Publications by authors named "Yoshiki Kobayashi"

105 Publications

Eosinophil-mediated inflammation in the absence of eosinophilia.

Asia Pac Allergy 2021 Jul 13;11(3):e30. Epub 2021 Jul 13.

Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.

The increase of eosinophil levels is a hallmark of type-2 inflammation. Blood eosinophil counts act as a convenient biomarker for asthma phenotyping and the selection of biologics, and they are even used as a prognostic factor for severe coronavirus disease 2019. However, the circulating eosinophil count does not always reflect tissue eosinophilia and vice versa. The mismatch of blood and tissue eosinophilia can be seen in various clinical settings. For example, blood eosinophil levels in patients with acute eosinophilic pneumonia are often within normal range despite the marked symptoms and increased number of eosinophils in bronchoalveolar lavage fluid. Histological studies using immunostaining for eosinophil granule proteins have revealed the extracellular deposition of granule proteins coincident with pathological conditions, even in the absence of a significant eosinophil infiltrate. The marked deposition of eosinophil granule proteins in tissue is often associated with cytolytic degranulation. Recent studies have indicated that extracellular trap cell death (ETosis) is a major mechanism of cytolysis. Cytolytic ETosis is a total cell degranulation in which cytoplasmic and nuclear contents, including DNA and histones that act as alarmins, are also released. In the present review, eosinophil-mediated inflammation in such mismatch conditions is discussed.
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http://dx.doi.org/10.5415/apallergy.2021.11.e30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331253PMC
July 2021

Omalizumab Restores Response to Corticosteroids in Patients with Eosinophilic Chronic Rhinosinusitis and Severe Asthma.

Biomedicines 2021 Jul 7;9(7). Epub 2021 Jul 7.

Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.

Eosinophilic chronic rhinosinusitis (ECRS), which is a subgroup of chronic rhinosinusitis with nasal polyps, is characterized by eosinophilic airway inflammation extending across both the upper and lower airways. Some severe cases are refractory even after endoscopic sinus surgery, likely because of local steroid insensitivity. Although real-life studies indicate that treatment with omalizumab for severe allergic asthma improves the outcome of coexistent ECRS, the underlying mechanisms of omalizumab in eosinophilic airway inflammation have not been fully elucidated. Twenty-five patients with ECRS and severe asthma who were refractory to conventional treatments and who received omalizumab were evaluated. Nineteen of twenty-five patients were responsive to omalizumab according to physician-assessed global evaluation of treatment effectiveness. In the responders, the levels of peripheral blood eosinophils and fractionated exhaled nitric oxide (a marker of eosinophilic inflammation) and of CCL4 and soluble CD69 (markers of eosinophil activation) were reduced concomitantly with the restoration of corticosteroid sensitivity. Omalizumab restored the eosinophil-peroxidase-mediated PP2A inactivation and steroid insensitivity in BEAS-2B. In addition, the local inflammation simulant model using BEAS-2B cells incubated with diluted serum from each patient confirmed omalizumab's effects on restoration of corticosteroid sensitivity via PP2A activation; thus, omalizumab could be a promising therapeutic option for refractory eosinophilic airway inflammation with corticosteroid resistance.
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http://dx.doi.org/10.3390/biomedicines9070787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301363PMC
July 2021

Shear bond strength of orthodontic brackets bonded with resin coating material.

Dent Mater J 2021 Jun 30. Epub 2021 Jun 30.

Department of Orthodontics, The Nippon Dental University School of Life Dentistry at Niigata.

The purpose of this study was to determine whether a system using a resin coating material (PRG Barrier Coat) with anticariogenic ability can effectively bond orthodontic brackets to human teeth. Resin-modified glass-ionomer cement system (Fuji Ortho LC, group 1) and resin composite cement systems (BeautyOrtho Bond) combined with a self-etching primer (group 2), with the resin coating material (group 3), and with the resin coating material after an organic acid etching agent (group 4) were used for bracket bonding. The mean shear bond strength (SBS) was significantly higher in group 1 than in groups 2, 3 and 4. Groups 2 and 4 exhibited a significantly higher mean SBS than group 3. The resin composite cement system combined with the resin coating material after the organic acid etching agent can serve as an alternative for orthodontic bracket bonding.
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http://dx.doi.org/10.4012/dmj.2020-249DOI Listing
June 2021

Treg and IL-1 receptor type 2-expressing CD4 T cell-deleted CD4 T cell fraction prevents the progression of age-related hearing loss in a mouse model.

J Neuroimmunol 2021 08 8;357:577628. Epub 2021 Jun 8.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata, Osaka, Japan.

We investigated the association between cellular immunity and age-related hearing loss (ARHL) development using three CD4 T cell fractions, namely, naturally occurring regulatory T cells (Treg), interleukin 1 receptor type 2-expressing T cells (I1R2), and non-Treg non-I1R2 (nTnI) cells, which comprised Treg and I1R2-deleted CD4 T cells. Inoculation of the nTnI fraction into a ARHL murine model, not only prevented the development of ARHL and the degeneration of spiral ganglion neurons, but also suppressed serum nitric oxide, a source of oxidative stress. Further investigations on CD4 T cell fractions could provide novel insights into the prevention of aging, including presbycusis.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577628DOI Listing
August 2021

Long-term sublingual immunotherapy provides better effects for patients with Japanese cedar pollinosis.

Auris Nasus Larynx 2021 Aug 29;48(4):646-652. Epub 2021 Jan 29.

Department of Otorhinolaryngology, Kansai Medical University, shinmachi 2-5-1, Hirakata, Osaka, Japan.

Objective: Japanese cedar pollinosis is an endemic disease affecting a large proportion of Japan's population. Five seasons have passed since sublingual immunotherapy (SLIT) for Japanese cedar pollinosis was included in the public insurance coverage in Japan. In this study, we evaluated the clinical effects of long-term SLIT for Japanese cedar pollinosis on upper respiratory symptoms primarily represented by nasal symptoms and inflammation of the respiratory tract in the 2019 season, in which considerable amount of cedar pollen was dispersed.

