human nasal mucosa exhibited relatively lower DPPIV expression than lung parenchymal tissues. The quantitative mRNA level of the MERS-CoV envelope (upE) gene was significantly induced in MERS-CoV-infected cultured NHNE and NHBE cells until 3 days after infection. The induction of IFNs was identified in NHNE and NHBE cells after MERS-CoV infection and IFN-λs were predominantly increased in MERS-CoV-infected respiratory epithelial cells. Inoculation of IFN-λs to NHNE and NHBE cells suppressed MERS-CoV replication and in particular, IFN-λ showed a strong therapeutic effect in reducing MERS-CoV infection with higher induction of IFN-stimulated genes. Thus, IFN-λ has a decisive function in the respiratory epithelium that greatly limits MERS-CoV replication, and may be a key cytokine for better therapeutic outcomes against MERS-CoV infection in respiratory tract.
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http://dx.doi.org/10.1016/j.antiviral.2020.104860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303047PMC
August 2020

Characteristics of Obstructive Sleep Apnea Patients With a Low Body Mass Index: Emphasis on the Obstruction Site Determined by Drug-Induced Sleep Endoscopy.

Clin Exp Otorhinolaryngol 2020 Nov 29;13(4):415-421. Epub 2020 Apr 29.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Objectives: This study aimed to elucidate the patterns of upper airway collapse in obstructive sleep apnea (OSA) patients with a low body mass index (BMI).

Methods: We designed and conducted a retrospective cohort study. Consecutive patients diagnosed with OSA who underwent drug-induced sleep endoscopy (DISE) were included. Patients were classified into four groups according to their BMI. Age, sex, and polysomnography data were investigated. The patterns of upper airway collapse were characterized by the structures involved (soft palate, tongue base, lateral pharyngeal wall, and epiglottis). We compared the patterns of upper airway collapse in the supine and lateral decubitus position among the four BMI groups using the chi-square test and multivariate binary logistic regression analysis.

Results: A total of 627 patients (male, 517; mean age, 47.6±12.8 years) were included, consisting of 45, 79, 151, and 352 patients who were underweight or lower normal-weight (defined as the low BMI group), upper normal-weight, overweight, and obese, respectively. Severity indicators of OSA, such as the overall apnea-hypopnea index and duration of SaO2 below 90%, were significantly lower in patients with a low BMI than in obese patients, while their average oxygen saturation was significantly higher. The most common obstruction site in the supine position was the tongue base in patients with a low BMI (100%), whereas this obstruction site was significantly less common in obese patients (54.8%). Tongue base obstruction was mostly relieved in the lateral position, with no discernible obstruction in 86.7% of the low BMI patients.

Conclusion: Airway obstruction in OSA patients with a low BMI is mostly due to tongue base obstruction, which improves in the lateral position. These characteristics should be kept in mind when considering treatment options for this subgroup of OSA patients.
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http://dx.doi.org/10.21053/ceo.2019.00794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669311PMC
November 2020

The clinical efficacy of relocation pharyngoplasty to improve retropalatal circumferential narrowing in obstructive sleep apnea patients.

Sci Rep 2020 02 7;10(1):2101. Epub 2020 Feb 7.

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.

Lateral pharyngeal wall appears to be a critical culprit of obstructive sleep apnea (OSA) subjects and relocation pharyngoplasty has been expected to be a promising surgical option to correct retropalatal circumferential narrowing in OSA patients. The purpose of our study is to evaluate the therapeutic outcomes of relocation pharyngoplasty and its clinical effectiveness in OSA patients with retropalatal circumferential narrowing. We performed relocation pharyngoplasty combined with nasal surgery in 133 OSA patients with the following characteristics: apnea-hypopnea index (AHI) over 10, retropalatal circumferential narrowing greater than grade I when awake, and redundant soft tissue around the lateral pharyngeal wall. The analysis of surgical success rate was performed with the data of 68 subjects who underwent pre and postoperative polysomnography. The objective success rate of relocation pharyngoplasty was 52.9%, and significant reduction of mean AHI with improvement of lowest SpO2 was seen in 69% of patients 3 months after the surgery. The median AHI was decreased from preoperative 37.3 to postoperative 21.4. Median lowest SpO2 changed from 78.4 to 84.1%. Total sleep time, daytime sleepiness, and visual analogue scale for snoring showed improvement as well. Postoperative complications including pain or bleeding were minimal in 133 subjects and a few patients complained of subtle taste loss. Our data demonstrate that relocation pharyngoplasty can be a favorable surgical option fighting against retropalatal circumferential narrowing.
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http://dx.doi.org/10.1038/s41598-020-58920-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005705PMC
February 2020

Superior immune responses induced by intranasal immunization with recombinant adenovirus-based vaccine expressing full-length Spike protein of Middle East respiratory syndrome coronavirus.

PLoS One 2019 22;14(7):e0220196. Epub 2019 Jul 22.

Graduate School of Pharmaceutical Sciences, Ewha Woman's University, Seoul, Republic of Korea.

Middle East respiratory syndrome coronavirus (MERS-CoV) causes an acute and severe lower respiratory illness as well as vomiting, diarrhea, and renal failure. Because no licensed MERS-CoV vaccines are currently available, preventive and therapeutic measures are urgently needed. The surface spike (S) glycoprotein of MERS-CoV, which binds to the cellular receptor dipeptidyl peptidase 4 (DPP4), is considered as a major target for MERS-CoV vaccine development. Here, we designed recombinant replication-deficient adenovirus-based vaccines expressing the N-terminal domain (rAd/NTD) and receptor-binding domain (rAd/RBD) of the MERS-CoV S1 subunit and full-length Spike protein (rAd/Spike). We found that immunization with candidate vaccines via intranasal route induced S1-specific IgG antibodies and neutralizing antibodies against MERS spike pseudotyped virus. Especially, rAd/Spike induced the highest neutralizing antibody titer and the strongest cytokine-induced T cell responses among the three candidate vaccines. To compare the immune responses induced by different administration routes, rAd/Spike was administered via intranasal, sublingual, or intramuscular route. All these administration routes exhibited neutralizing effects in the serum. MERS-CoV-specific neutralizing IgA antibodies in the bronchoalveolar lavage fluid were only induced by intranasal and sublingual administration but not by intramuscular administration. Intranasal administration with rAd/Spike also created resident memory CD8 T cells in the airway and lung parenchyma. Taken together, our results showed that both the humoral and cellular immune responses are highly induced by rAd/Spike administration, suggesting that rAd/Spike may confer protection against MERS-CoV infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645677PMC
February 2020

IL-17C Protects Nasal Epithelium from Infection.

