Details of a Researcher - Fukunaga, Koichi

Papers - Fukunaga, Koichi

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Characteristics of severe asthma with fungal sensitization

Masaki, K., Fukunaga, K., Matsusaka, M., Kabata, H., Tanosaki, T., Mochimaru, T., Kamatani, T., Ohtsuka, K., Baba, R., Ueda, S., Suzuki, Y., Sakamaki, F., Oyamada, Y., Inoue, T., Oguma, T., Sayama, K., Koh, H., Nakamura, M., Umeda, A., Kamei, K., Izuhara, K., Asano, K. and Betsuyaku, T.

Ann Allergy Asthma Immunol 119 ( 3 ) 253 - 257 2017.09

ISSN 1534-4436

BACKGROUND: Some patients with severe asthma also have fungal sensitization and are considered to have severe asthma with fungal sensitization. However, there is limited information on the clinical features of SAFS. OBJECTIVE: To investigate the clinical characteristics of severe asthma with fungal sensitization. METHODS: The present study enrolled 124 patients with severe asthma. We evaluated clinical aspects, such as various serum cytokines, fractional exhaled nitric oxide, pulmonary function, and serum immunoglobulin E (IgE). Fungal sensitization was assessed by determining serum levels of IgE specific to fungal allergens (Aspergillus, Alternaria, Candida, Cladosporium, Penicillium, and Trichophyton species and Schizophyllum commune). The protocol was registered at a clinical trial registry (www.umin.ac.jp/ctr/index-j.htm; UMIN 000002980). RESULTS: Thirty-six patients (29%) showed sensitization to at least 1 fungal allergen. The most common species were Candida (16%), Aspergillus (11%), and Trichophyton (11%). The rate of early-onset asthma (<16 years of age) was higher in patients with fungal sensitization than in those without fungal sensitization (45% vs 25%; P = .02). Interleukin-33 levels were higher in patients with fungal sensitization than in those without fungal sensitization. Of patients with atopic asthma, Asthma Control Test scores were worse in patients with multiple fungal sensitizations than in patients with a single fungal sensitization or those without fungal sensitization. CONCLUSION: Severe asthma with fungal sensitization is characterized by early onset of disease and high serum levels of interleukin-33. Multiple fungal sensitizations are associated with poor asthma control. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR; www.umin.ac.jp/ctr/index-j.htm): UMIN 000002980.

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Obstructive sleep apnea syndrome should be considered as a cause of nocturia in younger patients without other voiding symptoms

Maeda, T., Fukunaga, K., Nagata, H., Haraguchi, M., Kikuchi, E., Miyajima, A., Yamasawa, W., Shirahama, R., Narita, M., Betsuyaku, T., Asano, K. and Oya, M.

Can Urol Assoc J 10 ( 7-8 ) E241 - E245 2016.07

ISSN 1911-6470

INTRODUCTION: This study aimed to evaluate urination frequency among patients with obstructive sleep apnea syndrome (OSAS) and the effect of continuous positive airway pressure (CPAP) treatment. METHODS: We evaluated 138 men with moderate-to-severe OSAS by using polysomnography. Urination status was assessed at baseline and three months using the International Prostate Symptom Score and Overactive Bladder Symptom Score. Nocturia was defined as >/=2 nighttime urinations and patients were classified into Group A (<50 years old with nocturia), Group B (>/=50 years old with nocturia), and Group C (patients without nocturia). OSAS severity and other urinary symptoms were also evaluated. RESULTS: Patients with nocturia exhibited more severe OSAS, compared to patients without nocturia (apnea-hypopnea index [AHI]: 52.0 vs. 44.7; p=0.021). Group A had the worst AHI, but did not have additional voiding symptoms, compared to Group B (p<0.001). The number of urinations was significantly correlated with OSAS severity in <50-year-old patients (p=0.013). CPAP reduced the number of urinations in Group A (75% of patients) and Group B (90% of patients). Patients with and without improved nocturia exhibited significant differences in their baseline OSAS severity (AHI: 53.7 vs. 37.3; p=0.042). CONCLUSIONS: OSAS severity was associated with the number of urinations in <50-year-old patients. CPAP decreased the nocturia frequency in 85% of patients with nocturia and was most effective in patients with severe AHI. However, additional studies should evaluate voiding volume in order to elucidate the mechanism of nocturia in patients with OSAS.