Methods: This study involved 95 patients who were undergoing SLIT for Japanese cedar pollinosis after the initiation at some point between 2014 and 2018, and this group of patients was compared with a control group comprising 21 patients receiving preseasonal prophylactic treatment (with a second-generation antihistaminic drug). We evaluated the patients' nasal/eye symptoms, total nasal symptom and medication score (TNSMS), and quality of life according to relevant guidelines. In addition, the levels of peripheral blood eosinophils, serum total IgE, Japanese cedar antigen-specific IgE, Cryj1-specific IgG4, and fractional exhaled nitric oxide (FENO) were measured as objective indices.

Results: From the fourth season (SLIT4), nasal discharge, sneezing, nasal obstruction symptoms, and TNSMS significantly decreased compared with those in the preseasonal prophylactic treatment and SLIT1 groups. In the patients suspected to have eosinophilic airway inflammation (with a baseline FENO ≥25 ppb), the interannual variability of FENO levels significantly reduced after 5 years of treatment.

Conclusion: The efficacy of SLIT was noted from the first year of treatment, even in a year when pollen profusely dispersed. Thus, long-term continuous treatment with SLIT may alleviate nasal symptoms as well as eosinophilic airway inflammation.
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http://dx.doi.org/10.1016/j.anl.2021.01.003DOI Listing
August 2021

The multiple functions and subpopulations of eosinophils in tissues under steady-state and pathological conditions.

Allergol Int 2021 Jan 24;70(1):9-18. Epub 2020 Nov 24.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Osaka, Japan.

Eosinophils not only play a critical role in the pathogenesis of eosinophil-associated diseases, but they also have multiple important biological functions, including the maintenance of homeostasis, host defense against infections, immune regulation through canonical Th1/Th2 balance modulation, and anti-inflammatory and anti-tumorigenic activities. Recent studies have elucidated some emerging roles of eosinophils in steady-state conditions; for example, eosinophils contribute to adipose tissue metabolism and metabolic health through alternatively activated macrophages and the maintenance of plasma cells in intestinal tissue and bone marrow. Moreover, eosinophils exert tissue damage through eosinophil-derived cytotoxic mediators that are involved in eosinophilic airway inflammation, leading to diseases including asthma and chronic rhinosinusitis with nasal polyps characterized by fibrin deposition through excessive response by eosinophils-induced. Thus, eosinophils possessing these various effects reflect the heterogenous features of these cells, which suggests the existence of distinct different subpopulations of eosinophils between steady-state and pathological conditions. Indeed, a recent study demonstrated that instead of dividing eosinophils by classical morphological changes into normodense and hypodense eosinophils, murine eosinophils from lung tissue can be phenotypically divided into two distinct subtypes: resident eosinophils and inducible eosinophils gated by Siglec-F CD62L CD101 and Siglec-F CD62L CD101, respectively. However, it is difficult to explain every function of eosinophils by rEos and iEos, and the relationship between the functions and subpopulations of eosinophils remains controversial. Here, we overview the multiple roles of eosinophils in the tissue and their biological behavior in steady-state and pathological conditions. We also discuss eosinophil subpopulations.
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http://dx.doi.org/10.1016/j.alit.2020.11.001DOI Listing
January 2021

Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor.

Exp Cell Res 2021 01 21;398(1):112390. Epub 2020 Nov 21.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.

Although surgical treatment cures >90% of differentiated thyroid cancer (DTC) patients, the remaining patients, including advanced DTC cases, have poor clinical outcomes. These patients with inoperable disease have only two choices of radioactive iodine therapy and tyrosine kinase inhibitors such as lenvatinib, which have a high incidence of treatment-related adverse events and can only prolong progression free survival by approximately 5-15 months. In this study, we investigated the antitumor effects of combination therapy with lenvatinib and radiation (CTLR) for DTC. CTLR synergistically inhibited cell replication and colony formation in vitro and tumor growth in nude mice without apparent toxicities and suppressed the expression of proliferation marker (Ki-67). CTLR also induced apoptosis and G2/M phase cell cycle arrest. Moreover, quantitative analysis of the intracellular uptake of lenvatinib using liquid chromatography and mass spectrometry demonstrated that intracellular uptake of lenvatinib was significantly increased 48 h following irradiation. These data suggest that increased membrane permeability caused by irradiation increases the intracellular concentration of levatinib, contributing to the synergistic effect. This mechanism-based potential of combination therapy suggests a powerful new therapeutic strategy for advanced thyroid cancer with fewer side effects and might be a milestone for developing a regimen in clinical practice.
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http://dx.doi.org/10.1016/j.yexcr.2020.112390DOI Listing
January 2021

Early voice therapy for unilateral vocal fold paralysis improves subglottal pressure and glottal closure.

Am J Otolaryngol 2020 Nov - Dec;41(6):102727. Epub 2020 Sep 13.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, 2-5-1, Shinmachi, Hirakata, Osaka 573-1010, Japan.

Purpose: In cases of unilateral vocal fold paralysis (UVFP), voice disorders caused by glottic insufficiency can lead to a considerable reduction in the patient's quality of life. Voice therapy (VT) is an effective treatment that must be started early after the onset of vocal fold paralysis. This study examined the effect of early VT for patients with UVFP occurring after esophagectomy.

Materials And Methods: Patients who had residual UVFP at 1 month postoperatively after esophagectomy for esophageal cancer between November 2014 and March 2017 were evaluated. Seventeen patients were divided into the VT group (n = 6) and non-VT group (n = 11). We compared these two groups and retrospectively examined the effect of early VT. The study endpoints included aerodynamic tests, laryngeal endoscopy, laryngeal stroboscopy, and glottal closure. All of these evaluations were performed at preoperatively and at 1 and 3 months postoperatively.

Results: Subglottal pressure reduced notably in the VT group, and both the mean flow rate and maximum phonation time tended to improve after VT. Conversely, there were no significant differences in MFR and MPT in the non-VT group. Furthermore, although UVFP remained after VT, we achieved glottal closure for all three patients. Conversely, only two of the six patients with glottic insufficiency in the non-VT group achieved glottal closure.

Conclusion: VT may be effective for improving impaired vocal function in patients with UVFP. It is reasonable to expect that VT can be initiated 1 month after the onset of vocal fold paralysis.
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http://dx.doi.org/10.1016/j.amjoto.2020.102727DOI Listing
December 2020

Role of eosinophilic chronic rhinosinusitis in switching to benralizumab treatment in mepolizumab responders.