Am J Respir Cell Mol Biol 2020 01;62(1):95-103

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Republic of Korea.

IL-17 family cytokines are directly involved in host immune responses and the critical mediators for host defense against infection or inflammation. IL-17C is highly expressed in respiratory epithelium and is induced after acute bacterial lung infection. However, the definite function of IL-17C induced by (PAO1 strain) is not fully understood, and our study was designed to demonstrate IL-17C-induced immune response against PAO1 infection in nasal epithelium. Passage-2 normal human nasal epithelial (NHNE) cells were infected with PAO1 and the relationship between IL-17C-related immune responses and the iron absorption of PAO1, depending on inoculation of recombinant human IL-17C (rhIL-17C), was assessed by measuring the siderophore activity of PAO1. Microarray data showed that IL-17C expression increased 34.7 times at 8 hours postinfection (hpi) in NHNE cells, and IL-17C mRNA levels increased until 48 hpi. The PAO1 colonies significantly increased from 8 hpi in NHNE cells, and siderophore activity of PAO1 was enhanced in the supernatants of PAO1-infected NHNE cells. Interestingly, PAO1 colonies were reduced in PAO1-infected NHNE cells treated with rhIL-17C, and supernatants from NHNE cells treated with rhIL-17C also exhibited decreased PAO1 colonies. We found that the siderophore activity of PAO1 was significantly reduced in the supernatants of NHNE cells treated with rhIL-17C where LCN2 expression was highly elevated. Our findings indicate that IL-17C mediates an antibacterial effect against PAO1 by inhibiting siderophore activity in nasal epithelium. We propose that IL-17C might be an efficient mediator to suppress PAO1 infection through disturbing iron absorption of PAO1 in nasal epithelium.
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http://dx.doi.org/10.1165/rcmb.2018-0377OCDOI Listing
January 2020

Nasal commensal Staphylococcus epidermidis enhances interferon-λ-dependent immunity against influenza virus.

Microbiome 2019 05 30;7(1):80. Epub 2019 May 30.

Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Background: Staphylococcus epidermidis is one of the most abundant colonizers of healthy human mucosa including that in the respiratory tract. As the respiratory microbiome has been linked to host immune responses, this study sought to determine the role of nasal mucosa-associated S. epidermidis in innate immune responses against the influenza A virus (IAV). S. epidermidis strains were isolated from nasal mucus samples of healthy individuals. The effects of these mucosa-derived commensal strains on interferon (IFN)-dependent innate immunity and IAV infection dynamics were tested in vitro using normal human nasal epithelial (NHNE) cells and human turbinate mucosa. The effects of S. epidermidis on antiviral immunity were also tested in vivo using an acute IAV infection mouse model.

Results: Exposure of NHNE cells to nasal mucosa-derived S. epidermidis increased IFN-λ mRNA and secreted protein levels in the absence of viral stimulation. In the context of IAV infection, NHNE exposure to S. epidermidis prevented an increase in the viral burden, as revealed by IAV PA mRNA abundance, IAV nucleoprotein levels, and viral titers. S. epidermidis also enhanced transcription of IFN-stimulated genes independently of Toll-like receptor 2 and further induced IFN-λ production in IAV-infected cells by promoting phosphorylation of interferon regulatory factor 7. In a murine infection model, S. epidermidis prevented the spread of IAV to the lungs by stimulating IFN-λ innate immunity and suppressing IAV replication in the nasal mucosa.

Conclusion: The human nasal commensal S. epidermidis mediates front-line antiviral protection against IAV infection through modulation of IFN-λ-dependent innate immune mechanisms in the nasal mucosa, thereby demonstrating the role of host-bacterial commensalism in shaping human antiviral responses.
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http://dx.doi.org/10.1186/s40168-019-0691-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542144PMC
May 2019

Inhaled delivery of Interferon-lambda restricts epithelial-derived Th2 inflammation in allergic asthma.

Cytokine 2019 07 9;119:32-36. Epub 2019 Mar 9.

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Republic of Korea; Seoul National University Hospital, Seoul, Republic of Korea. Electronic address:

The possibility has been suggested that interferon (IFN)-λs can be induced rapidly for restricting respiratory viral infection in asthmatic mice and may modulate Th2-related immune responses that underlie the pathogenesis of asthma. We sought to determine the in vivo contribution of IFN-λs on decrease of Th2 cytokines in the respiratory tract of in vivo asthma. Lungs of asthmatic mice were severely inflamed, with extensive inflammatory cell infiltration and increased goblet cell metaplasia with higher total lung resistance. The mean protein levels of TSLP and IL-33 from BAL fluid of asthmatic mice were significantly higher until 7 days. Following the collection of lung tissue of 20 asthmatic mice, TSLP and IL-33 gene expressions inversely correlated with mRNA levels of IFN-λ. Asthmatic mice were administered recombinant IFN-λ via the intranasal route and the mRNA levels of IFN-stimulated genes were elevated to an even greater extent in the lung tissue of the mice without intranasal IFN-λ. Asthma-related histopathologic lung inflammation was significantly improved and total lung resistance was maintained within normal range in IFN-λ-treated asthmatic mice. Moreover, IFN-λ-treated asthmatic mice exhibited significant decrease of secreted protein levels of TSLP and IL-33 in the BAL fluid until 7 days after IFN administration. The current data provide compelling evidence that the compensation of IFN-λs can restrict the secretion of epithelial-derived Th2 cytokines, accompanied with reduced asthmatic immunopathology and IFN-λs are critical for limiting Th2-mediated allergic responses in allergic asthma.
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http://dx.doi.org/10.1016/j.cyto.2019.02.010DOI Listing
July 2019

Indications for and Outcomes of Expansion Sphincter Pharyngoplasty to Treat Lateral Pharyngeal Collapse in Patients With Obstructive Sleep Apnea.