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Mechanisms to Suppress ILC2-induced Airway Inflammation

Kabata, H., Moro, K., Koyasu, S., Fukunaga, K., Asano, K. and Betsuyaku, T.

Ann Am Thorac Soc 13 Suppl 1 S95 2016.03

ISSN 2325-6621

Epithelial cell-derived cytokines such as IL-33 and IL-25 activate group 2 innate lymphoid cells (ILC2s), which are known to be important sources of type 2 cytokines such as IL-5 and IL-13 in a variety of asthma mouse models. Recently, human studies have also reported the involvement of ILC2s in asthma, as ILC2s are increased in peripheral blood and bronchoalveolar lavage fluid in patients with asthma. Compared with positive regulators such as IL-25 and IL-33, the mechanisms to suppress the ILC2s-induced inflammation remain unclear. Because ILC2s express various cytokine receptors, the function of ILC2s would likely be influenced by cytokines present around ILC2s in the lungs. We reported that IL-2, IL-7, and thymic stromal lymphopoietin (TSLP) induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) and promoted the proliferation of ILC2s and type 2 cytokine production when combined with IL-33. TSLP enhanced the expression of Bcl-xL, an antiapoptotic molecule, and caused corticosteroid-resistant airway inflammation via ILC2s in mice. Furthermore, pimozide, a STAT5 inhibitor, counteracted the TSLP-induced corticosteroid resistance and suppressed airway inflammation. As a negative regulator, we have found that IFN-gamma and IL-27 suppressed the proliferation and type 2 cytokine production of ILC2s in vitro and in vivo. Interestingly, ILC2s-induced eosinophilic inflammation was more severe in IFN-gamma receptor-deficient mice than in control mice. These findings suggest the importance of environmental cytokines for the regulation of ILC2s, and this would lead to a new approach to control airway inflammation in asthma.

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Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses

Moro, K., Kabata, H., Tanabe, M., Koga, S., Takeno, N., Mochizuki, M., Fukunaga, K., Asano, K., Betsuyaku, T. and Koyasu, S.

Nat Immunol 17 ( 1 ) 76 - 86 2016.01

ISSN 1529-2916

Group 2 innate lymphoid cells (ILC2 cells) are type 2 cytokine-producing cells of the innate immune system with important roles in helminth infection and allergic inflammation. Here we found that tissue-resident ILC2 cells proliferated in situ without migrating during inflammatory responses. Both type I and type II interferons and interleukin 27 (IL-27) suppressed ILC2 function in a manner dependent on the transcription factor STAT1. ILC2-mediated lung inflammation was enhanced in the absence of the interferon-gamma (IFN-gamma) receptor on ILC2 cells in vivo. IFN-gamma effectively suppressed the function of tissue-resident ILC2 cells but not that of inflammatory ILC2 cells, and IL-27 suppressed tissue-resident ILC2 cells but not tissue-resident TH2 cells during lung inflammation induced by Alternaria alternata. Our results demonstrate that suppression mediated by interferon and IL-27 is a negative feedback mechanism for ILC2 function in vivo.

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A Case of Non-Small Cell Lung Cancer with Possible "Disease Flare" on Nivolumab Treatment

Chubachi, S., Yasuda, H., Irie, H., Fukunaga, K., Naoki, K., Soejima, K. and Betsuyaku, T.

Case Rep Oncol Med 2016 1075641 2016

ISSN 2090-6706

Background. Recent clinical trials proven the clinically significant efficacy and tolerability of nivolumab, a programmed death 1 (PD-1) inhibitor, in previously treated patients with non-small cell lung cancer (NSCLC). Case Presentation. Here, we describe the case of a patient who experienced possible "disease flare" immediately after initiation of nivolumab treatment. A 54-year-old man was diagnosed with Stage IIB (T2N1M0) lung adenocarcinoma. After 7 years from recurrence, 10th line chemotherapy, nivolumab, was initiated. Six weeks later, after 3 cycles of nivolumab treatment, rapid lung cancer progression was observed with an increase in the size of the primary lesion, multiple novel nodules on both lungs, and multiple novel brain metastases. Conclusion. We believe that physicians should be made aware that, in a subset of NSCLC patients, disease flare might occur on nivolumab treatment.

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Distinct effects of endogenous interleukin-23 on eosinophilic airway inflammation in response to different antigens

Ogawa, R., Suzuki, Y., Kagawa, S., Masaki, K., Fukunaga, K., Yoshimura, A., Fujishima, S., Terashima, T., Betsuyaku, T. and Asano, K.

