Ai Higashi

Karolinska Institutet, Сольна, Stockholm, Sweden

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Publications (13)74.04 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: There is no in vitro test to diagnose aspirin-intolerant asthma (AIA). The aim of this study was to test if challenge with aspirin of sputum cells from subjects with AIA triggers the release of cysteinyl leukotrienes (CysLTs), known to be mediators of bronchoconstriction in AIA. Sputum induction was performed at baseline and at another visit 2 h after a lysine-aspirin bronchoprovocation in 10 subjects with AIA and 9 subjects with aspirin-tolerant asthma (ATA). The isolated sputum cells were incubated for ex vivo challenge. Release of CysLTs by sputum cells from patients with AIA was not induced by lysine-aspirin ex vivo, neither when cells were collected at baseline nor in sputum cells recovered after lysine-aspirin-induced bronchoconstriction, whereas release of CysLTs from sputum cells was triggered by an ionophore on both occasions. However, the CysLT levels elicited by the ionophore were higher in the AIA group both at baseline (AIA vs. ATA: 3.3 vs. 1.6 ng/million cells; p < 0.05) and after the lysine-aspirin bronchoprovocation (3.9 vs. 1.7 ng/million cells; p < 0.05). This difference in the amount of CysLTs released between the groups appeared to be related to the number of eosinophils. Intolerance to aspirin could not be triggered in sputum cells isolated from subjects with AIA. Together with the previous inability to demonstrate intolerance to non-steroidal anti-inflammatory drugs in isolated blood cells, these results support the requirement of tissue-resident cells in the adverse reaction. However, ex vivo stimulation of sputum cells may be developed into a new test of capacity for LT release in inflammatory cells recovered from airways.
    No preview · Article · Mar 2012 · International Archives of Allergy and Immunology
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    ABSTRACT: The fraction of exhaled nitric oxide (FeNO) is a useful marker of asthma control. The FeNO measurement with our offline method using SIEVERS bag collection kit may be more affordable, but there have been no studies to show the effect of anti-asthmatic therapy on FeNO with our offline method. The study population comprised 36 steroid-naïve asthmatics at our outpatient clinic. We treated them according to asthma prevention and management guideline 2006, Japan. We also measured eNO levels by our offline method and spirometory on baseline, 4weeks, and 12 weeks of treatment. All asthmatics were symptom-free on 12 weeks of treatment. The levels of FeNO FEV1/FVC were significantly decreased on 4 weeks and 12 weeks of treatment, compared with that on first visit. We classified the subjects into two groups; (A) FEV1/FVC <70% (n=11) or (B) FEV1/FVC > or =70% (n=25) on baseline. In (A) group, the level of FeNO and FEV1/FVC were significantly improved on 4 and 12 weeks of treatment. In (B) group, on 4 weeks of treatment, the level of FEV1/FVC was significantly increased but the level of FeNO was not significantly changed. On 12 weeks of treatment, the levels of FeNO was significantly decreased, but the level of FEV1/FVC was not significantly changed. The levels of FeNO were decreased by antiasthmatic therapy, so that offline monitoring of eNO will facilitate the management of bronchial asthma in patients treated with these drugs.
    No preview · Article · Dec 2008 · Arerugī = [Allergy]
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    ABSTRACT: A diagnosis of aspirin-intolerant asthma requires aspirin provocation in specialist clinics. Urinary leukotriene E(4) (LTE(4)) is increased in aspirin-intolerant asthma. A study was undertaken to investigate new biomarkers of aspirin intolerance by comparing basal levels of cysteinyl-leukotrienes (CysLTs) and leukotriene B(4) (LTB(4)) in saliva, sputum and ex vivo stimulated blood in subjects with aspirin-intolerant and aspirin-tolerant asthma. The effects of aspirin- and allergen-induced bronchoconstriction on leukotriene levels in saliva and ex vivo stimulated blood were also compared with the effects of the provocations on urinary mediators. Induced sputum, saliva, urine and blood were obtained at baseline from 21 subjects with asthma. At a separate visit, 11 subjects showed a positive response to lysine-aspirin inhalation and 10 were aspirin tolerant. Saliva, blood and urine were also collected on the provocation day. Analyses of CysLTs and LTB(4) and the prostaglandin D(2) metabolite 9alpha,11beta-prostaglandin F(2) were performed and the