Ai Higashi

Karolinska Institutet

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Noritaka Higashi

Japanese Red Cross Kumamoto Hospital

Masami Taniguchi

National Sagamihara Hospital

Kazuo Akiyama

International University of Health and Welfare

Haruhisa Mita

National Sagamihara Hospital

Emiko Ono

National Sagamihara Hospital

Chiyako Oshikata

National Hospital Organization

Takahiro Tsuburai

Yokohama City Seibu Hospital

Yuji Maeda

University of Virginia

Kunihiko Ikehara

Yokohama City University

Naomi Tsurikisawa

National Hospital Organization

Cooperative Institutions

National Sagamihara Hospital

Karolinska Institutet

Karolinska University Hospital

ENT and Allergy

The Kids Research Institute Australia

National Hospital Organization

Tel Aviv University

Gunma University

Ege University

Instituto de Salud Carlos III

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Challenge of Isolated Sputum Cells Supports in vivo Origin of Intolerance Reaction to Aspirin/Non-Steroidal Anti-Inflammatory Drugs in Asthma

International Archives of Allergy and Immunology (2012)

Ai Higashi Maria Kumlin Noritaka Higashi Kameran Daham Flora Gaber

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

10.1159/000331433

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Increase in urinary leukotriene B₄ glucuronide concentration in patients with aspirin‐intolerant asthma after intravenous aspirin challenge

Clinical & Experimental Allergy (2004)

Haruhisa Mita Noritaka Higashi Masami Taniguchi Ai Higashi Kohki Akiyama

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.

Leukotriene E4

Leukotriene B4

10.1111/j.1365-2222.2004.02034.x

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Serum vitamin E concentration in patients with severe multiple handicaps treated with anticonvulsants.

PubMed (1980)

Ai Higashi Hirosato Tamari Tomikazu Ikeda Yoshihisa Ohtani Makoto Matsukura

Serum vitamin E concentrations were measured in 47 severely handicapped patients, aged from 4 to 23 years, and in 22 controls. Thirty-three of the handicapped patients with seizures were treated with phenytoin and phenobarbital; the remaining 14 patients were not treated. The serum vitamin E levels were lower in the handicapped than in controls. Among the handicapped, those treated with anticonvulsants showed much lower levels of serum vitamin E than those untreated. Ten patients under anticonvulsant therapy were selected to receive d-1-alpha tocopherol acetate, 100 mg/day, based on their low serum vitamin E levels (range of 0.27 to 0.61 mg/100 ml). After one month of tocopherol treatment, both their serum vitamin E levels and hemolysis tests returned to normal. During a three-month tocopherol treatment period, both the frequencies of seizure attacks and the electroencephalogram (EEG) patterns remained unchanged. Supplementation with vitamin E is recommended in some patients under anticonvulsant therapy.

Phenobarbital

Anticonvulsant drugs

Serum concentration

alpha-Tocopherol

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Clinical features of asthmatic patients with increased urinary leukotriene E4 excretion (hyperleukotrienuria)Involvement of chronic hyperplastic rhinosinusitis with nasal polyposis

Journal of Allergy and Clinical Immunology (2004)

Noritaka Higashi Masami Taniguchi Haruhisa Mita Yukio Kawagishi Toyota Ishii

Leukotriene E4

Nasal Polyps

Hypereosinophilia

10.1016/j.jaci.2003.10.068

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Citations (131)

The methodological aspects of nasal and exhaled nitric oxide levels in adult Japanese asthmatics

Arerugī (Allergy) (2008)

Takahiro Tsuburai Naomi Tsurikisawa Toyota Ishii Noritaka Higashi Ai Higashi

BACKGROUND 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. METHODS 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. RESULTS 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-naive, 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-naive 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). CONCLUSION nNO levels measured by the off-line method are useful markers of allergic rhinitis.

Exhalation

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Increased levels of cysteinyl-leukotrienes in saliva, induced sputum, urine and blood from patients with aspirin-intolerant asthma

Thorax (2008)

Flora Gaber Kameran Daham Ai Higashi Noritaka Higashi A. Gülich

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.

Leukotriene E4

10.1136/thx.2008.101196

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Citations (97)

Front & Back Matter

International Archives of Allergy and Immunology (2012)

Giovanni Rolla Enrico Heffler Riccardo Asero Laura Farioli Elide A. Pastorello

10.1159/000339897

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Involvement of eicosanoids and surfactant protein D in extrinsic allergic alveolitis

European Respiratory Journal (2005)

Ai Higashi

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.

Pathophysiology

Pulmonary alveolar proteinosis

10.1183/09031936.05.00106104

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Citations (10)

[A comparative study of psycho-social factors in peptic ulcer disease].

PubMed (1994)

Hiroko Yashiro Ai Higashi Nobuko Miyaji Kotaro Ozasa Y. Watanabe

To evaluate the psycho-social factors of peptic ulcer, we carried out a comparative study. Seventy-six men and 19 women with peptic ulcers diagnosed at seven hospitals in Kyoto, Osaka and Hyogo Prefectures in Japan were surveyed during November 1990 about their daily hassles, depressive state, social support and life style using a self-administered questionnaire. The results were compared to those for two control groups. One control group was diagnosed with normal, atrophic gastritis, or superficial gastritis by the gastro-duodenal endoscopic examinations in the same hospitals. The other control group consisted of participants in a health-screening examination at one of the above hospitals. There were no significant differences between patients and controls in daily hassles, depressive state, and social support. However, being unmarried, smoking and eating irregular meals significantly increased the relative risk of peptic ulcer in men and family history of peptic ulcer significantly increased the risk in women.

Peptic

Atrophic gastritis

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[The effect of inhaled corticosteroid on the fraction of exhaled nitric oxide (FeNO) with off-line method in adult Japanese asthmatics].

PubMed (2008)

Takahiro Tsuburai Naomi Tsurikisawa Noritaka Higashi Ai Higashi Sonoko Morita

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.

Guideline

Outpatient clinic

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