Int J Clin Pharmacol Ther 2020 Dec;58(12):703-708

Background: There are currently three anti-interleukin-5 (IL-5) pathway-directed therapies: mepolizumab, reslizumab, and benralizumab. Of these, benralizumab was most recently approved. Benralizumab is administered every 8 weeks after an initial 3 doses given every 4 weeks, whereas mepolizumab and reslizumab are administered every 4 weeks. This convenience in benralizumab administration indicates that it is potentially beneficial for patients. Therefore, we potentially have an opportunity to change to benralizumab in patients who responded to mepolizumab or reslizumab. However, other than eosinophil levels, factors that could predict patients responding to anti-IL-5 pathway-directed therapies have been unknown. In this study, we examine the clinical characteristics of mepolizumab responders who achieved successful switching to benralizumab.

Materials And Methods: A total of 18 consecutive severe asthmatic patients treated with sequential mepolizumab and benralizumab, each for at least 1 year, were enrolled in this study. This study was a single-center case series. Patients were defined as having achieved successful switching to benralizumab if they satisfied either of the following for 1 year before and after the benralizumab treatment: (1) they experienced no exacerbation; or (2) they experienced no exacerbation and discontinued oral corticosteroids.

Results: All 18 patients responded to mepolizumab treatment, and 11 of them achieved successful switching to benralizumab. The proportion of patients who achieved successful switching to benralizumab was higher in patients with eosinophilic chronic rhinosinusitis (ECRS) than in those without (76.9 vs. 20.0%; p = 0.025).

Conclusion: Our findings imply that in responders to mepolizumab, there may be a higher response rate to benralizumab in patients with ECRS than in those without.
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http://dx.doi.org/10.5414/CP203767DOI Listing
December 2020

Reduced Local Response to Corticosteroids in Eosinophilic Chronic Rhinosinusitis with Asthma.

Biomolecules 2020 02 18;10(2). Epub 2020 Feb 18.

Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.

Eosinophilic chronic rhinosinusitis (ECRS), a subgroup of chronic rhinosinusitis with nasal polyps, is recognized as a refractory eosinophilic disorder characterized by both upper and lower airway inflammation. In some severe cases, disease control is poor, likely due to local steroid insensitivity. In this study, we focused on protein phosphatase 2A (PP2A), a key factor regulating glucocorticoid receptor (GR) nuclear translocation, and examined its association with local responses to corticosteroids in eosinophilic airway inflammation. Our results indicated reduced responses to corticosteroids in nasal epithelial cells from ECRS patients with asthma, which were also associated with decreased PP2A mRNA expression. Eosinophil peroxidase stimulates elevated PP2A phosphorylation levels, reducing PP2A protein expression and activity. In addition, mRNA levels of inflammatory mediators (TSLP, IL-25, IL-33, CCL4, CCL5, CCL11, and CCL26) associated with eosinophilic airway inflammation in epithelial cells were increased in nasal polyps (eosinophil-rich areas) compared with those in uncinate process tissues (eosinophil-poor areas) from the same patients. PP2A reduction by siRNA reduced GR nuclear translocation, whereas PP2A overexpression by plasmid transfection, or PP2A activation by formoterol, enhanced GR nuclear translocation. Collectively, our findings indicate that PP2A may represent a promising therapeutic target in refractory eosinophilic airway inflammation characterized by local steroid insensitivity.
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http://dx.doi.org/10.3390/biom10020326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072408PMC
February 2020

Increased CD69 expression on activated eosinophils in eosinophilic chronic rhinosinusitis correlates with clinical findings.

Allergol Int 2020 Apr 10;69(2):232-238. Epub 2020 Jan 10.

Department of Otorhinolaryngology, Head & Neck Surgery, Kansai Medical University, Osaka, Japan.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis associated with asthma. CD69 is an important marker of activation for eosinophils. But, whether a correlation exist between the CD69 expression on eosinophils and clinical findings is unclear.

Methods: We performed quantitative PCR and/or flow cytometry using tissue and purified eosinophils from the blood and nasal polyps of 12 patients with ECRS and from 8 patients without ECRS (controls). We assessed clinical findings including nasal polyp (NP) scores, sinus CT findings, and pulmonary function test results, and examined their possible association with the CD69 expression. We also performed CD69 cross-linking experiments in mouse eosinophils to investigate the functional role of CD69.

Results: Levels of cytokine mRNAs (IL-4, -5, -10, and -13) were significantly higher in purified NP eosinophils and tissues from patients with ECRS than the levels of those in controls. The expressions of major basic protein (MBP), eosinophilic cationic protein (ECP), eosinophilic-derived neurotoxin (EDN), eosinophil peroxidase (EPX) in cytotoxic granules, and CD69 mRNA were significantly higher in purified eosinophils from NPs than in those from blood. We also found a correlation between expression of CD69 and clinical findings. Moreover, we found EPX release from mouse eosinophils following CD69 cross-linking.

Conclusions: These data suggest that increased CD69 expression by eosinophils is not only a biomarker for nasal obstruction and pulmonary dysfunction, but also a potential therapeutic target for patients with ECRS and asthma.
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http://dx.doi.org/10.1016/j.alit.2019.11.002DOI Listing
April 2020

Multiple Biological Aspects of Eosinophils in Host Defense, Eosinophil-Associated Diseases, Immunoregulation, and Homeostasis: Is Their Role Beneficial, Detrimental, Regulator, or Bystander?

Biol Pharm Bull 2020 ;43(1):20-30

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University.

Eosinophils are innate immune leukocytes and play important roles as terminal effector cells owing to their mediators, such as tissue-destructive cationic proteins, cytokines, chemokines, and lipid mediators. Historically, they are not only considered an important player in host defense against parasitic, viral, fungal, and bacterial infections but also implicated in the pathogenesis of eosinophil-associated diseases, such as allergic rhinitis, asthma, eosinophilic chronic rhinosinusitis, esophagitis, atopic dermatitis, myopathies, and hypereosinophilic syndrome. Moreover, recent studies have shown that eosinophils have an immune regulatory and homeostatic function. Interestingly, there is emerging evidence that eosinophils are accumulated through adoptive T-helper 2 (Th2) and innate Th2 responses, mechanisms of the classical allergen-specific immunoglobulin E (IgE)-mediated response, and group 2 innate lymphoid cell-derived interleukin-5, respectively. Furthermore, in agreement with current concepts of eosinophil subtypes, it has been shown that resident and phenotypically distinct eosinophils, i.e., resident and recruited inflammatory eosinophils, exist in inflamed sites, and each has different functions. Thus, the classical and novel studies suggest that eosinophils have multiple functions, and their roles may be altered by the environment. In this article, we review multiple biological aspects of eosinophils (novel and classical roles), including their beneficial and detrimental effects, immunoregulation, and homeostatic function.
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http://dx.doi.org/10.1248/bpb.b19-00892DOI Listing
November 2020

Eosinophilic Cholecystitis Occurred in a Patient With Refractory Eosinophilic Airway Inflammation: A Case Report.