JAMA Otolaryngol Head Neck Surg 2019 May;145(5):405-412

Department of Otorhinolaryngology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Importance: The lateral pharyngeal wall is recognized as an important site of upper airway collapse during sleep in patients with obstructive sleep apnea (OSA), and expansion sphincter pharyngoplasty (ESP) may have promising clinical utility in patients with OSA and lateral pharyngeal wall collapse.

Objectives: To evaluate the therapeutic outcomes of ESP in conjunction with other surgical procedures and to investigate indications for ESP in patients with OSA.

Design, Setting, And Participants: Cohort study of 63 patients with OSA diagnosed with lateral pharyngeal collapse under drug-induced sleep endoscopy who underwent ESP combined with tonsillectomy, uvuloplasty, or nasal surgery at Seoul National University Hospital in Seoul, Korea, between March 1, 2015, and December 1, 2016.

Main Outcomes And Measures: The primary outcome measure was the change in the apnea-hypopnea index (AHI) after surgery (AHI represents the number of apnea-hypopnea events per hour). Other outcome measures were differences in the surgical response rates, lowest oxygen saturation, subjective visual analog scale scores for snoring and apnea, and Epworth Sleepiness Scale score.

Results: Fifty of the 63 patients (79%) were male; the mean age was 42.1 (range, 20-54) years, and the mean body mass index (calculated as weight in kilograms divided by height in meters squared) was 27.6 (range, 19.0-32.1). Expansion sphincter pharyngoplasty was performed in patients with OSA with an AHI greater than 15 events per hour, more than 75% retropalatal circumferential narrowing when awake, and narrowed oropharynx due to bulky soft tissue around the lateral pharyngeal wall. In 42 of the 63 patients (67%), ESP was objectively successful in correcting lateral pharyngeal collapse; there was a significant reduction in mean AHI from 35.5 to 17.3 (mean difference, 18.1; 95% CI, 16.3-20.0) and improvement of the lowest mean (SD) oxygen saturation measurement from 78.2% (21.3%) to 86.4% (10.6%) (mean difference, 8.60%; 95% CI, 6.60%-10.60%) 6 months after the operation. The rate of postoperative complications, including pain and bleeding, was minimal after ESP, and a few patients reported an abnormal sensation around the soft palate and swallowing difficulty after ESP.

Conclusions And Relevance: Expansion sphincter pharyngoplasty appears to be a promising surgical technique to reduce lateral pharyngeal collapse in patients with moderate or severe OSA. Clinical data suggest that both severe palatal circumferential narrowing and bulky lateral pharyngeal tissue are favorable surgical indications for ESP in patients with OSA.
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http://dx.doi.org/10.1001/jamaoto.2019.0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537807PMC
May 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

Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study.

Oncologist 2019 08 29;24(8):e740-e748. Epub 2019 Jan 29.

Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

Background: NUT carcinoma is a rare aggressive disease caused by fusion, and upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological characteristics of Korean patients with NUT carcinoma and the in vitro efficacy of MYC-targeting agents against patient-derived NUT carcinoma cell lines.

Materials And Methods: Thirteen patients with NUT carcinoma were evaluated for p53, C-MYC, epidermal growth factor receptor (EGFR), HER2, and programmed cell death ligand 1 (PD-L1) by immunohistochemistry. The half maximal inhibitory concentration (IC) values of NUT carcinoma cell lines (SNU-2972-1, SNU-3178S, HCC2429, and Ty-82) were determined using MYC-targeting agents, including bromodomain and extraterminal (BET) inhibitors (I-BET, OTX-015, AZD5153) and histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat, CUDC-907).

Results: Primary tumor sites included head and neck ( = 9) and lung ( = 4). The patient age ranged from 8 to 73 years with the male/female ratio of 1.2:1. Nine patients died at 3-23.6 months (median, 10.6) after diagnosis. Eight patients had been misdiagnosed initially with other diseases. One patient with metastatic NUT carcinoma who received mass excision plus metastasectomy followed by chemoradiotherapy was a long-term survivor (>27 months). Although expressions of C-MYC (8/12, 73%) and p53 (12/12, 100%) were commonly observed, EGFR, HER2, and PD-L1 expressions were observed in 2 of 7 (29%), 2 of 8 (25%), and 1 of 12 (8.3%) patients, respectively. BET and HDAC inhibitors showed variable but limited in vitro efficacy. However, a dual HDAC/PI3K inhibitor, CUDC-907, was most potent against NUT carcinoma cells, with an IC of 5.5-9.0 pmol/L. Consistent with these findings, kinome short interfering RNA screening showed a positive hit for in NUT carcinoma cells. Panobinostat (IC, 0.4-1.3 nmol/L) and a bivalent BET inhibitor, AZD5153 (IC, 3.7-8.2 nmol/L), also showed remarkable efficacies.

Conclusion: East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC-907 might be promising in NUT carcinoma treatment.

Implications For Practice: NUT carcinoma (NC) is a disease caused by fusion leading to upregulation. NC is often misdiagnosed and very aggressive, requiring development of effective therapeutic strategy. This article presents the clinicopathological features of the largest series of NCs in East Asians and preclinical sensitivities to MYC-targeting agents in NC cell lines. Patients with NC had grave outcomes and poor response to treatment. Among MYC-targeting agents, including BET and HDAC inhibitors, CUDC-907 (a dual PI3K/HDAC inhibitor) was most effective against NC cells, followed by panobinostat (an HDAC inhibitor) and AZD5153 (a bivalent BET inhibitor). CUDC-907 might be promising in NC treatment.
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http://dx.doi.org/10.1634/theoncologist.2018-0477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693698PMC
August 2019

The association between obstructive sleep apnea during REM sleep and autonomic dysfunction as measured by heart rate variability.