fraction of exhaled nitric oxide was measured. Subjects with aspirin-intolerant asthma had higher exhaled nitric oxide levels and higher baseline levels of CysLTs in saliva, sputum, blood ex vivo and urine than subjects with aspirin-tolerant asthma. There were no differences in LTB(4) levels between the groups. Levels of urinary LTE(4) and 9alpha,11beta-prostaglandin F(2) increased after aspirin provocation whereas leukotriene levels in saliva and ex vivo stimulated blood did not increase. These findings support a global and specific increase in CysLT production in aspirin-intolerant asthma. Measurement of CysLTs in saliva has the potential to be a new and convenient non-invasive biomarker of aspirin-intolerant asthma.
    Preview · Article · Sep 2008 · Thorax
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    ABSTRACT: Because both allergic rhinitis and asthma are caused by eosinophilic airway inflammation, using the same method to measure the eosinophilic inflammation of both the upper and lower airway would be advantageous. The levels of nitric oxide in exhaled air (FeNO) and nasal air (nNO) are useful as noninvasive markers of eosinophilic airway inflammation. Although the off-line method of measuring these parameters is easier and more useful than the on-line method, studies using the off-line method are rare in Japan. In Study 1, we measured the levels of nNO and FeNO in 9 healthy controls and 9 subjects with allergic rhinitis, to validate the methodology for using the off-line method to measure nNO. In Study 2, we measured the nNO and FeNO levels of and performed spirometry on 69 stable asthmatics treated with inhaled corticosteroid. In Study 1, nNO levels were significantly increased in patients with allergic rhinitis compared with healthy subjects (31.0 [20.8 to 41.2] versus 7.4 [0.0 to 14.8] ppb {median [95% confidence interval]}, p=0.018). The 69 patients with asthma that comprised the study population in Study 2 were classified as asthmatics with rhinitis (treatment-naïve, n=14; treated with antiallergic drugs, n=11; treated with intranasal corticosteroid, n=19) and asthmatics without rhinitis (n=15). Although FeNO did not differ among groups, nNO was significantly increased in treatment-naïve asthmatics with rhinitis compared with patients with asthma only (26.5 [17.1 to 35.9] versus 8.0 [-1.1 to 17.1] ppb, p=0.033). nNO levels measured by the off-line method are useful markers of allergic rhinitis.
    No preview · Article · Sep 2008 · Arerugī = [Allergy]
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    ABSTRACT: Evidences have shown that the fraction of exhaled nitric oxide (FeNO) is a useful marker of eosinophilic airway inflammation in asthmatics. There is no study to show the FeNO cutoff point for detecting asthma and the influence of smoking, measured by the Sievers Bag collection kit. The study population comprised 60 steroid-naive asthmatic patients (BA) (32 non-smokers, 28 smokers) and 59 patients with chronic cough (CC) without asthma (42 non-smokers, 17 smokers) in our outpatient clinic. We measured FeNO levels, spirometory, bronchial hyperresponsiveness against acetylcholine, and other parameters. The levels of FeNO were significantly increased in asthmatics compared with subjects with chronic cough. According to the ROC curve, the cutoff point of FeNO was 30 ppb (AUC = 0.83, sensitivity 78.1%, specificity 73.5%, p < 0.001) in non-smokers. The levels of FeNO in smokers were not significantly different from those in non-smokers, both bronchial asthma and chronic cough subjects. But the cutoff point of FeNO was 40 ppb (AUC = 0.65, sensitivity 67.8%, specificity 70.6%, p = 0.012). In conclusion, the cutoff point of FeNO was 30 ppb in non-smokers and 40 ppb in smokers. In smokers, FeNO measurement was less useful.
    No preview · Article · May 2008
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    ABSTRACT: The measurement of exhaled nitric oxide (eNO) is a non-invasive biomarker of bronchial inflammation. Despite the usefulness of eNO measurement, NO analyzers are too expensive for widespread use by general practitioners. In comparison, the off-line (bag collection) method of eNO measurement may be more useful. In Japan, however, there have been few studies about eNO in asthmatics using the off-line method. This study shows methodological aspects of the off-line method. Briefly, with a SIEVERS bag collection kit, we recommend that the flow rate and pressure level of exhaled air should be 70 ml/sec and 10 cm H2O, respectively and that the sampled air should be measured within 12 hours.
    No preview · Article · Mar 2007