Allergol Int 64 Suppl S24 - 9 2015.09

ISSN 1440-1592

BACKGROUND: The role of interleukin (IL)-23 in asthma pathophysiology is still controversial. We examined its role in allergic airway inflammation in response to two distinct antigens using IL-23-deficient mice. METHODS: Allergic airway inflammation was evaluated in wild-type and IL-23p19(-/-) mice. Mice were sensitized to ovalbumin (OVA) or house dust mite (HDM) by intraperitoneal injection of antigen and their airways were then exposed to the same antigen. Levels of antigen-specific immunoglobulins in serum as well as cytokines in bronchoalveolar or peritoneal lavage fluid and lung tissue were determined by enzyme-linked immunosorbent assay and/or quantitative polymerase chain reaction. RESULTS: Deficiency of IL-23p19 decreased eosinophils and Th2 cytokines in bronchoalveolar lavage fluid (BALF) of OVA-treated mice, while it increased BALF eosinophils of HDM-treated mice. Peritoneal injection of OVA with alum, but not of HDM, induced local synthesis of IL-6, IL-10, and IL-23. Systemic production of antigen-specific IgG1 was partially dependent on IL-23. In contrast, airway exposure to HDM, but not to OVA, induced IL-23p19 mRNA expression in the lungs. In IL-23p19-deficient mice, HDM-exposed lungs did not exhibit the induction of IL-17A, which negatively regulates eosinophilic inflammation. CONCLUSIONS: Different antigens induced IL-23 at different part of the body in our similar asthma models. Endogenous IL-23 production at the site of antigen sensitization facilitates type-2 immune responses, whereas IL-23 production and subsequent IL-17A synthesis in the airways suppresses allergic inflammation.

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Immune reconstitution inflammatory syndrome due to Mycobacterium avium complex successfully followed up using 18 F-fluorodeoxyglucose positron emission tomography-computed tomography in a patient with human immunodeficiency virus infection: A case report

Namkoong, H., Fujiwara, H., Ishii, M., Yagi, K., Haraguchi, M., Matsusaka, M., Suzuki, S., Asakura, T., Asami, T., Saito, F., Fukunaga, K., Tasaka, S., Betsuyaku, T. and Hasegawa, N.

BMC Med Imaging 15 24 2015.07

ISSN 1471-2342

BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, immune reconstitution inflammatory syndrome (IRIS) due to nontuberculous mycobacteria (NTM) infection is one of the most difficult types of IRIS to manage. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been suggested as a useful tool for evaluating the inflammatory status of HIV-infected patients. We present the first case of Mycobacterium avium complex (MAC)-associated IRIS (MAC-IRIS) that was successfully followed up using 18F-FDG PET/CT. CASE PRESENTATION: A 44-year-old homosexual Japanese man was referred to our hospital with fever and dyspnea. He was diagnosed with Pneumocystis jiroveci pneumonia and found to be HIV positive. After the initiation of combined antiretroviral therapy (cART), the patient's mediastinal and bilateral hilar lymphadenopathy gradually enlarged, and bilateral infiltrates appeared in the upper lung fields. 18F-FDG PET/CT was performed five months after the initiation of cART and showed intense accumulation of fluorodeoxyglucose (FDG) corresponding to the lesions of infiltration as well as the mediastinal and bilateral hilar lymphadenopathy. A bronchial wash culture and pathology findings led to a diagnosis of MAC-IRIS. Anti-mycobacterial chemotherapy with rifampicin, ethambutol, clarithromycin, and levofloxacin was started. One year after the chemotherapy was initiated, there was a significant reduction in FDG uptake in the area of the lesions except in the mediastinal lymph node. This implied incomplete resolution of the MAC-IRIS-related inflammation. Anti-mycobacterial chemotherapy was continued because of the residual lesion. To date, the patient has not experienced a recurrence of MAC-IRIS, a period of nine months. CONCLUSION: We present a case of MAC-IRIS in an HIV-infected patient whose disease activity was successfully followed up using 18F-FDG PET/CT. Our data suggest that 18F-FDG PET/CT is useful for evaluating the disease activity of NTM-IRIS and assessing the appropriate duration of anti-mycobacterial chemotherapy for NTM-IRIS in HIV-infected patients.