Sleep Breath 2019 Sep 26;23(3):865-871. Epub 2019 Jan 26.

Department of Psychiatry and Center for Sleep and Chronobiology, Seoul National University Hospital, Seoul, Republic of Korea.

Purpose: To determine the effect of obstructive sleep apnea (OSA) during rapid eye movement (REM) sleep on autonomic dysfunction using heart rate variability (HRV) analysis.

Methods: The medical records of adults who underwent nocturnal polysomnography at the Sleep and Chronobiology Center at Seoul National University Hospital were retrospectively reviewed. HRV parameters (mean RR interval, the standard deviation of all normal RR intervals [SDNN], square root of the mean squared differences of adjacent RR intervals [RMSSD], normalized low frequency [LF], normalized high frequency [HF], and the ratio of LF to HF [LF/HF]) were measured in 5-min electrocardiogram recordings obtained during W, N2, and R sleep stages. Comparisons were made among the control (apnea-hypopnea index (AHI < 15 and AHI during REM sleep (AHI) < 15, n = 27), REM-associated OSA (AHI < 15 and AHI ≥ 15, n = 27), and OSA (AHI ≥ 15, n = 27) groups. The groups were matched for age, sex, and body mass index.

Results: No significant differences were observed between the control and the REM-associated OSA groups for any of the HRV parameters. In contrast, compared with controls, the OSA group showed significantly lower normalized HF (p = 0.031) and higher LF/HF (p = 0.018) in stage W and a significantly shorter mean RR interval (p = 0.046) and lower RMSSD (p = 0.034) in stage N2.

Conclusions: Our findings suggest that OSA during REM sleep is not a major contributor to autonomic dysfunction.
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http://dx.doi.org/10.1007/s11325-018-01779-yDOI Listing
September 2019

Robot-assisted Tongue Base Resection ensures favorable therapeutic outcome to Obstructive Sleep Apnea patients with Lingual tonsil hypertrophy.

Sci Rep 2019 01 24;9(1):613. Epub 2019 Jan 24.

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.

Tongue base (TB) narrowing is recognized as a significant site of upper airway collapse during sleep in obstructive sleep apnea (OSA) patients and robot technology is expected to have promising clinical utility in OSA patients with TB narrowing. The purpose of our study is to demonstrate the better therapeutic conditions and favorable indications of robot-assisted TB resection (TBR) in OSA. We performed robot-assisted TBR combined with nasal and palatal surgery in 16 OSA patients with any of the following characteristics: severe TB narrowing (over grade II) and moderate or severe OSA. The preoperative median AHI was 48.8/hr and the median lowest SaO was 82.0%. The median AHI decreased to 18.7/hr and ten patients (62.5%) were included in the responder group following robot-assisted TBR combined with nasal and palatal surgery. The lowest SaO improved to 90.5% and the posterior airway space (PAS) was significantly increased following robot-assisted TBR. Cephalometric results showed that wider PAS were observed in responders compared to non-responders prior to robot-assisted TBR. Interestingly, there was greater improvement in the objective parameters including PAS in the OSA patients with lingual tonsilar hypertrophy than they were in those without and all patients with lingual tonsillar hypertrophy (n = 6) responded to robot-assisted TBR. Robot-assisted TBR exhibited minimal morbidity and postoperative complications in OSA patients. Robot-assisted TBR can be considered a promising and innovative surgical option to reduce TB volume and improve sleep parameters in OSA patients with TB narrowing. OSA patient with TB narrowing due to lingual tonsil hypertrophy shows greater therapeutic outcome and lingual tonsil hypertrophy appears to be most favorable surgical indications of robot-assisted TBR.
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http://dx.doi.org/10.1038/s41598-018-36800-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346104PMC
January 2019

Immunologic modification in mono- and poly-sensitized patients after sublingual immunotherapy.

Laryngoscope 2019 05 13;129(5):E170-E177. Epub 2018 Dec 13.

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

Objectives/hypothesis: To compare immunologic modification and treatment outcomes after 2 years of sublingual immunotherapy (SLIT) with house dust mite extracts (HDM) between monosensitized and polysensitized patients with allergic rhinitis.

Study Design: Retrospective cohort study.

Methods: Among the patients who were prospectively enrolled in the SLIT cohort study, patients with allergic rhinitis who were sensitized to HDM and treated with SLIT for at least 2 years were studied. All participants underwent serologic tests at baseline and after SLIT to evaluate changes in immunologic parameters. The total nasal symptom score (TNSS) was measured before and after SLIT, and effective and less effective responder groups were categorized depending on whether patients had a TNSS reduction of 50%, as compared with baseline.

Results: The increase in Dermatophagoides pteronyssinus and Dermatophagoides farinae specific immunoglobulin G4 levels was significantly higher in monosensitized patients than in polysensitized patients (P = .020 and P = .005, respectively). The TNSS significantly improved after SLIT in both the monosensitized and polysensitized groups (P < .001 in both groups). However, the difference in the changes in TNSS from baseline was not significant between the two groups (P = .374).

Conclusions: This study demonstrated different immunologic modifications after SLIT between monosensitized and polysensitized patients. However, patients in the polysensitized group who were treated with single-allergen SLIT experienced clinical improvement in TNSS that was comparable with that in the monosensitized group despite demonstrating different immunologic changes.

Level Of Evidence: 2b Laryngoscope, 129:E170-E177, 2019.
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http://dx.doi.org/10.1002/lary.27721DOI Listing
May 2019

Principal Clinical Factors Predicting Therapeutic Outcomes After Surgical Drainage of Postoperative Cheek Cysts: Experience From a Single Center.