  • No preview · Article · Feb 2006 · Journal of Allergy and Clinical Immunology
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    ABSTRACT: The pathophysiology of extrinsic allergic alveolitis (EAA) involves oxidative lung damage as well as interstitial and alveolar inflammation. Macrophages and mast cells are inflammatory components of EAA that produce both leukotrienes (LTs) and prostaglandin D2 (PGD2). In addition, PGD2 is also produced by the free-radical-catalysed peroxidation of arachidonic acid during oxidative stress. Urinary 8-iso prostaglandin F2alpha (8-isoPGF2alpha) and serum surfactant protein D (SP-D) are considered appropriate biomarkers of oxidative stress and interstitial lung disease activity, respectively. The present study aimed to assess the association of these biomarkers with the pathophysiology of EAA. Two cases of acute EAA caused by the inhalation of fungi spores were reported. Eight asthmatic patients and six healthy control subjects were also enrolled in the current study. The serum SP-D and urinary eicosanoid (LTE4, PGD2 metabolite (9alpha,11betaPGF2), 8-isoPGF2alpha) concentrations markedly increased during the acute exacerbation phase. These concentrations decreased following corticosteroid therapy in the EAA patients. There was a significant correlation between serum SP-D and urinary 9alpha,11betaPGF2 concentrations in the EAA patients. In conclusion, although the present study proposes that serum surfactant protein-D and urinary eicosanoids are new biomarkers involved in the various immunological responses in extrinsic allergic alveolitis, further large-scale studies are needed to investigate the role of these compounds, not just as biomarkers, but also as biological potentiators of extrinsic allergic alveolitis.
    No preview · Article · Jan 2006 · European Respiratory Journal
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    ABSTRACT: Vasculitides are classified on the basis of the type of cell involved, namely, eosinophilic vasculitides such as Churg-Strauss syndrome (CSS) and noneosinophilic vasculitides. However, knowledge on inflammatory mediators and oxidative tissue damage associated with vasculitides is insufficient. We measured the urinary concentrations of inflammatory mediators and tyrosine derivatives to assess biomarkers associated with the pathophysiology of vasculitides. Urine was collected from 9 patients with CSS during acute exacerbation and during clinical remission, 24 patients with rheumatoid arthritis in stable condition, and 8 patients with vasculitis diseases (VDs) during acute exacerbation. Leukotriene E 4 (LTE 4 ), 9alpha,11beta prostaglandin F 2 , and eosinophil-derived neurotoxin (EDN) concentrations were determined by enzyme immunoassay. 3-Bromotyrosine (BrY) and 3-chlorotyrosine (ClY) concentrations were determined by gas chromatography-mass spectrometry. The urinary LTE 4 , EDN, BrY, and ClY concentrations were significantly higher in the patients with CSS during acute exacerbation than in healthy control subjects and, except for urinary ClY concentration, significantly decreased during clinical remission. The urinary EDN and BrY concentrations were significantly higher in patients with CSS during acute exacerbation than in patients with VD during acute exacerbation. Only urinary LTE 4 concentration was significantly different between the patients with rheumatoid arthritis in stable condition and the patients with VD during acute exacerbation. Oxidative tissue damage caused by eosinophil peroxidase is a pathophysiological characteristic of eosinophil-associated diseases such as CSS. Urinary LTE 4 concentration may reflect a pathophysiological event involved in eosinophilic and noneosinophilic vasculitides. Cysteinyl-leukotriene pathways are potential therapeutic targets for small-vessel vasculitides.
    No preview · Article · Jan 2005 · Journal of Allergy and Clinical Immunology
  • H Mita · N Higashi · M Taniguchi · A Higashi · K Akiyama
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    ABSTRACT: Aspirin challenge of aspirin-intolerant asthma (AIA) patients causes a significant increase in leukotriene E4 (LTE4) concentration in urine. However, knowledge on leukotriene B4 (LTB4) generation in patients with AIA is insufficient. Recent research has demonstrated that exogenously administered LTB4 is excreted as glucuronide into the urine in human healthy subjects. The purpose of this study is to estimate urinary LTB4 glucuronide (LTBG) concentration in the clinically stable condition in healthy subjects and asthmatic patients and to investigate changes in urinary LTBG concentration in patients with AIA after aspirin challenge. A provocation test was performed by intravenous aspirin challenge. After urine was hydrolysed by beta-glucuronidase, the fraction containing LTB4 was purified by high-performance liquid chromatography and LTB4 concentration was quantified by enzyme immunoassay. Urinary LTBG concentration was calculated as the difference between the concentration obtained with hydrolysis and that without hydrolysis. (1) After hydrolysis, the presence of urinary LTB4 was verified by gas chromatography-mass spectrometry-selected ion monitoring. (2) The urinary LTBG concentration was significantly higher in the asthmatic patients than in the healthy subjects (median, 5.37 pg/mg creatinine [range 1.2-13] vs. 3.32 pg/mg creatinine [range, 0.14-10.5], P = 0.0159). (3) The patients with AIA (n = 7), but not those with aspirin-tolerant asthma (n = 6), showed significant increases in LTBG and LTE4 excretions after aspirin challenge. (4) When the concentrations after aspirin challenge were analysed simultaneously, a significant linear correlation was observed between urinary LTBG concentration and urinary LTE4 concentration in patients with AIA (Spearman's rank correlation test, r = 0.817, P = 0.0003). LTBG is present in human urine, albeit at a concentration lower than urinary LTE4. In addition to a marked increase in cysteinyl-leukotriene production, aspirin challenge induced LTB4 production in AIA patients.