Allergy Rhinol (Providence) 2019 Jan-Dec;10:2152656719869607. Epub 2019 Aug 19.

Department of Otolaryngology, Kansai Medical University, Osaka, Japan.

Background: Eosinophilic cholecystitis (EC) is a rare condition that presents in a manner comparable to acute cholecystitis. The diagnosis is based on classical symptoms of cholecystitis with excessive eosinophilic infiltration within the gallbladder. EC has been reported alone or in combination with manifestations, such as eosinophilic gastrointestinal tract inflammation. However, association with airway inflammation in patients with EC is rare. We report the case of a 65-year-old man who had refractory eosinophilic chronic rhinosinusitis with bronchial asthma. A second endoscopic sinus surgery (ESS) was performed as treatment for recurrent nasal polyps. EC occurred while inhaled corticosteroids were reduced after ESS. Pathologic examination of the excised gallbladder demonstrated submucosal infiltration with a number of eosinophils. Furthermore, immunohistostaining revealed many galectin-10-positive cells in both the gallbladder mucosa and the paranasal sinus mucosa. Galectin-10 is a major constituent of human eosinophils, also known as the Charcot-Leyden crystal protein, which has been linked with eosinophilic inflammation. Interestingly, nasal polyps were reduced without any additional treatments 1 month after the cholecystectomy.

Conclusions: We experienced a rare case wherein EC onset occurred in a patient with refractory eosinophilic airway inflammation during inhaled corticosteroid tapering. Galectin-10 might help diagnose rare cases of eosinophilic inflammation in multiple organs.
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http://dx.doi.org/10.1177/2152656719869607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700860PMC
August 2019

A Novel Approach for Investigating Upper Airway Hyperresponsiveness Using Micro-CT in Eosinophilic Upper Airway Inflammation such as Allergic Rhinitis Model.

Biomolecules 2019 06 27;9(7). Epub 2019 Jun 27.

Department of Otorhinolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata 573-1010, Japan.

Airway hyperresponsiveness (AHR) has been proposed as a feature of pathogenesis of eosinophilic upper airway inflammation such as allergic rhinitis (AR). The measurement system for upper AHR (AHR) in rodents is poorly developed, although measurements of nasal resistance have been reported. Here we assessed UAHR by direct measurement of swelling of the nasal mucosa induced by intranasal methacholine (MCh) using micro-computed tomography (micro-CT). Micro-CT analysis was performed in both naïve and ovalbumin-induced AR mice following intranasal administration of MCh. The nasal cavity was segmented into two-dimensional horizontal and axial planes, and the data for nasal mucosa were acquired for the region of interest threshold. Then, a ratio between the nasal mucosa area and nasal cavity area was calculated as nasal mucosa index. Using our novel method, nasal cavity structure was clearly identified on micro-CT, and dose-dependent increased swelling of the nasal mucosa was observed upon MCh treatment. Moreover, the nasal mucosa index was significantly increased in AR mice compared to controls following MCh treatment, while ovalbumin administration did not affect swelling of the nasal mucosa in either group. This UAHR following MCh treatment was completely reversed by pretreatment with glucocorticoids. This novel approach using micro-CT for investigating UAHR reflects a precise assessment system for swelling of the nasal mucosa following MCh treatment; it not only sheds light on the mechanism of AR but also contributes to the development of new therapeutic drugs in AR patients.
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http://dx.doi.org/10.3390/biom9070252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681309PMC
June 2019

Critical role of CCL4 in eosinophil recruitment into the airway.

Clin Exp Allergy 2019 06 29;49(6):853-860. Epub 2019 Mar 29.

Department of General Medical Practice and Laboratory Diagnostic Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Background: Excessive eosinophil airway infiltration is a clinically critical condition in some cases. Eosinophilic pneumonia (EP) is a pulmonary condition involving eosinophil infiltration of the lungs. Although several chemokines, including eotaxin-1 (CCL11), RANTES (CCL5) and macrophage inflammatory protein 1β (MIP-1β or CCL4), have been detected in bronchoalveolar lavage fluid (BALF) from patients with EP, the pathophysiological mechanisms underlying EP, including potential relationships between eosinophils and CCL4, have not been fully elucidated.

Objective: To examine the involvement of CCL4 in eosinophilic airway inflammation.

Methods: We analysed supernatants of activated eosinophils and BALF from 16 patients with eosinophilic pneumonia (EP). Further, we examined the effects of CCL4 on eosinophil functions in vitro and those of anti-CCL4 neutralizing antibody in an in vivo model.

Results: We found that purified human eosinophils stimulated with IL-5 predominantly secreted CCL4 and that patients with EP had elevated CCL11 and CCL4 levels in BALF compared with samples from individuals without EP. Because CCL4 levels were more strongly correlated with eosinophil count and expression of eosinophil granule proteins than CCL11, in vitro experiments using purified eosinophils concentrated on the former chemokine. Interestingly, CCL4 acted as a chemoattractant for eosinophils. In a mouse model, administration of a CCL4-neutralizing antibody attenuated eosinophilic airway infiltration and airway hyperresponsiveness.

Conclusions And Clinical Relevance: Overall, these findings highlight an important role of CCL4 in the mechanisms underlying eosinophil recruitment into the airway and may provide a novel insight into this potential therapeutic target.
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http://dx.doi.org/10.1111/cea.13382DOI Listing
June 2019

Eosinophilic Upper Airway Inflammation in a Murine Model Using an Adoptive Transfer System Induces Hyposmia and Epithelial Layer Injury with Convex Lesions.