Clin Exp Otorhinolaryngol 2019 Feb 28;12(1):79-85. Epub 2018 Sep 28.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Objectives: Postoperative cheek cyst (POCC) is a late postoperative complication of radical maxillary sinus surgery including the Caldwell-Luc (C-L) operation. The present study aimed to evaluate the therapeutic outcomes of surgical treatment for POCC and to assess the clinical factors correlated to these outcomes.

Methods: This study included 57 patients (67 nostrils) diagnosed with POCC who underwent surgical drainage. The medical records of the patients were retrospectively reviewed for radiological findings, treatment modalities, residual symptoms, and recurrences.

Results: In total, 30 patients were male and 27 patients were female with a mean age of 55 years, and the patients were usually diagnosed with POCC 28.2 years after radical surgery. Endonasal endoscopic marsupialization was performed via inferior meatal antrostomy, and if possible, middle meatal antrostomy was performed at the same time. In patients with cysts that were difficult to reach using an endonasal endoscopic approach, additional open C-L approaches were performed. The median follow-up period was 19.4 months. Overall, adequate drainage and symptomatic relief were achieved in 91% (61/67) of the patients. The recurrence rate was significantly higher in patients who had anterolateral POCC. Failure to achieve symptomatic relief was correlated to a smaller cyst and the use of the open C-L approach for drainage.

Conclusion: The location and size of the cyst as well as the use of the open surgical approach were important factors in predicting the therapeutic outcome of POCC. The time point of treatment and surgical approaches should be based on the above-mentioned findings.
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http://dx.doi.org/10.21053/ceo.2018.00528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315216PMC
February 2019

Orbital Apex Lesions: A Diagnostic and Therapeutic Challenge.

J Neurol Surg B Skull Base 2018 Aug 13;79(4):386-393. Epub 2017 Dec 13.

Department of Otorhinolaryngology, Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea.

 To analyze the clinical characteristics of and treatment outcomes for orbital apex lesions according to their pathological diagnosis and identify clinical characteristics that could aid in their differential diagnosis.  Retrospective analysis design was used for this study.  The study was conducted in a single tertiary institution.  Patients with pathologically confirmed lesions centered in the orbital apex who were admitted between January 2011 and December 2015.  Clinical characteristics, including demographics, predisposing factors, presenting symptoms, radiological findings, intraoperative findings, biopsy results, and treatment outcomes.  Nine patients with invasive fungal sinusitis, six with inflammatory pseudotumor, and six with neoplastic or tumorous lesions were enrolled. The most common presenting symptom was orbital pain or headache, followed by ophthalmoplegia and vision loss, which exhibited overall recovery rates of 62.5% and 33.3%, respectively, after definitive treatment. The prognosis was worse for patients with invasive fungal sinusitis. There was no significant difference in age, underlying medical conditions, absolute neutrophil count, C-reactive protein level, and radiological findings among the three groups. Grossly necrotic tissues around the orbital apex area at biopsy were more frequently found in patients with invasive fungal sinusitis than in the other patients. In most cases, pain ameliorated after surgical intervention. There were no surgery-related morbidities.  Lesions centered in the orbital apex included invasive fungal sinusitis, inflammatory pseudotumor, and tumorous lesions. However, clinical features that clearly differentiated chronic invasive fungal sinusitis from inflammatory pseudotumor could not be identified. Our findings suggest that prompt biopsy is warranted for timely diagnosis, symptom relief, and early implementation of definitive treatment.
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http://dx.doi.org/10.1055/s-0037-1612616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043169PMC
August 2018

Initial Influenza Virus Replication Can Be Limited in Allergic Asthma Through Rapid Induction of Type III Interferons in Respiratory Epithelium.

Front Immunol 2018 17;9:986. Epub 2018 May 17.

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, South Korea.

Although asthmatics has been considered to be highly susceptible to respiratory viral infection and most studies have focused on exacerbation of asthma by influenza A virus (IAV) infection, few experimental evidences exist to directly demonstrate that asthmatic mice are actually resistant to IAV infection. Here, we show that asthmatic mice are not highly susceptible to IAV in the early stage of infection and type III interferon (IFN) maintains antiviral immune response in the lung of IAV-infected asthmatic mouse resulting in inhibition of initial viral spread. C57BL/6 mice with allergic asthma were infected with IAV (WS/33: H1N1) and survival rate, body weight, viral titer, histopathological findings of lung and cytokine profiles including IFNs and Th2 cytokines were measured. Notably, asthmatic mice were significantly resistant to IAV and showed lower viral load until 7 days after infection. Furthermore, IAV-infected asthmatic mice exhibited decreased Th2-related inflammation in lung tissue until 7 days. These increased antiviral resistant mechanism and reduced Th2 inflammation were attributable to rapid induction of type III IFNs and blockade of type III IFNs in asthmatic lung led to aggravated IAV infection and to enhance the production of Th2 cytokines. Asthmatic mice showed bi-phasic responses against IAV-caused lung infection such as rapid production of type III IFNs and subsequent induction of type II IFNs. Actually, IAV-infected asthmatic mice become vulnerable to IAV infection after 7 days with noticeable morbidity and severe weight loss. However, intranasal administration of type III IFNs protects completely asthmatic mice from IAV-mediated immunopathology and lung infection until 14 days after infection. Taken together, our study indicates that the rapid induction of type III IFN might be distinctive immunological findings in the respiratory tract of IAV-infected asthmatic mice at the early stage of infection and crucial for suppression of initial viral spread asthma accompanying with restriction of Th2 cytokine productions.
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http://dx.doi.org/10.3389/fimmu.2018.00986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966536PMC
July 2019

Acute invasive fungal rhinosinusitis: MR imaging features and their impact on prognosis.

Neuroradiology 2018 Jul 17;60(7):715-723. Epub 2018 May 17.