    No preview · Article · Sep 2004 · Clinical & Experimental Allergy
  • H Mita · N Higashi · M Taniguchi · A Higashi · Y Kawagishi · K Akiyama
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    ABSTRACT: Eosinophil peroxidase and myeloperoxidase halogenate tyrosine residues in plasma proteins and generate 3-bromotyrosine (BY) and 3-chlorotyrosine (CY), respectively. (1) To estimate urinary concentrations of BY and CY in asthmatic patients. (2) To investigate BY concentration in relation to urinary leukotriene E4 (LTE4) concentration in order to evaluate the activation of eosinophils in patients with aspirin-induced asthma (AIA). BY and CY were quantified with a gas chromatograph-mass spectrometer using (13)C-labelled compounds as internal standards. (1) Activation of eosinophils and neutrophils by immobilized IgG1 induced preferential formation of BY and CY, respectively. (2) A significantly higher concentration of BY was observed in the urine from asthmatic patients than in that from healthy control subjects (45+/-21.7 vs. 22.6+/-10.8 ng/mg-creatinine, P<0.01). CY concentration was also elevated in the urine from asthmatic patients (4.4+/-3.2 vs. 1.5+/-1.0 ng/mg-creatinine, P<0.01). (3) After intravenous aspirin challenge of aspirin-induced asthmatic patients, the concentration of BY in urine did not significantly change. No significant change was also observed in the ratio of BY concentration to total tyrosine concentration in plasma proteins. In contrast, the concentration of urinary LTE4 significantly increased after the intravenous aspirin challenge. Determination of BY and CY concentrations may be useful for monitoring the activation of eosinophils and neutrophils in asthmatic patients, respectively. After aspirin challenge of AIA patients, the increased concentration of urinary LTE4 did not accompany changes in BY concentration in both urine and plasma proteins. These results may preclude the activation of eosinophils after aspirin challenge in patients with AIA.
    No preview · Article · Jun 2004 · Clinical & Experimental Allergy
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    ABSTRACT: The urinary leukotriene E4 (U-LTE4) concentration is significantly increased in patients with aspirin-intolerant asthma (AIA). However, the relationship between the clinicopathogenetic factors of asthma and the U-LTE4 concentration remains undetermined. We sought to examine the clinical features of asthmatic patients with increased excretion levels of U-LTE4 (hyperleukotrienuria). We measured the U-LTE4 concentrations in 137 asthmatic patients (including 64 patients with AIA) who were in clinically stable condition. A U-LTE4 concentration of 150 pg/mg creatinine or greater (mean U-LTE4 + 3 SDs of normal healthy control subjects) was indicative of hyperleukotrienuria. The basal concentration of U-LTE4 was significantly higher in the patients with AIA than in those with aspirin-tolerant asthma (ATA; median, 227.2 vs 90.3 pg/mg creatinine; P <.01). Compared with normal leukotrienuria in the patients with AIA, hyperleukotrienuria in the patients with AIA was associated with older age and decrease in pulmonary function. On the other hand, compared with normal leukotrienuria in the patients with ATA, hyperleukotrienuria in the patients with ATA was associated with severe asthma and chronic hyperplastic rhinosinusitis with nasal polyposis (CHRS/NP), which are well-known symptoms of the aspirin triad, as well as hypereosinophilia and anosmia. The patients with ATA with CHRS/NP excreted U-LTE4 at significantly high concentrations. There were significant decreases in the U-LTE4 concentrations before and after the sinus surgery in both the AIA and ATA groups (P <.05). Cysteinyl leukotrienes are not strictly associated with aspirin intolerance itself but rather with clinical features, such as CHRS/NP, that are similar to those seen in AIA. CHRS/NP might be involved in cysteinyl leukotriene overproduction in asthmatic patients.
    No preview · Article · Mar 2004 · Journal of Allergy and Clinical Immunology

  • No preview · Article · Nov 2002 · Journal of Allergy and Clinical Immunology

Publication Stats

246 Citations
74.04 Total Impact Points

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  • 2008-2012
    • Karolinska Institutet
      Сольна, Stockholm, Sweden
  • 2002-2008
    • Sagamihara National Hospital
      Йокосука, Kanagawa, Japan
  • 2006
    • Kagoshima University
      • Department of Neurology and Geriatrics
      Kagosima, Kagoshima, Japan