Kazuko Mitsuta

Correlation between airway hyperresponsiveness and airway inflammation in a young adult population : eosinophil, ECP, and cytokine levels in induced sputum

BACKGROUND Eosinophil counts and eosinophil cationic protein (ECP) levels in the airway are elevated in asthmatic patients. However, few studies have examined the correlation between various cytokines in the sputum and airway hyperresponsiveness (AHR) in young adults with or without asthma. OBJECTIVE We examined the correlation between AHR and eosinophil counts or ECP, and levels of several cytokines in the sputum. METHODS We studied 120 nonsmoker students (group 1: intermittent mild asthmatic patients; group 2: subjects with history of childhood asthma; group 3: subjects sensitized by Dermatophagoides farinae with atopic disease; group 4: normal subjects sensitized by D. farinae; group 5: subjects with cedar pollinosis; and group 6: normal subjects). In each subject, AHR and lung function tests were measured, together with eosinophil count, ECP, granulocyte-macrophage colony-stimulating factor, TNF-alpha, IL-5, and interleukin-1beta in induced sputum. RESULTS AHR in groups 1 and group 2 were high, in groups 5 and 6 low, and in groups 3 and 4 lower than in groups 1 and 2 but higher than groups 5 and 6. Percentages of eosinophils, ECP, and TNF-alpha in induced sputum in groups 1 and 2 were high, those in groups 5 and 6 were below detection limits, and those in groups 3 and 4 were lower than the percentages in groups 1 and 2. Granulocyte-macrophage colony-stimulating factor in the sputum was elevated only in group 1. The correlations between AHR and sputum eosinophil count, ECP, and TNF-alpha were significant, with the strongest correlation with TNF-alpha. CONCLUSIONS Our results suggest that TNF-alpha levels in the sputum play an important role in determining the severity of AHR in young individuals. Further once AHR develops, it does not disappear, and the severity of airway inflammation influences the extent of AHR.

Hypogammaglobulinemia in Steroid-Dependent Asthmatics Correlates with the Daily Dose of Oral Prednisolone

Background: Steroid-induced adverse effects including suppression of humoral immunity should be considered in steroid-dependent severe asthma. Only a few studies have determined the exact steroid dose that could potentially suppress humoral immunity in asthmatics. Methods: Randomly selected 100 adult asthmatics treated with inhaled beclomethasone dipropionate (BDP) were classified into three groups based on the dose of steroid to determine the serum IgG, IgA and IgM levels by radioimmunoassay. Relationships between serum immunoglobulin levels and the daily dose and duration of oral prednisolone (PSL) therapy were examined. Results: None of the patients on inhaled corticosteroid alone had hypogammaglobulinemia. Patients on oral PSL at a dose >12.5 mg/day for at least 1 year had low serum IgG. There was no significant correlation between the duration of oral PSL therapy and serum IgG. Conclusions: Oral PSL can potentially suppress humoral immunity in severe asthma. In asthmatics, hypogammaglobulinemia could develop in those on a daily dose of PSL >12.5 mg, but is independent of the duration of such treatment. No suppression of humoral immunity was noted on inhaled corticosteroid therapy alone, either at low or high dose.

Clinical Evaluation of Anaphylactic Reactions to Intravenous Corticosteroids in Adult Asthmatics

Background: Corticosteroids form an important component of the treatment of acute asthma. Systemic anaphylactic reactions to intravenous corticosteroids have been reported, although their incidence is extremely rare. Objectives: To determine the clinical features and underlying mechanisms of anaphylactic reactions to intravenous corticosteroids in adult asthmatics. Subjects and Methods: The clinical features of 7 adult asthmatics (4 males, 3 females, mean age 39.4 ± 16.9 years), who had developed systemic anaphylactic reactions to intravenous administration of corticosteroids for the treatment of acute asthma, were studied retrospectively on the basis of their medical records. Skin tests using various injectable steroid preparations were performed in 3 cases to determine the mechanism of this reaction. Results: Systemic anaphylactic reactions to intravenous administration of corticosteroids occurred in severe atopic asthmatics with previous exposure to parenteral corticosteroids, irrespective of age and gender. Aspirin-intolerant asthma was identified in only 3 subjects. In all cases, anaphylactic reactions were induced following intravenous administration of succinate-containing corticosteroid preparations, i.e. hydrocortisone and methylprednisolone. Administration of phosphate-containing corticosteroids, i.e. dexamethasone and betamethasone, was safe and resulted in a resolution of anaphylactic symptoms. Immunological examination with skin tests suggested that anaphylactic reactions were an IgE-mediated hypersensitivity. Conclusions: Intravenous injection of succinate-containing corticosteroids in high-risk asthmatics should be performed slowly by drip injection under continuous monitoring. Once anaphylactic reactions occur, it is important to stop the injection immediately and to use conventional medication for anaphylaxis.