Med Sci (Basel) 2019 Feb 5;7(2). Epub 2019 Feb 5.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata 573-1010, Japan.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a refractory upper airway disease, accompanied mainly by eosinophilia and/or asthma. In addition, the disease correlates with a high rate of hyposmia, following a marked infiltration of eosinophils into the inflamed site, the paranasal sinus. Although eosinophils are known to contribute to the development of hyposmia and CRSwNP pathology, the underlying mechanisms remain unclear. This study aimed to investigate whether eosinophilic upper airway inflammation induces hyposmia and CRSwNP in a murine model using an adoptive transfer system.

Methods: To induce eosinophilic rhinosinusitis, splenocytes, including a high proportion (over 50%) of activated eosinophils (SPLhEos), were collected from interleukin-5 transgenic mice following double intraperitoneal injections of antigens, such as ovalbumin, house dust mite, or fungus. Activated SPLhEos with corresponding antigens were then transferred into the nasal cavity of recipient mice, which were sensitized and challenged by the corresponding antigen four times per week. Olfactory function, histopathological, and computed tomography (CT) analyses were performed 2 days after the final transfer of eosinophils.

Results: Hyposmia was induced significantly in mice that received SPLhEos transfer compared with healthy and allergic mice, but it did not promote morphological alteration of the paranasal sinus. Pathological analysis revealed that epithelial layer injury and metaplasia similar to polyps, with prominent eosinophil infiltration, was induced in recipient tissue. However, there was no nasal polyp development with interstitial edema that was similar to those recognized in human chronic rhinosinusitis.

Conclusions: This study supports the previously unsuspected contribution of eosinophils to CRS development in the murine model and suggests that murine-activated eosinophilic splenocytes contribute to the development of hyposmia due to more mucosal inflammation than physical airway obstruction and epithelial layer injury with convex lesions.
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http://dx.doi.org/10.3390/medsci7020022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409781PMC
February 2019

Regulation of Interaction between the Upper and Lower Airways in United Airway Disease.

Med Sci (Basel) 2019 Feb 11;7(2). Epub 2019 Feb 11.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University, Hirakata, 573-1010, Japan.

The concept of united airway disease comprises allergic rhinitis (AR) with asthma, and eosinophilic chronic rhinosinusitis (ECRS) with asthma. It embodies a comprehensive approach to the treatment of upper and lower airway inflammation. The treatment of upper airway inflammation reduces asthma symptoms and decreases the dose of inhaled corticosteroids (ICS) necessary to treat asthma. However, little is known about the mechanisms of interaction between upper and lower airway inflammation. Here we review these mechanisms, focusing on neural modulation and introduce a novel therapeutic approach to united airway disease using a fine-particle ICS. Our understanding of the relationship between the upper and lower airways and its contribution to T helper 2 (Th2)-skewed disease, such as AR and/or ECRS with asthma, has led us to this novel therapeutic strategy for a comprehensive approach to the treatment of upper airway inflammation with asthma.
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http://dx.doi.org/10.3390/medsci7020027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410259PMC
February 2019

Establishment of a novel platform cell line for efficient and precise evaluation of T cell receptor functional avidity.

Oncotarget 2018 Sep 25;9(75):34132-34141. Epub 2018 Sep 25.

Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.

Adoptive T-cell therapy with T cell receptor (TCR) -engineered T cells is an attractive strategy for cancer treatment and the success in this therapy is dependent on the functional avidity of the transduced TCRs against targeted tumor antigens. Therefore, the establishment of the methodology of the efficient and precise evaluation of TCR functional avidity has been awaited. Here, we show a novel platform cell line, named 2D3, which enables the functional avidity of transduced TCRs to be evaluated efficiently and precisely. In the 2D3, the precise TCR functional avidity of transduced TCRs is easily evaluable by the expression of green fluorescent protein (GFP) reporter gene driven by nuclear factor of activated T cells (NFAT) activation via TCR signaling. Four different TCRs of HLA-A24:02-restricted Wilms' tumor gene 1 (WT1)-specific CD8 cytotoxic T lymphocytes (CTLs) were transduced into 2D3 cells and the functional avidities of these four TCRs were evaluated. The evaluated functional avidity of these TCRs positively correlated with cell proliferation, cytokine production, and WT1-specific cytotoxicity of the TCR-transduced CD8 T cells in response to WT1 antigen. These results showed that 2D3 cell line was a novel and stable tool useful for the efficient and precise evaluation of the functional avidity of isolated and transduced TCRs in developing TCR-based immunotherapy.
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http://dx.doi.org/10.18632/oncotarget.26139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6183340PMC
September 2018

HFA-BDP Metered-Dose Inhaler Exhaled Through the Nose Improves Eosinophilic Chronic Rhinosinusitis With Bronchial Asthma: A Blinded, Placebo-Controlled Study.

Front Immunol 2018 25;9:2192. Epub 2018 Sep 25.

Airway Disease Section, Department of Otorhinolaryngology, Kansai Medical University, Osaka, Japan.

Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis with nasal polyps in Japanese. ECRS highly associated with asthma is a refractory eosinophilic airway inflammation and requires comprehensive care as part of the united airway concept. We recently reported a series of ECRS patients with asthma treated with fine-particle inhaled corticosteroid (ICS) exhalation through the nose (ETN). To evaluate fine-particle ICS ETN treatment as a potential therapeutic option in ECRS with asthma. Twenty-three patients with severe ECRS under refractory to intranasal corticosteroid treatment were randomized in a double-blind fashion to receive either HFA-134a-beclomethasone dipropionate (HFA-BDP) metered-dose inhaler (MDI) ETN ( = 11) or placebo MDI ETN ( = 12) for 4 weeks. Changes in nasal polyp score, computed tomographic (CT) score, smell test, and quality of life (QOL) score from baseline were assessed. Fractionated exhaled nitric oxide (FENO) was measured as a marker of eosinophilic airway inflammation. Response to corticosteroids was evaluated before and after treatment. Additionally, deposition of fine-particles was visualized using a particle deposition model. To examine the role of eosinophils on airway inflammation, BEAS-2B human bronchial epithelial cells were co-incubated with purified eosinophils to determine corticosteroid sensitivity. HFA-BDP MDI ETN treatment improved all assessed clinical endpoints and corticosteroid sensitivity without any deterioration in pulmonary function. FENO and blood eosinophil number were reduced by HFA-BDP MDI ETN treatment. The visualization study suggested that ETN at expiratory flow rates of 10-30 L/min led to fine particle deposition in the middle meatus, including the sinus ostia. Co-incubation of eosinophils with BEAS-2B cells induced corticosteroid resistance. Additional HFA-BDP MDI ETN treatment was beneficial in patients with ECRS and should be considered as a potential therapeutic option for eosinophilic airway inflammation such as ECRS with asthma. (UMIN-CTR: R000019325) (http://www.umin.ac.jp/ctr/index.htm).
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http://dx.doi.org/10.3389/fimmu.2018.02192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178134PMC
October 2019

A comparison of short-term outcomes of neck dissection for head and neck cancers using Thunderbeat™, LigaSure™ or treatment without an energy-based device: A case controlled study.