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Fatal Fulminant Pneumonia Caused by Methicillin-Sensitive Staphylococcus aureus Negative for Major High-Virulence Factors Following Influenza B Virus Infection

Masaki, K., Ishii, M., Anraku, M., Namkoong, H., Miyakawa, R., Nakajima, T., Fukunaga, K., Naoki, K., Tasaka, S., Soejima, K., Sayama, K., Sugita, K., Iwata, S., Cui, L., Hanaki, H., Hasegawa, N. and Betsuyaku, T.

Am J Case Rep 16 454 - 8 2015.07

ISSN 1941-5923

BACKGROUND: Increasing evidence has indicated that Staphylococcus aureus pneumonia complicated with influenza virus infection is often fatal. In these cases, disease severity is typically determined by susceptibility to antimicrobial agents and the presence of high-virulence factors that are produced by Staphylococcus aureus, such as Panton-Valentine leukocidin (PVL). CASE REPORT: We describe a rare case of fatal community-acquired pneumonia caused by methicillin-sensitive Staphylococcus aureus (MSSA), which did not secrete major high-virulence factors and coexisted with influenza type B infection. The 32-year-old previously healthy male patient presented with dyspnea, high fever, and cough. His roommate had been diagnosed with influenza B virus infection 3 days earlier. Gram-positive clusters of cocci were detected in the patient's sputum; therefore, he was diagnosed with severe pneumonia and septic shock, and was admitted to the intensive care unit. Despite intensive antibiotic and antiviral treatment, he died of multiple organ failure 5 days after admission. His blood culture from the admission was positive for MSSA, and further analysis revealed that the strain was negative for major high-virulence factors, including PVL and enterotoxins, although influenza B virus RNA was detected by PCR. CONCLUSIONS: Physicians should pay special attention to patients with pneumonia following influenza and Staphylococcus aureus infection, as it may be fatal, even if the Staphylococcus aureus strain is PVL-negative and sensitive to antimicrobial agents.

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Determinants of Long-Term Persistence with Tiotropium Bromide for Chronic Obstructive Pulmonary Disease

Tanaka, K., Kamiishi, N., Miyata, J., Kabata, H., Masaki, K., Ogura-Tomomatsu, H., Tomomatsu, K., Suzuki, Y., Fukunaga, K., Sayama, K., Betsuyaku, T. and Asano, K.

COPD 12 ( 3 ) 233 - 9 2015.06

ISSN 1541-2563

Tiotropium bromide, a long-acting anticholinergic agent, improves pulmonary function and quality of life of patients suffering from chronic obstructive pulmonary disease (COPD). We retrospectively examined the factors that determine the long-term persistence with tiotropium bromide. Among 6,301 patients who underwent pulmonary function tests in our pulmonary clinic between 2006 and 2009, 644 met the following criteria: 1) age > 40 years, 2) >/= 20 pack-years smoking history, and 3) forced expiratory volume in 1 sec / forced vital capacity ratio < 0.7. The clinical information, including the prescription of tiotropium, was obtained from the patients' records. Tiotropium was administered to 255 patients (40%), of whom 48 (19%) discontinued treatment within 1 year, and 65 (25%) discontinued treatment within the median observation period of 32 months. The drug was discontinued because of ineffectiveness in 35 patients (73%), and because of adverse drug effects in 13 patients (27%). Young age, current smoking, absence of respiratory symptoms alleviation, and less severe disease characterized by a) mild airflow limitation, b) mild to moderate emphysema, or c) no exacerbation of COPD during the 1(st) year of treatment were predictors of drug discontinuation.

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Attenuation of lipopolysaccharide-induced acute lung injury after (pro)renin receptor blockade

Ishii, K., Takeuchi, H., Fukunaga, K., Hirano, Y., Suda, K., Hagiwara, T., Miyasho, T., Yamada, S., Nakamura, R., Takahashi, T., Wada, N., Kawakubo, H., Saikawa, Y., Omori, T., Betsuyaku, T., Ichihara, A. and Kitagawa, Y.