Department of Radiology, GangNeung Asan Hospital, GangNeung, South Korea.

Purpose: Acute invasive fungal rhinosinusitis (AIFRS) is a life-threatening disease that is difficult to diagnose. Its overall imaging features have not been evaluated and the prognostic impact is unclear. The purpose of our study was to present MR imaging features and their impact on prognosis of AIFRS.

Methods: MR images and clinical records of 23 patients with AIFRS were retrospectively evaluated to identify the imaging features and to determine the factors affecting patients' survival. A multivariable Cox proportional hazard model was used to estimate the hazard ratio of the prognostic factors, and Kaplan-Meier survival curves were compared by using a log-rank test.

Results: All cases showed extra-sinonasal involvement and the orbit was the most common (65.2%, 15/23) location. The lesion enhancement pattern was classified into lack of contrast enhancement (LoCE) (47.8%, 11/23) and homogeneous (34.8%, 8/23) and heterogeneous (17.4%, 4/23) enhancement. Although LoCE showed variable signal intensity (SI), homogeneously or heterogeneously enhancing lesions showed exclusively low SI (100%, 12/12) on T2WI. Among various clinical and imaging factors, LoCE was correlated with coagulation necrosis, probably provoked by numerous fungal hyphae, and was found to be a sole independent prognostic factor for disease-specific mortality (hazard ratio = 16.819; 95% CI, 1.646-171.841, p = 0.017). In addition, patients with LoCE showed worse survival than patients without LoCE (p = 0.008).

Conclusion: AIFRS showed frequent extra-sinonasal involvement and variable MR enhancement patterns. An enhancement pattern of LoCE was seen in about half of the cases and was a unique prognostic factor among the various clinico-radiologic factors.
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http://dx.doi.org/10.1007/s00234-018-2034-0DOI Listing
July 2018

Duox2-induced innate immune responses in the respiratory epithelium and intranasal delivery of Duox2 DNA using polymer that mediates immunization.

Appl Microbiol Biotechnol 2018 May 30;102(10):4339-4343. Epub 2018 Mar 30.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, South Korea.

Respiratory mucosa especially nasal epithelium is well known as the first-line barrier of air-borne pathogens. High levels of reactive oxygen species (ROS) are detected in in vitro cultured human epithelial cells and in vivo lung. With identification of NADPH oxidase (Nox) system of respiratory epithelium, the antimicrobial role of ROS has been studied. Duox2 is the most abundant Nox isoform and produces the regulated amount of ROS in respiratory epithelium. Duox2-derived ROS are involved in antiviral innate immune responses but more studies are needed to verify the mechanism. In respiratory epithelium, Duox2-derived ROS is critical for recognition of virus through families retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) at the early stage of antiviral innate immune responses. Various secreted interferons (IFNs) play essential roles for antiviral host defense by downstream cell signaling, and transcription of IFN-stimulated genes is started to suppress viral replication. Type I and type III IFNs are verified more responsible for influenza A virus (IAV) infection in respiratory epithelium and Duox2 is required to regulate IFN-related immune responses. Transient overexpression of Duox2 using cationic polymer polyethylenimine (PEI) induces secretion of type I and type III IFNs and significantly attenuated IAV replication in respiratory epithelium. Here, we discuss Duox2-mediated antiviral innate immune responses and the role of Duox2 as a mucosal vaccine to resist respiratory viral infection.
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http://dx.doi.org/10.1007/s00253-018-8956-yDOI Listing
May 2018

Chemiluminescence imaging of Duox2-derived hydrogen peroxide for longitudinal visualization of biological response to viral infection in nasal mucosa.

Theranostics 2018 12;8(7):1798-1807. Epub 2018 Feb 12.

Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Korea.

Hydrogen peroxide (HO) provides an important mechanism for resisting infectious pathogens within the respiratory tract, and accordingly, the analysis of HO generation in real time provides a valuable tool for assessing immune response. In this study, we applied a chemiluminescent nanoparticle-based real-time imaging approach to noninvasive evaluation of the Duox2-mediated HO generation after viral infection, and assessed its usefulness for analytical purposes in mouse nasal mucosa. The chemiluminescent nanoprobe employed herein (BioNT) possesses appropriate physicochemical properties, such as high sensitivity and selectivity toward HO, no background noise, deliverability to the respiratory tract, and capability of multiple injections to a single animal subject for long-term repetitive imaging. The favorable characteristics of BioNT allowed for a longitudinal study with the same mice to noninvasively evaluate the long-term evolution of endogenous HO in the nasal epithelium after infection with influenza A virus (WS/33/H1N1). We found that nasal epithelial cells by themselves respond to viral infection by generating HO, and that the cumulative HO level in the nasal mucosa peaks at day 3 post-infection. Such and temporal behaviors of the endogenous HO generation showed a good correlation with those of Duox2 expression after infection. This correlation could be further confirmed with Duox2-deficient subjects (Duox2-knockdown NHNE cells and Duox2-knockout mutant mice) where no HO-induced chemiluminescence was detectable even after viral infection. Importantly, upon knock-down of Duox2 expression, the condition of mice caused by viral infection in the upper airway was significantly aggravated, evidencing the involvement of Duox2 in the immune defense. All these results reveal a critical role of Duox2 in the infection-induced HO production and the HO-mediated immune response to infection in the respiratory tract, well elucidating the potential of BioNT as a noninvasive tool for fundamental studies of infectious diseases.
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http://dx.doi.org/10.7150/thno.22481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858501PMC
February 2019

Influencing factors on CPAP adherence and anatomic characteristics of upper airway in OSA subjects.

Medicine (Baltimore) 2017 Dec;96(51):e8818

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Korea.