Int J Surg 2018 Oct 21;58:60-64. Epub 2018 Sep 21.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University Hospital, Japan.

Objective: The aim of this study was to evaluate the efficacy of the new energy-based device Thunderbeat in neck dissection (ND) for head and neck cancer.

Materials And Methods: We retrospectively examined 95 consecutive patients who underwent ND for head and neck squamous cell carcinoma between April 2013 and March 2018. The patients were divided into three groups: ND without the energy-based device (control group), ND using the LigaSure Small Jaw (LS group), and ND using the Thunderbeat Open Fine Jaw (TB group). The outcomes were compared among the three groups, as measured by the duration of ND (dissection time), blood loss during ND, and postoperative complications. We also analyzed the factors that may influence dissection time using multivariate analysis.

Results: Compared to the control group, dissection time was found to be significantly shorter in both energy-based device groups (LS group and TB group) (96.4, 71.1, and 66.0 min, respectively, p = 0.0015) by univariate analysis. Blood loss during ND did not differ significantly among the three groups. Multivariate analysis showed that ND using the Thunderbeat as well as elderly patients (70 years and over), less extensive surgery (3 or fewer neck levels), and absence of extracapsular invasion were independently and significantly associated with shorter dissection time (p = 0.0069, 0.0337, <0.0001, and 0.0015, respectively). The incidence of postoperative complications in the LS group (20%) tended to be higher than those in the other groups (5.6% in the control group and 3.4% in the TB group), although the differences were not significant.

Conclusion: ND for head and neck cancers using the Thunderbeat is a safe and reliable method in terms of duration of dissection without increasing postoperative complications.
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http://dx.doi.org/10.1016/j.ijsu.2018.09.009DOI Listing
October 2018

Effect of nasally exhaling budesonide/formoterol dry powder inhaled at "fast" inspiratory flow on eosinophilic chronic rhinosinusitis
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Int J Clin Pharmacol Ther 2018 Nov;56(11):539-543

Background: Budesonide (BUD)/formoterol (FM) dry powder inhaler has a feature that the fine particle fraction output is dependent on users' inspiratory flow rate. The aim of this study was to assess the amount of nasally exhaled BUD/FM inhaled in the different inspiratory flow rate. We also examined the effect of nasal exhalation of BUD/FM dry powder inhaled on radiographic evidence of sinonasal inflammation in asthmatic patients with eosinophilic chronic rhinosinusitis (ECRS).

Materials And Methods: The quantitative amount of nasally exhaled BUD/FM was analyzed by high-performance liquid chromatography in 3 healthy subjects. We retrospectively evaluated the effect of nasal exhalation of BUD/FM dry powder inhaled at > 60 L/min on radiographic evidence of sinonasal inflammation, which was assessed according to the Lund-Mackay staging (LMS) system, in 7 consecutive patients with asthma and ECRS.

Results: The amount of nasally exhaled BUD in the setting of inhaling BUD/FM dry powder inhaler at 60 L/min (subject 1: 25.8 ng/mL; subject 2: 37.3 ng/mL; subject 3: 30.0 ng/mL) was high compared to at 30 L/min (subject 1: 9.3 ng/mL; subject 2: 4.1 ng/mL; subject 3: 9.2 ng/mL) in each healthy subject. Nasal exhalation of BUD/FM dry powder significantly reduced total (p = 0.018) and ethmoid LMS scores (p = 0.0077).

Conclusion: Nasal exhalation technique of BUD/FM dry powder inhaled at "fast" inspiratory flow has a potential of simultaneously treating asthma and ECRS.
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http://dx.doi.org/10.5414/CP203272DOI Listing
November 2018

Association between skeletal morphology and agenesis of all four third molars in Japanese orthodontic patients.

Odontology 2018 Jul 12;106(3):282-288. Epub 2018 Jan 12.

Orthodontics and Dentofacial Orthopedics, Field of Oral and Maxillofacial Growth and Development, Course of Clinical Science, The Nippon Dental University Graduate School of Life Dentistry at Niigata, 1-8 Hamaura-cho, Chuo-ku, Niigata, 951-8580, Japan.

The purpose of this study was to clarify differences in skeletal morphologies between male and female orthodontic patients with and without agenesis of all four third molars. A total of 64 patients (32 males and 32 females) with agenesis of all four third molars without agenesis of other teeth were selected as the third molars agenesis group (group 1). In addition, 64 patients (32 males and 32 females) with all these teeth were selected as controls (group 2). Lateral cephalograms taken between the ages of 14 and 30 years were used to compare skeletal morphology between groups 1 and 2 and between sexes. Maxillary length (P < 0.001), lower facial height (P < 0.05), gonial angle (P < 0.001) and mandibular plane angle (P < 0.001) were significantly smaller in group 1 than in group 2. Irrespective of the presence or absence of all four third molars, males had significantly smaller lower facial height (P < 0.01) and mandibular plane angle (P < 0.001) and significantly greater total mandibular length (P < 0.001), mandibular body length (P < 0.001) and mandibular ramus height (P < 0.001) than females. Japanese orthodontic patients with agenesis of all four third molars had significantly small maxillary length, lower facial height, gonial angle and mandibular plane angle.
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http://dx.doi.org/10.1007/s10266-017-0336-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995980PMC
July 2018

Cells Expressing Prominin-1 in Neonatal Murine Inferior Colliculus Differentiate into Neurons and Glia.

Mol Neurobiol 2018 Jun 9;55(6):4998-5005. Epub 2017 Aug 9.

Department of Public Health, Kansai Medical University, Osaka, Japan.