Acetaldehyde Induces Histamine Release from Human Airway Mast Cells to Cause Bronchoconstriction

Backgrounds: Approximately half of the Japanese asthmatics experience exacerbation of asthma after alcohol consumption. We previously reported that this phenomenon is probably caused by histamine release from mast cells by acetaldehyde stimulation. However, no reports have described the effects of acetaldehyde on human airway mast cells. The purpose of the present study was to demonstrate acetaldehyde-induced histamine release from human airway mast cells with subsequent airway smooth muscle contraction and to investigate the ensuing mechanisms. Methods: Human tissue samples were prepared from the lungs resected from patients with lung cancer. The effect of acetaldehyde on airway muscle tone and the concentration of chemical mediators released in the organ bath were measured before and after acetaldehyde stimulation. Mast cells were prepared from lung parenchyma by the immunomagnetic method and then stimulated with acetaldehyde to determine the chemical mediators released. Results: Acetaldehyde (>3 × 10–4M) increased airway muscle tone, which was associated with a significant increase in the release of histamine, but not thromboxane B2 or cysteinyl-leukotrienes. A histamine (H1 receptor) antagonist completely inhibited acetaldehyde-induced bronchial smooth muscle contraction. Acetaldehyde also induced a significant histamine release from human lung mast cells and degranulation of mast cells. Conclusions: The present results strongly suggest that acetaldehyde stimulates human airway mast cells to release histamine, which may be involved in bronchial smooth muscle contraction following alcohol consumption.

Effects of pranlukast, a cysteinyl leukotriene receptor 1 antagonist, combined with inhaled beclomethasone in patients with moderateor severe asthma

BACKGROUND Although inhaled steroids are used as the first line of therapy in asthmatic patients, symptoms of asthma do not improve completely in some patients. OBJECTIVE To investigate the effects of pranlukast, a cysteinyl leukotriene receptor 1 antagonist, in patients with moderate/severe asthma, when combined with beclomethasone dipropionate (BDP). METHODS Protocol 1: After a 2-week observation period, 41 patients with moderate asthma were divided into those receiving BDP at 1,600 microg/day or 800 microg/day + pranlukast (450 mg/day). The effect of treatment was evaluated by measuring AM peak expiratory flow rate, symptom score, frequency of beta2-agonists, and daily variability of peak expiratory flow rate. Protocol 2: 39 patients participated in this study including those with moderate asthma on 800 microg/day BDP (group I), severe asthma on BDP at 1,600 microg/day (group II), and severe asthma on 1,600 microg/day BDP + 5 to 20 mg prednisolone (group III). Patients of all groups were additionally treated with pranlukast. RESULTS Protocol 1: Both treatment regimens resulted in improvement in each clinical parameter. There were no significant differences in the effects of two treatment regimens. Protocol 2: Pranlukast was effective in group I and II, but not in group III. In groups I and II, pranlukast tended to be more effective when BDP was introduced within the first year of onset of asthma. CONCLUSIONS Pranlukast is effective for patients with moderate asthma and those patients with severe asthma who are not treated with oral steroids. Pranlukast is more effective in patients treated with BDP early after onset.