Exp Lung Res 41 ( 4 ) 199 - 207 2015.05

ISSN 1521-0499

PURPOSE/AIM: We performed a randomized, prospective animal study to investigate whether inhibiting the renin-angiotensin system with a (pro)renin receptor blocker (PRRB) prevents acute lung injury (ALI) in a rodent model. MATERIALS: We used Thirty-six male Sprague-Dawley rats. We administered lipopolysaccharide (LPS; 2 mg/kg) intratracheally with or without PRRB pretreatment (1 mg/kg/d). METHODS: We performed bronchoalveolar lavage (BAL) and lung removal at 4 h after LPS administration and measured levels of inflammatory cytokines, high mobility group box 1 (HMGB-1) protein, and total protein in bronchoalveolar lavage fluid (BALF). Myeloperoxidase (MPO) activity was detected in lung tissue homogenates using a sensitive ELISA. We performed hematoxylin and eosin staining and immunohistochemical staining for nonproteolytically activated prorenin in the left lung. RESULTS: The PRRB decreased leukocyte counts and total protein, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-2, IL-6, and IL-10 levels in the BALF and MPO activity in lung tissue. The PRRB reduced interstitial edema, hemorrhage, and the neutrophil count in the lung tissues. Consistent with the reduction in lung tissue damage, immunohistochemical staining showed that the PRRB decreased the amount of nonproteolytically activated prorenin. CONCLUSIONS: The PRRB blocked LPS-induced inflammatory response in the lung and protected against ALI. Therefore, it is a potential therapeutic agent for preventing ALI.

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Phenotype of asthma related with high serum periostin levels

Matsusaka, M., Kabata, H., Fukunaga, K., Suzuki, Y., Masaki, K., Mochimaru, T., Sakamaki, F., Oyamada, Y., Inoue, T., Oguma, T., Sayama, K., Koh, H., Nakamura, M., Umeda, A., Ono, J., Ohta, S., Izuhara, K., Asano, K. and Betsuyaku, T.

Allergol Int 64 ( 2 ) 175 - 80 2015.04

ISSN 1440-1592

BACKGROUND: Asthma is a heterogeneous disease composed of various phenotypes. Periostin, a molecule inducible with interleukin (IL)-4 or IL-13 in bronchial epithelial cells, is a biomarker of "TH2-high" asthma. The objective of this study is to examine whether the serum periostin concentrations are correlated with the severity, specific phenotype(s), or comorbidity of asthma. METHODS: Serum concentrations of periostin were measured in 190 Japanese asthmatic patients and 11 healthy controls. The protocol was registered under UMIN 000002980 in the clinical trial registry. RESULTS: The serum concentrations of periostin were significantly higher (P = 0.014) in asthmatics [70.0 (54.0-93.5) ng/ml] than in healthy subjects [57.0 (39.0-63.0) ng/ml], though we found no correlation between serum periostin concentrations and treatment steps required to control asthma. To characterize "high-periostin" phenotype(s), the patients with asthma were divided among tertiles based on the serum concentrations of periostin. The high-periostin group was older at onset of asthma (P = 0.04), had a higher prevalence of aspirin intolerance (P = 0.04) or concomitant nasal disorders (P = 0.03-0.001), higher peripheral eosinophil counts (P < 0.001), and lower pulmonary function (P = 0.02-0.07). The serum concentrations of periostin were particularly high in asthmatic patients complicated by chronic rhinosinusitis with nasal polyps and olfactory dysfunction. In contrast, neither atopic status, control status of asthma, nor quality of life were related with the "high-periostin" phenotype. CONCLUSION: Elevated periostin concentrations in serum were correlated with a specific phenotype of eosinophilic asthma, late-onset and often complicated by obstructive pulmonary dysfunction and nasal disorders.

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The reasons for triple therapy in stable COPD patients in Japanese clinical practice

Miyazaki, M., Nakamura, H., Takahashi, S., Chubachi, S., Sasaki, M., Haraguchi, M., Terai, H., Ishii, M., Fukunaga, K., Tasaka, S., Soejima, K., Asano, K., Betsuyaku, T. and Keio, Copd Comorbidity Research group