Inferior colliculus (IC) is a major center for the integration and processing of acoustic information from ascending auditory pathways. Damage to the IC as well as normal aging can impair auditory function. Novel strategies such as stem cell (SC)-based regenerative therapy are required for functional recovery because mature neural cells have a minimal regenerative capacity after an injury. However, it is not known if there are neural stem cells (NSCs) in the IC. Herein, we screened for NSCs by surface marker analysis using flow cytometry. Isolated IC cells expressing prominin-1 (CD133) exhibited the cardinal NSC properties self-renewal capacity, expression of known NSC markers (SOX2 and nestin), and multipotency. Prominin-1-expressing cells from neonatal IC generated neurospheres, and culture of these neurospheres in differentiation-conditioned medium gave rise to gamma-aminobutyric acid-ergic (GABAergic) neurons, astrocytes, and oligodendrocytes. The presence of NSC-like cells in the IC has important implications for understanding IC development and for potential regenerative therapy.
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http://dx.doi.org/10.1007/s12035-017-0701-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948249PMC
June 2018

Radiographic Evidence of Sinonasal Inflammation in Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome: An Underrecognized Association.

J Allergy Clin Immunol Pract 2017 Nov - Dec;5(6):1657-1662. Epub 2017 Apr 29.

Department of Airway Medicine, Mitsubishi Kyoto Hospital, Kyoto, Japan.

Background: Sinonasal inflammation on both clinical examinations and imaging significantly impacts both asthma and chronic obstructive pulmonary disease (COPD).

Objective: The objective of this study was to examine the association between sinonasal inflammation and asthma-COPD overlap syndrome (ACOS).

Methods: A total of 112 patients with a ratio of forced expiratory volume in 1 s to forced vital capacity of less than 70% were enrolled. COPD, asthma, and ACOS were clinically diagnosed according to the 2014 Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease guidelines. Sinonasal inflammatory condition was evaluated using sinus computed tomography, and its severity was assessed according to the Lund-Mackay staging (LMS) system. Ethmoid sinus-dominant shadow was defined as the presence of greater LMS scores for the anterior and posterior ethmoid sinuses than for the maxillary sinus.

Results: COPD, asthma, and ACOS were diagnosed in 55 (49.1%), 39 (34.8%), and 18 patients (16.1%), respectively. The frequency of radiographic evidence of sinonasal inflammation in patients with COPD, asthma, ACOS was 60.0%, 94.9%, and 72.2%, respectively. Patients with ACOS and COPD had only mild radiographic evidence of sinonasal inflammation (LMS score, 1-7), whereas moderate (LMS score, 8-11) and severe (LMS score, ≥12) radiographic evidence of sinonasal inflammation were detected only in patients with asthma. Furthermore, the frequency of ethmoid sinus-dominant shadow was significantly higher in patients with asthma than in those with COPD and ACOS.

Conclusions: Radiographic evidence of sinonasal inflammation was a common comorbidity in ACOS. Future studies are required to examine the role of sinonasal inflammation in ACOS.
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http://dx.doi.org/10.1016/j.jaip.2017.03.031DOI Listing
June 2018

Residual Recurrent Nerve Paralysis After Esophagectomy is Associated with Preoperative Lower Serum Albumin.

Dysphagia 2017 08 24;32(4):520-525. Epub 2017 Apr 24.

Department of Otolaryngology Head & Neck Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.

Esophagectomy for esophageal cancer is invasive thoracic surgery with a high incidence rate of postoperative complications and prolongation of hospitalization, even if the standardized clinical pathway improves the outcome (mortality and morbidity). Postoperative recurrent nerve paralysis (RNP) is related to respiratory complications concomitant with prolonged hospitalization. However, it has not been elucidated which factors affect the incidence and recovery of RNP. To detect the predictive factor for postoperative RNP, we focused on preoperative serum albumin. Patients who had esophageal cancer with standard esophagectomy were evaluated. In total, 94 patients were divided into three groups depending on the presence of RNP (46 in patients without RNP, 29 in those with transient RNP who recovered within 6 months follow-up and 19 in those with residual RNP). We retrospectively investigated factors associated with residual RNP. Preoperative lower serum albumin was associated with residual RNP. In addition, days to the resumption of oral intake and duration of stay in the hospita postoperatively were delayed in the group of residual RNP. Multiple regression analysis indicated that preoperative serum albumin was a predictive factor for residual RNP. Preoperative lower serum albumin level might be linked to residual RNP which could prolong the resumption of postoperative oral intake and shorten the period of stay at the hospital after esophagectomy, leading to unfavorable outcomes for patients.
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http://dx.doi.org/10.1007/s00455-017-9793-3DOI Listing
August 2017

Mammary Analogue Secretory Carcinoma Presenting as a Cervical Lymph Node Metastasis of Unknown Primary Site: A Case Report.

Case Rep Oncol 2017 Jan-Apr;10(1):192-198. Epub 2017 Feb 15.

Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University Hospital, Hirakata, Japan.

Background: Mammary analogue secretory carcinoma (MASC) is a pathological entity arising in the salivary glands first described by Skalova et al. [Am J Surg Pathol 2010;34: 599-608]. Here, we report the first case of MASC presenting as a cervical lymph node metastasis of unknown primary site together with a brief review of the literature.

Case Report: We present a 74-year-old male with a painless lump in his left neck. Based on the fine-needle aspiration cytological findings, a possible malignant tumor was suspected. No evidence of a primary lesion was observed using imaging modalities including positron emission tomography/computed tomography. The patient underwent an ipsilateral modified radical neck dissection. Immunohistochemical staining showed that the neoplastic cells were positive for S100 protein and GATA3. A rearrangement of the ETV6 gene was noted during fluorescence in situ hybridization, and the final histopathological diagnosis was MASC.

Conclusion: We encountered a MASC presenting as a cervical lymph node metastasis of unknown primary site. No adjuvant therapy was administered, and no local recurrence or metastatic disease has been detected during a follow-up period of 9 months. This is the first case report of MASC presenting as a cervical lymph node metastasis of unknown primary site and suggests the new properties of MASC.
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http://dx.doi.org/10.1159/000457949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346937PMC
February 2017

Impaired Dual-Specificity Protein Phosphatase DUSP4 Reduces Corticosteroid Sensitivity.

Mol Pharmacol 2017 05 10;91(5):475-481. Epub 2017 Mar 10.

Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (Y.K., K.I., N.M., P.J.B.); and Airway Disease Section, Department of Otolaryngology, Kansai Medical University, Moriguchi, Osaka, Japan (Y.K., A.K., K.T.)

We have reported that phosphorylation of the glucocorticoid receptor (GR) at Ser reduces GR nuclear translocation, resulting in corticosteroid insensitivity in patients with severe asthmas. A serine/threonine protein phosphatase 2A, which regulates c-Jun N-terminal kinase (JNK) 1 and GR-Ser signaling, is involved in this mechanism. Here, we further explored protein kinase dual-specificity phosphatases (DUSPs) with the ability to dephosphorylate JNK, and identified DUSP4 as a phosphatase involved in the regulation of corticosteroid sensitivity. The effects of knocking down DUSPs (DUSP1, 4, 8, 16, and 22) by small interfering RNA (siRNA) were evaluated in a monocytic cell line (U937). Corticosteroid sensitivity was determined by dexamethasone enhancement of FK506-binding protein 51 or inhibition of tumor necrosis factor (TNF)-induced interferon and interleukin 8 expression and GR translocation from cell cytoplasm to nucleus. The nuclear/cytoplasmic GR, phosphorylation levels of GR-Ser and JNK1, coimmunoprecipitated GR-JNK1-DUSP4, and DUSP4 expression were analyzed by western blotting and/or imaging flow cytometry. Phosphatase activity of immunoprecipitated (IP)-DUSP4 was measured by fluorescence-based assay. Knockdown of DUSP4 enhanced phosphorylation of GR-Ser and JNK1 and reduced GR nuclear translocation and corticosteroid sensitivity. Coimmunoprecipitation experiments showed that DUSP4 is associated with GR and JNK1. In peripheral blood mononuclear cells from severe asthmatics, DUSP4 expression was reduced versus healthy subjects and negatively correlated with phosphorylation levels of GR-Ser and JNK1. Formoterol enhanced DUSP4 activity and restored corticosteroid sensitivity reduced by DUSP4 siRNA. In conclusion, DUSP4 regulates corticosteroid sensitivity via dephosphorylation of JNK1 and GR-Ser DUSP4 activation by formoterol restores impaired corticosteroid sensitivity, indicating that DUSP4 is crucial in regulating corticosteroid sensitivity, and therefore might be a novel therapeutic target in severe asthma.
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http://dx.doi.org/10.1124/mol.116.107656DOI Listing
May 2017

Replacement of SFC-DPI with SFC-MDI exhaled through the nose improves eosinophilic chronic rhinosinusitis in patients with bronchial asthma.

Int J Clin Pharmacol Ther 2017 Jan;55(1):89-94

Objective: Eosinophilic chronic rhinosinusitis (ECRS), a subgroup of chronic rhinosinusitis with nasal polyps, is a refractory disease closely associated with bronchial asthma. We recently reported on the efficacy of ultra-fine particle inhaled corticosteroids (ICS) (hydrofluoroalkane-134a-beclomethasone dipropionate: HFA-BDP) exhalation through the nose (ETN) treatment for mild-to-moderate asthmatics with ECRS. However, the effect of HFA-BDP ETN was found to be transient in some cases with severe ECRS and asthma, requiring treatment with higher-dose ICS and long-acting β2-agonists (LABA). Here, we present a case of refractory ECRS with severe asthma treated with a combination of high-dose ICS and LABA ETN, and we discuss the mechanisms for its effectiveness.

Methods: A 57-year-old man was treated with the combined regimen of HFA-BDP ETN and salmeterol/fluticasone combination (SFC) dry powder inhaler (DPI) for his refractory ECRS with severe asthma. For better control, we replaced SFC-DPI with SFC metered-dose inhaler (MDI) ETN and evaluated the clinical effect and corticosteroid sensitivity. We also examined the flow and deposition of fine particles released by SFC-MDI ETN.

Results: After switching to SFC-MDI ETN, the patient's conditions markedly resolved with the restoration of corticosteroid sensitivity and PP2A activity. The fine particles released by SFC-MDI ETN at least partially flowed out through the external nares and seemed to be deposited on the ethmoid sinus.

Conclusion: Fine particle ICS/LABA ETN might be an additional therapeutic option for refractory ECRS with severe asthma and corticosteroid insensitivity.
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http://dx.doi.org/10.5414/CP202633DOI Listing
January 2017

Nasal nitric oxide improved by continuous positive airway pressure therapy for upper airway inflammation in obstructive sleep apnea.

Sleep Breath 2017 May 12;21(2):405-410. Epub 2016 Nov 12.

Department of Airway Medicine, Mitsubishi Kyoto Hospital, 1 Katsuragoshocho, Nishikyo-ku, Kyoto, 615-8087, Japan.

Purpose: In this report, we examined the association between obstructive sleep apnea (OSA) and upper and lower airway inflammation based on nitric oxide (NO) measurements.

Methods: Study subjects included 51 consecutive participants. Sleep-disordered breathing was evaluated by a type 3 portable monitor and quantified by respiratory disturbance index (RDI). Airway inflammation was noninvasively analyzed by the measurement of nasally and orally exhaled NO; nasal value was presented as nasally exhaled NO minus orally exhaled NO. In 15 patients prescribed nasal continuous positive airway pressure (nCPAP) therapy, exhaled NO was re-evaluated in 10.7 ± 6.3 months after nCPAP therapy.

Results: Nasal NO was significantly higher in patients with severe OSA (RDI ≥ 30/h) than those with non-OSA (RDI < 10/h) (76.9 ± 26.0 ppb vs. 47.9 ± 22.0 ppb, respectively, p = 0.016) and correlated with RDI (rho = 0.36, p = 0.0099), whereas orally exhaled NO did not differ between non-OSA and OSA patients and was not correlated with RDI. In 15 patients, nasal NO after nCPAP therapy was significantly decreased than that before nCPAP therapy (81.9 ± 31.2 ppb vs. 53.7 ± 27.2 ppb, respectively, p = 0.0046); in 11 patients having good compliance to nCPAP therapy (nCPAP use >4 h per night on more than 70% of nights), this association was more remarkable.

Conclusions: In OSA, upper but not lower airway inflammation can be increased by repetitive collapse of the upper airway. Future studies are required to determine the role of nasal NO in OSA.
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http://dx.doi.org/10.1007/s11325-016-1431-zDOI Listing
May 2017
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