Although continuous positive airway pressure (CPAP) is the most effective treatment modality, poor adherence still remains a problem for obstructive sleep apnea (OSA) treatment and there is little evidence regarding how this might be improved. This study aims to analyze the anatomic and clinical factors of OSA subjects who failed to comply with CPAP therapy.The medical records of 47 OSA subjects who received CPAP therapy as a first-line treatment modality were retrospectively reviewed. The medical records were reviewed for demographic and polysomnographic data and anatomic findings of the nasal cavity and oropharynx.24 patients who adhered to CPAP therapy and 23 patients who were nonadherent were enrolled in the study. There were no statistically significant differences in sleep parameters between CPAP-adherent patients and CPAP nonadherent subjects. Mean body mass index of CPAP nonadherent group was significantly higher than CPAP adherent group. Higher grades of septal deviation and hypertrophic change of the inferior turbinate were observed more in the CPAP nonadherent group. In addition, CPAP nonadherent subjects showed considerably bigger tonsils and higher grade palatal position comparing with the CPAP adherent subjects. Subjective discomfort including inconvenience, mouth dryness, and chest discomfort were the main problems for OSA subjects who did not comply with CPAP therapy.Excessive upper airway blockage in the nasal cavity and oropharynx was predominant in CPAP nonadherent subjects, which might cause the reported subjective discomfort that reduces CPAP compliance. Therefore, resolution of these issues is needed to enhance CPAP compliance for control of OSA.
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http://dx.doi.org/10.1097/MD.0000000000008818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758121PMC
December 2017

Healing of the nasal septal mucosa in an experimental rabbit model of mucosal injury.

World J Otorhinolaryngol Head Neck Surg 2017 Mar 9;3(1):17-23. Epub 2017 Mar 9.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, 03080, South Korea.

Objective: The aim of this study was to investigate the regeneration process of the nasal mucosa after a surgically created mucosal defect in the rabbit nasal septum, and to evaluate the effects of different interventions.

Methods: A 7 mm-diameter circular mucosal defect was made in the septum of forty New Zealand white rabbits. The rabbits were divided into four groups (ten rabbits in each group) according to the type of intervention; no treatment (control), silastic sheet (SS), hyaluronic acid (HA), and silastic sheet and hyaluronic acid (SS + HA) group. The diameter of the defect, mucosal thickness, epithelial thickness, and ciliated cell count were evaluated every week for five weeks.

Results: The average diameter of the defect in the control group were 5.1, 3.65, 1.2, 0.75, and 0.05 mm at postoperative 1, 2, 3, 4, and 5 weeks. In the SS group, the diameter decreased to 4.35, 2.1, 0.35, 0.15, and 0 mm at postoperative 1, 2, 3, 4, and 5 weeks, respectively, in which the mean diameter of the postoperative week 2 was significantly smaller compared to control (3.65 mm vs. 2.1 mm,  = 0.039). For the HA group and SS + HA group, the diameter of the defect did not show a significant difference from the control group during the five weeks. The mucosal thickness, epithelial thickness, and ciliated cell count of the regenerated mucosa were not significantly different among the groups.

Conclusion: The regeneration process of the nasal septal mucosa was identified using a novel rabbit model. Mucosal regeneration can be accelerated by applying silastic sheets.
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http://dx.doi.org/10.1016/j.wjorl.2017.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683622PMC
March 2017

Intranasal delivery of Duox2 DNA using cationic polymer can prevent acute influenza A viral infection in vivo lung.

Appl Microbiol Biotechnol 2018 Jan 21;102(1):105-115. Epub 2017 Sep 21.

Department of Otorhinolaryngology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, South Korea.

We studied the contribution of Duox2 in mucosal host defense against influenza A virus (IAV) infection in in vivo lung. We found that Duox2 was required for the induction of type I and III interferon (IFN)s and transient Duox2 overexpression using cationic polymer polyethyleneimine (PEI) leads to suppression of IAV infection in in vivo lung. Twenty mice (C57BL/6J) were anesthetized and challenged by intranasal administration of 213 pfu/30 μl of IAV (WS/33/H1N1), and IAV-infected mice were euthanized at 1, 3, 5, 7, 10, 14 days post infection (dpi). Duox2 small hairpin RNA (shRNA) and pCMV-Duox2 formulated with PEI were inoculated to mice to assess the regulatory mechanism between Duox2 and IFN secretion. Following intranasal IAV inoculation, viral infection was significantly aggravated from 3 dpi in in vivo lung and viral titer was highest at 7 dpi. Consistent with this, Duox2 messenger RNA (mRNA) and protein expressions were significantly induced from 3 dpi in the lung tissue of IAV-infected mice. Viral titer was much higher in IAV-infected mice that were inoculated with Duox2 shRNA accompanied with lower survival rate and extensive lung pathologies. Interestingly, severe lung pathologies in IAV-infected mice were not observed and viral titer was significantly reduced in mice with pulmonary administration of pCMV-Duox2 formulated with PEI before IAV inoculation. Both mRNA and secreted protein levels of IFN-β and IFN-λ were highly elevated in IAV-infected mice with pCMV-Duox2 formulated with PEI. Duox2 is necessary for the regulation of IFN secretion in in vivo lung, and pulmonary administration of Duox2 DNA using cationic polymer triggers the induction of type I and III IFNs resulting in more complete suppression of IAV infection.
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http://dx.doi.org/10.1007/s00253-017-8512-1DOI Listing
January 2018

Radioanatomic study of the skull base and septum in Asians: implications for using the nasoseptal flap for anterior skull-base reconstruction.

Int Forum Allergy Rhinol 2017 10 21;7(10):999-1005. Epub 2017 Aug 21.

Department of Otorhinolaryngology and Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea.

Background: The objective of this work was to assess the feasibility of using the nasoseptal flap (NSF) for covering the anterior skull-base defect in Asians, and to compare the results in whites.

Methods: A retrospective radioanatomic analysis was conducted in 100 Korean adult patients. Septal and skull-base dimensions were measured and the feasibility of the NSF in reconstructing a full anterior skull-base defect was evaluated. Scans of 49 white patients were analyzed for a comparative study.