Int J Chron Obstruct Pulmon Dis 10 1053 - 9 2015

ISSN 1178-2005

BACKGROUND: Triple combination therapy involving long-acting muscarinic antagonists long-acting beta2 agonists, and inhaled corticosteroids has recently become an option for maintenance treatment of COPD. Some add-on clinical trials have reported the benefits of these combinations. However, the process to step up to triple therapy varies for individual cases. METHODS: Keio University and affiliated hospitals conducted an observational COPD cohort study, recruiting patients diagnosed as having COPD by pulmonary physicians and those referred for investigation of possible COPD. Their prescription history and clinical course were retrospectively analyzed based on the physicians' medical records and patient questionnaires. This study was registered with UMIN (UMIN000003470, April 10, 2010). RESULTS: A total of 95 of the 445 COPD patients (21%) were treated with inhaled corticosteroids/long-acting beta2 agonists/long-acting muscarinic antagonists as maintenance therapy, including 12 in COPD Grade I, 31 in Grade II, 38 in Grade III, and 14 in Grade IV, based on the Global Initiative for Chronic Obstructive Lung Disease spirometric grading. For more than half of the patients on triple therapy, the treatment had been intensified due to unsatisfactory improvement of symptoms, and 32% were treated with triple therapy due to comorbid asthma. In contrast, there were COPD patients whose therapy was maintained after starting with triple therapy because of their serious conditions or concurrent exacerbation at diagnosis (8%). CONCLUSION: Triple therapy was often prescribed in the real-life management of COPD, even in patients whose airflow limitation was not severe. To better control symptoms was the major reason for choosing triple therapy, regardless of the severity of COPD, in Japan.

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Dual role of interleukin-23 in epicutaneously-sensitized asthma in mice

Masaki, K., Suzuki, Y., Kagawa, S., Kodama, M., Kabata, H., Miyata, J., Tanaka, K., Fukunaga, K., Sayama, K., Oguma, T., Kimura, T., Amagai, M., Betsuyaku, T. and Asano, K.

Allergol Int 63 Suppl 1 13 - 22 2014.05

ISSN 1440-1592

BACKGROUND: Interleukin (IL)-23/Th17 axis plays an important role in the pathophysiology of asthma and eczema, however, there are some conflicting data about the effects of this system on allergic airway inflammation. In the present study, we aim to dissect the spatiotemporal differences in the roles of IL-23 in an epicutaneously-sensitized asthma model of mice. METHODS: C57BL/6 mice were sensitized to ovalbumin (OVA) by patch application on the skin, followed by airway exposure to aerosolized OVA. During sensitization and/or challenge phase, either a specific neutralizing antibody (Ab) against IL-23 or control IgG was injected intraperitoneally. On days 1 and 8 after the final OVA exposure, airway inflammation and responsiveness to methacholine, immunoglobulin levels in serum, and cytokine release from splenocytes were evaluated. Skin Il23a mRNA levels were evaluated with quantitative RT-PCR. RESULTS: Patch application time-dependently increased the expression of Il23a mRNA expression in the skin. Treatment with the anti-IL-23 Ab during sensitization phase alone significantly reduced the number of eosinophils in bronchoalveolar lavage fluids and peribronchial spaces after allergen challenge compared with treatment with control IgG. Anti-IL-23 Ab also reduced serum levels of OVA-specific IgG1. In contrast, treatment with the anti-IL-23 Ab during the challenge phase alone rather exacerbated airway hyperresponsiveness to methacholine with little effects on airway eosinophilia or serum IgG1 levels. CONCLUSIONS: IL-23 expressed in the skin during the sensitization phase plays an essential role in the development of allergic phenotypes, whereas IL-23 in the airways during the challenge phase suppresses airway hyperresponsiveness.

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Combination therapy of 15-epi-lipoxin A4 with antibiotics protects mice from Escherichia coli-induced sepsis*

Ueda, T., Fukunaga, K., Seki, H., Miyata, J., Arita, M., Miyasho, T., Obata, T., Asano, K., Betsuyaku, T. and Takeda, J.

Crit Care Med 42 ( 4 ) e288 - 95 2014.04

ISSN 1530-0293

OBJECTIVES: Inflammation occurs along with infection during sepsis. 15-Epi-lipoxin A4 has protective and resolving effects in experimental models of infection. In this study, we examined the effects of 15-epi-lipoxin A4 combined with antibiotics on Escherichia coli-induced peritonitis. DESIGN: Prospective experimental study. SETTING: University research laboratory. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: Mice were injected with E. coli to induce peritonitis and were given either 15-epi-lipoxin A4 (1 mug/mouse) or placebo (saline) with antibiotics (ceftazidime). The effects of 15-epi-lipoxin A4 on peritoneal cell populations, bacterial burden, and cytokine production were assessed. Survival rates were observed for up to 7 days. In addition, we examined the effects of 15-epi-lipoxin A4 on peritoneal macrophages stimulated with lipopolysaccharide, CpG DNA, or live E. coli. MEASUREMENTS AND MAIN RESULTS: Treatment with 15-epi-lipoxin A4 significantly reduced the number of neutrophils in the peritoneum, inhibited production of cytokines and chemokines, and decreased bacterial load in the serum. Combined treatment of 15-epi-lipoxin A4 with antibiotics significantly improved survival in E. coli-infected mice. 15-Epi-lipoxin A4 also attenuated the production of interleukin-6 and tumor necrosis factor-alpha by lipopolysaccharide- or CpG DNA-stimulated peritoneal macrophages. Furthermore, 15-epi-lipoxin A4 combined with antibiotics synergistically reduced the production of interleukin-6 and tumor necrosis factor-alpha by peritoneal macrophages stimulated with live E. coli. CONCLUSIONS: 15-Epi-lipoxin A4 combined with antibiotics attenuated systemic inflammation, inhibited bacteria dissemination, and improved survival in E. coli-infected mice. The reduced production of interleukin-6 and tumor necrosis factor-alpha by peritoneal macrophages suggested that 15-epi-lipoxin A4 blocked the initial proinflammatory response. Taken together, these data suggested that 15-epi-lipoxin A4 combined with antibiotics was beneficial in regulating the proinflammatory response in sepsis without exacerbating infection.