Sensitivity to the house dust mite and airway hyperresponsiveness in a young adult population

BACKGROUND The pathogenic mechanisms of airway hyperresponsiveness (AHR) in asthma are unknown and only a few studies have examined the importance of sensitivity to antigens in AHR in young adults. OBJECTIVE We investigated the correlation between AHR and sensitivity to specific antigens, atopy, history of childhood asthma and spirometry in a young adult population. METHODS Based on the results of interviews with 447 students at our university, 308 non-smoker students were classified into six groups. Group 1 comprised subjects with intermittent mild bronchial asthma; group 2, subjects with history of childhood asthma; group 3, subjects with atopic disease, and a RAST score for Dermatophagoides farinae (Def) of > or = 2; group 4, normal subjects with a RAST score for Def of > or = 2; group 5, subjects with cedar pollinosis; and group 6, normal subjects. We measured AHR to methacholine (MCh), spirometry, immunoglobulin E-radioimmunosorbent test (IgE-RIST), IgE-radioallergosorbent test to six common antigens, eosinophil cationic protein (ECP), and eosinophil count in peripheral blood in each subject. RESULTS Airway hyperresponsiveness to MCh did not correlate with IgE-RIST, eosinophil count, or ECP. The highest AHR to MCh was present in groups 1 and 2 and lowest in groups 5 and 6. Multiple regression analysis showed that sensitivity to Def was the only factor that significantly influenced AHR to MCh. Airway hyperresponsiveness to MCh of groups with a RAST score for Def of 0/1 was lower than groups with a RAST score of 2 to 6. Airway hyperresponsiveness to MCh did not correlate with the degree of positivity to Def antigen among positive sensitized groups (RAST score 2 to 6). CONCLUSIONS Sensitivity to mite antigen may be important in the pathogenesis of AHR and Def is a major contributing antigen in young adults in Japan. Once asthma occurs, AHR remains positive for a long time even after the disappearance of asthma-related symptoms.

Inhibitory effects of azelastine hydrochloride in alcohol-induced asthma

BACKGROUND Alcohol-induced bronchoconstriction is due to high blood concentrations of acetaldehyde, a metabolic product of ethanol, which lead to the release of histamine from basophils and mast cells. OBJECTIVE We examined the inhibitory effects of azelastine hydrochloride, which inhibits histamine release and blocks H1 receptors, in alcohol-induced asthma. METHODS Subjects were 13 Japanese asthmatic patients. We measured the change in FEV1 after ingestion of 30 g of pure ethanol. Blood ethanol, acetaldehyde, histamine, leukotriene C4 (LTC4), and thromboxane B2 (TXB2) concentrations were also measured. Alcohol challenge test was repeated in responders after administration of azelastine for 1 week at 4 mg/day. RESULTS Of 13 asthmatic patients, five (38.5%) tested positive during an ethanol challenge test, represented by a fall more than 20% in FEV1. The responders had a high blood ethanol, and showed a rise in blood acetaldehyde and histamine concentrations, but not in LTC4 or TXB2. After azelastine treatment, there was no significant fall in FEV1 among responders. Neither the rise in blood ethanol nor blood acetaldehyde levels were blunted by treatment with azelastine, but the rise in blood histamine was blunted by this treatment. CONCLUSION Our results suggest that antihistamine agents may be effective against alcohol-induced asthma by both blocking H1 receptors and inhibiting histamine release.

Efficacy and safety of long-term treatment of asthmatic patients with pranlukast, a cysteinyl-leukotriene-receptor antagonist: four-year followup study

BACKGROUND There are few studies that have examined the long-term efficacy and safety of pranlukast, a leukotriene receptor antagonist, in asthmatic patients. METHODS Sixty-three asthmatic patients were entered in this 4-year study [group 1, mild or moderate (N = 22); group 2, severe without using oral prednisolone (N = 22); group 3, severe with using oral prednisolone (N = 19)]. Pranlukast was administered at 225 mg twice daily to 14 subjects in group 1 (group 1p), 14 in group 2 (group 2p), and 11 in group 3 (group 3p), chosen for pranlukast additional therapy at random. Another group of 24 asthmatic patients was assigned to conventional therapy group (groups 1c, 2c, and 3c). Efficacy was determined by improvement in symptom score, peak expiratory flow rate (PEFR) percentage predicted, reduced daily variability of PEFR (percentage), and reduced frequency of use of rescue beta2-agonist (times per week). RESULTS In groups 1p and 2p, PEFR percentage predicted began to improve from 2 weeks after commencement of treatment. The symptom score, daily variability of PEFR, and use of rescue beta2-agonist diminished significantly. In group 3p, pranlukast was ineffective in improving PEFR percentage predicted. All but two patients continued to receive pranlukast and no adverse effects were noted, at least during the 16-week therapy. Further, 22 patients continued to receive pranlukast for 4 years, and none experienced any adverse effects. CONCLUSIONS We showed in this study that long-term treatment with pranlukast is effective for asthmatic patients without any adverse effects.