Results: Among various septal dimensions, the length of the septum was significantly different in Koreans when compared to whites. Skull-base dimensions such as anterior skull-base length and width at the level of the anterior ethmoidal artery were different between the 2 ethnic groups. Individual differences between the anterior width of the hypothetical NSF and the anterior margin of the skull-base defect (2.8 ± 3.1 vs 6.4 ± 4.8) and the difference between the hypothetical NSF length and the length of the flap needed for full coverage of the defect were significantly smaller in Korean patients (7.2 ± 3.8 vs 13.1 ± 5.6), leading to a statistically higher chance of flap insufficiency. The insufficiency was more often found in female patients.

Conclusion: The risk of NSF insufficiency for covering the anterior skull-base defect in Koreans is higher relative to whites, and is accentuated in female patients. Efforts to increase the size of the NSF as well as efforts to avoid intraoperative shrinkage of the NSF should be considered to compensate for the relatively small NSF in Asians.
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http://dx.doi.org/10.1002/alr.21993DOI Listing
October 2017

The structural changes of upper airway and newly developed sleep breathing disorders after surgical treatment in class III malocclusion subjects.

Medicine (Baltimore) 2017 Jun;96(22):e6873

Department of Otolaryngology and Head & Neck Surgery Department of Oral and Maxillofacial Surgery Chung-Ang University College of Medicine, Department of Otorhinolaryngology, Seoul University College of Medicine, Seoul, South Korea.

Bimaxillary surgery is the traditional treatment of choice for correcting class III malocclusion which is reported to cause an alteration of oropharyngeal structures and upper airway narrowing that might be a predisposing factor for obstructive sleep apnea (OSA). This study aimed to analyze sleep parameters in class III malocclusion subjects and ascertain the prevalence of snoring or OSA following bimaxillary surgery.A total of 22 patients with Le Fort I osteotomy and mandibular setback for class III malocclusion were prospectively enrolled. All patients received endoscopic examination, cephalometry, 3-dimensional computed tomography (3D-CT), and sleep study twice at 1 month before and 3 months after surgery.The patient population consisted of 5 males and 17 females with a mean body mass index of 22.5 kg/m and mean age of 22.1 years. No patients complained of sleep-related symptoms, and the results of sleep study showed normal values before surgery. Three patients (13%) were newly diagnosed with mild or moderate OSA and 6 patients (27%) showed increased loudness of snoring (over 40 dB) after bimaxillary surgery. According to cephalometric analysis and 3D-CT results, the retropalatal and retroglossal areas were significantly narrowed in class III malocclusion patients, showing snoring and sleep apnea after surgery. In addition, the total volume of the upper airway was considerably reduced following surgery in the same patients.Postoperative narrowing of the upper airway and a reduction of total upper airway volume can be induced, and causes snoring and OSA in class III malocclusion subjects following bimaxillary surgery.
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http://dx.doi.org/10.1097/MD.0000000000006873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459700PMC
June 2017

A Genetic Screen Reveals Novel Targets to Render Sensitive to Lysozyme and Cell Wall-Targeting Antibiotics.

Front Cell Infect Microbiol 2017 1;7:59. Epub 2017 Mar 1.

Department of Microbiology and Immunology, Yonsei University College of MedicineSeoul, South Korea; Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of MedicineSeoul, South Korea; Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of MedicineSeoul, South Korea.

is capable of establishing airway infections. Human airway mucus contains a large amount of lysozyme, which hydrolyzes bacterial cell walls. , however, is known to be resistant to lysozyme. Here, we performed a genetic screen using a mutant library of PAO1, a prototype strain, and identified two mutants (Δ and Δ) that exhibited decrease in survival after lysozyme treatment. The and genes encode an outer membrane assembly protein and a fatty acid synthesis enzyme, respectively. These two mutants displayed retarded growth in the airway mucus secretion (AMS). In addition, these mutants exhibited reduced virulence and compromised survival fitness in two different infection models. The mutants also showed susceptibility to several antibiotics. Especially, Δ mutant was very sensitive to vancomycin, ampicillin, and ceftazidime that target cell wall synthesis. The Δ displayed compromised membrane integrity. In conclusion, this study uncovered a common aspect of two different mutants with pleiotropic phenotypes, and suggests that BamB and FabY could be novel potential drug targets for the treatment of infection.
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http://dx.doi.org/10.3389/fcimb.2017.00059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331053PMC
September 2017

Therapeutic outcomes of mandibular advancement devices as an initial treatment modality for obstructive sleep apnea.

Medicine (Baltimore) 2016 Nov;95(46):e5265

Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.

Although continuous positive airway pressure (CPAP) is a highly efficacious treatment for obstructive sleep apnea (OSA), there is a need for alternative treatment options, such as sleep surgeries and mandibular advancement devices (MADs), to overcome the limitations of CPAP.This study aimed to analyze the therapeutic outcomes of OSA subjects who were treated with a MAD, and to estimate the clinical impact of MAD as a first-line treatment for OSA.Forty-seven patients diagnosed with OSA received an adjustable MAD as an initial treatment. Drug-induced sleep endoscopic findings and sleep parameters (both pre-MAD and post-MAD treatment), such as apnea index, oxygen saturation, and degree of daytime sleepiness, were assessed retrospectively.The MAD treatment resulted in a significant reduction in apnea-hypopnea index, and also a significant elevation in lowest oxygen saturation. Satisfactory results of MAD treatment as a first treatment modality were observed in 27 patients, and a successful outcome was reached in approximately 72% of patients. The OSA patients who had lower body mass index and upper airway narrowing at the level of palate and tongue base showed relatively higher rates of a satisfactory outcome even in cases of moderate or severe OSA.These results suggest that the use of a MAD may be an alternative treatment option in OSA patients with retropalatal and retroglossal area narrowing regardless of disease severity. Additionally, MADs can be recommended as an initial treatment modality, and the effectiveness of MADs in achieving success may not be inferior to CPAP.
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http://dx.doi.org/10.1097/MD.0000000000005265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120906PMC
November 2016