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HIRA-TAN: a real-time PCR-based system for the rapid identification of causative agents in pneumonia

Hirama, T., Minezaki, S., Yamaguchi, T., Kishi, E., Kodama, K., Egashira, H., Kobayashi, K., Nagata, M., Ishii, T., Nemoto, M., Tanaka, M., Fukunaga, K., Kanazawa, M. and Hagiwara, K.

Respir Med 108 ( 2 ) 395 - 404 2014.02

ISSN 1532-3064

UNLABELLED: Identification of the causative pathogen(s) of pneumonia would allow the selection of effective antibiotics and thus reduce the mortality rate and the emergence of drug-resistant pathogens. To identify such pathogens and to obtain these benefits, it is necessary that a clinical test is rapid, accurate, easily performed, and cost-effective. Here, we devised a PCR-based test, named HIRA-TAN, which is able to discriminate therapeutic targets from commensal organisms (e.g. Streptococcus pneumoniae or Haemophilus influenzae) and to detect foreign organisms (e.g. Mycoplasma pneumoniae or Legionella pneumophila) in the sputum. The utility of this system was validated in a prospective study, using sputum samples from patients with pneumonia. 568 patients were enrolled and the HIRA-TAN assay identified the causative pathogens with an accuracy of 96.7% for H. influenzae; 93.2% for Pseudomonas aeruginosa; 80.6% for Klebsiella pneumoniae; 90.9% for Moraxella catarrhalis; 87.5% for Escherichia coli; 78.1% for MRSA and 91.6% for S. pneumoniae. Overall the HIRA-TAN procedure was able to identify the causative pathogens of pneumonia in 60% of the cases. Additionally, this procedure was able to determine when the pneumonia-causing organism was a commensal organism or a foreign organism in a single assay. The HIRA-TAN approach yielded reproducible results and provided valuable information to plan the course of treatment of pneumonia. Through the rapid identification of the causative pathogens, the HIRA-TAN will promote targeted treatments for pneumonias. CLINICAL TRIALS REGISTRATION: UMIN000001694.

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[Case report; A case of acute respiratory failure following influenza virus infection successfully treated by direct hemoperfusion using a polymyxin B immobilized fiber column]

Arai, D., Fukunaga, K., Fujii, K., Namkoong, H., Haraguchi, M., Funatsu, Y., Naoki, K., Tasaka, S. and Betsuyaku, T.

Nihon Naika Gakkai Zasshi 102 ( 2 ) 429 - 32 2013.02

ISSN 0021-5384

Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma

Miyata, J., Fukunaga, K., Iwamoto, R., Isobe, Y., Niimi, K., Takamiya, R., Takihara, T., Tomomatsu, K., Suzuki, Y., Oguma, T., Sayama, K., Arai, H., Betsuyaku, T., Arita, M. and Asano, K.