Effects of pranlukast on aspirin-induced bronchoconstriction: differences in chemical mediators between aspirin-intolerant and tolerant asthmatic patients.

BACKGROUND Aspirin inhibits cyclooxygenase activity and modifies production of the arachidonate cascade in aspirin-induced asthma. The aim of the present study was to examine the effects of leukotriene (LT) receptor antagonist on aspirin challenge on eosinophil activity and chemical mediators released into the airway of asthmatic patients. METHODS Aspirin oral provocation test was performed in aspirin-intolerant asthmatic patients (AIA; N = 7) and aspirin-tolerant asthmatic patients (ATA; N = 7). In AIA, LT receptor antagonist (pranlukast) was administered orally 2 hours before the test, and its inhibitory effects on sputum LTC4+C4, eosinophil cationic protein (ECP), eosinophil count, urinary LTE4/creatinine (Cr), 11-dehydrothromboxane (11-dhTX) B2/Cr, serum LTC4+D4, ECP, and peripheral blood eosinophil count were compared with the findings in ATA subjects. RESULTS In AIA, aspirin induced an immediate reaction associated with increased urinary LTE4/Cr and sputum ECP and a fall in urinary 11-dhTXB2/Cr. Pranlukast inhibited the bronchial reaction and an increase in sputum ECP after threshold dosed of ASA, but failed to change aspirin-induced LT production in sputum and urine. In ATA, aspirin challenge was only associated with a fall in urinary 11-dhTXB2. CONCLUSIONS Our results indicated that aspirin-induced asthma is associated with overproduction of LT with a shift to the 5-lipoxygenase series of the arachidonate cascade and that leukotriene receptor antagonist are useful for AIA through inhibition of production of LT and eosinophilic inflammation in the airway.

Tacrolimus inhibits cytokine production and chemical mediator release following antigen stimulation of passively sensitized human lung tissues

BACKGROUND The immunosuppressive effects of tacrolimus are mediated by inhibition of cytokine production by inflammatory cells. The role of tacrolimus on cytokine production and release of chemical mediators in asthma is not known at present. OBJECTIVES We compared the effects of tacrolimus on interleukin (IL)-5 and tumor necrosis factor-alpha (TNF-alpha) production and chemical mediator release from excised human lung tissue with those of steroids. METHODS Human lung tissue was passively sensitized with serum from atopic patients then preincubated with tacrolimus (10(-6), 10(-7), 10(-8) M) or dexamethasone (10(-6) M) for 2 hours. The lung tissue was then exposed to 1.5 microg/mL of mite antigen and then cultured for 48 hours. Culture supernatants were collected and IL-5 and TNF-alpha levels were measured by ELISA. IL-5 and TNF-alpha messenger ribonucleic acid (mRNA) expression was also investigated by reverse transcriptase-polymerase chain reaction. The level of histamine and leukotriene E4 was also measured in the culture supernatant. In addition, tryptase staining was performed to compare degranulation of mast cells. RESULTS Antigen stimulation increased histamine and leukotriene release in the supernatant. Tacrolimus significantly and dose-dependently inhibited the release of histamine and leukotriene; dexamethasone did not. The results of tryptase staining demonstrated that tacrolimus dose-dependently inhibited degranulation of mast cells, whereas dexamethasone did not. Antigen stimulation increased TNF-alpha and IL-5 protein production and mRNA expression. Tacrolimus and dexamethasone significantly inhibited TNF-alpha and IL-5 protein production and mRNA expression. CONCLUSIONS Our results indicated that tacrolimus is more powerful in inhibition of cytokine production and release of chemical mediators than steroids, and suggested that this immunosuppressor drug might be useful for the treatment of asthma.