J Allergy Clin Immunol 131 ( 2 ) 353 - 60 e1-2 2013.02

ISSN 1097-6825

BACKGROUND: Protectin D1 (PD1) is an anti-inflammatory and proresolving lipid mediator biosynthesized from the omega-3 fatty acid docosahexaenoic acid (DHA). Exogenous PD1 conferred protection against eosinophilic inflammation in animals with experimental asthma, although its endogenous cellular source and functions in human airways are of interest. OBJECTIVE: We sought to investigate the synthesizing capacity of PD1 in eosinophils from healthy subjects and patients with severe asthma and its direct effects on eosinophil functions. METHODS: Human eosinophil-derived metabolites of arachidonic acid and DHA were analyzed with liquid chromatography-tandem mass spectrometry-based lipidomic analysis. The biological activities of PD1 on the function of human eosinophils, including chemotaxis, adhesion molecule expressions, degranulation, superoxide anion generation, or survival, were examined. RESULTS: We identified PD1 as one of the main anti-inflammatory and proresolving molecules synthesized in human eosinophils. PD1, in nanomolar concentrations, suppressed the chemotaxis induced by CCL11/eotaxin-1 or 5-oxo-eicosatetraenoic acid and modulated the expression of the adhesion molecules CD11b and L-selectin, although it had no effects on the degranulation, superoxide anion generation, or survival of the eosinophils. Compared with the cells harvested from healthy subjects, we observed a prominent decrease in the biosynthesis of PD1 by eosinophils from patients with severe asthma, even in presence of DHA. CONCLUSION: These observations are a first indication that activated human eosinophils represent a major source of PD1, which can act as a self-resolving machinery in eosinophilic inflammation, whereas the production of PD1 is impaired in patients with severe asthma.

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Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

Kabata, H., Moro, K., Fukunaga, K., Suzuki, Y., Miyata, J., Masaki, K., Betsuyaku, T., Koyasu, S. and Asano, K.

Nat Commun 4 2675 2013

ISSN 2041-1723

Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NH-cell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma.

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Predictors of osteoporosis and vertebral fractures in patients presenting with moderate-to-severe chronic obstructive lung disease

Ogura-Tomomatsu, H., Asano, K., Tomomatsu, K., Miyata, J., Ohmori, N., Kodama, M., Ueda, S., Takihara, T., Tanaka, K., Kamiishi, N., Suzuki, Y., Fukunaga, K., Oguma, T., Sayama, K. and Betsuyaku, T.

COPD 9 ( 4 ) 332 - 7 2012.08

ISSN 1541-2563

Bone mineral density (BMD) alone does not reliably predict osteoporotic fractures. The Fracture Risk Assessment Tool (FRAX) was developed to estimate the risk of fracture in the general population. This study was designed to identify predictors of osteoporosis and vertebral fractures in patients presenting with chronic obstructive pulmonary disease (COPD). We studied 85 patients (mean age = 75 years; 92% men) with moderate to very severe COPD. Osteoporosis and vertebral fractures were diagnosed with dual energy X-ray absorptiometric scan and vertebral X-rays, respectively. Patient characteristics, including age, gender, body mass index (BMI), and results of pulmonary function tests, chest computed tomography scan, blood and urinary biomarkers of bone turnover were recorded, and a FRAX score was calculated by a computer-based algorithm. Osteoporosis, defined as a T score < -2.5, found in 20 patients (24%), was associated with female gender, BMI, dyspnea scale, long-term oxygen therapy (LTOT), vital capacity (VC), emphysema score on computed tomography, measurements of serum and urinary biomarkers of bone turnover. Vertebral fractures, diagnosed in 29 patients (35%), were strongly correlated with age, LTOT, VC, and forced expiratory volume in 1 sec, treatment with oral corticosteroid or warfarin, and weakly associated with the presence of osteoporosis. There was no correlation between FRAX score and prevalence of vertebral fractures, suggesting that neither BMD alone nor FRAX score would predict the presence of vertebral fractures in COPD patients. A disease-specific algorithm to predict osteoporotic fractures is needed to improve the management of patients suffering from COPD.

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Resolvin E1 maintains macrophage function under cigarette smoke-induced oxidative stress

Takamiya, R., Fukunaga, K., Arita, M., Miyata, J., Seki, H., Minematsu, N., Suematsu, M. and Asano, K.

FEBS Open Bio 2 328 - 33 2012

ISSN 2211-5463

Cigarette smoke (CS) induces oxidative stress, which disables macrophage function. In this study, we examined whether Resolvin E1 (RvE1), a pro-resolving mediator known to enhance macrophage functions, attenuates the damage of macrophages by CS extract (CSE) induced oxidative stress. RvE1 blocked p47phox translocation to plasma membrane induced by CSE in a macrophage cell line, RAW264.7 cells, resulting in suppression of superoxide production. Furthermore, pretreatment of RAW264.7 cells with RvE1 restored the phagocytic activity and reduced cell death induced by treatment of CSE. These results suggest that RvE1 plays important roles in preserving macrophage function under CS-induced oxidative stress.

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